Blast Crisis Of Myeloid Leukemia Research Articles

Acute Myeloid Leukemia in a Three-Year-Old Girl Mimicking Chronic Myeloid Leukemia in Blast Crisis, Challenge in Diagnosis and Treatment in Limited-Resourced Health Care Facility: A Case Report

Introduction: : Acute myeloid leukemia (AML) is the second most common hematologic cancer in childhood. Clinically, AML has similar symptoms to other types of leukemias, and diagnosis remains a challenge due to limited access to pediatric hemato-oncology diagnostic examination. This study aims to report AML in a 3-year-old girl who was first suspected of Chronic Myeloid Leukemia (CML) in blast crisis, using a combination of clinical-hematology parameters and conventional morphology examination in a limited-resourced healthcare facility. Case Presentation: A 3-year-old girl was referred from a rural Eastern Indonesia hospital with symptoms of prolonged fever, leucocytosis, severe anemia, and severe thrombocytopenia. In the previous hospital, the patient had a history of hyperleukocytosis and peripheral blood smear suspected of CML in blast crisis. A peripheral blood smear was repeated in our hospital and showed findings of Auer rod cells suggesting AML. Two bags of packed red cells and 2 thrombocyte concentrations were administered before referral for further diagnostic evaluation with bone marrow aspiration. Bone marrow aspiration revealed multiple nucleoli suggested for AML with FAB classification as M4 subtypes, and she received chemotherapy in a tertiary hospitalConclusions: With limited resources, suspicion based on persistent clinical symptoms, routine hematology tests, and peripheral blood smear examination are important to distinguish AML from CML in blast crisis. Understanding clinical hematology parameters and peripheral blood smears is the first step in AML diagnosis pathway and decision for further diagnostic referral. Supportive therapy and early recognition of oncologic emergency must be done before referral to a tertiary referral hospital.

Acquired Factor VII Deficiency Associated With Chronic Myeloid Leukemia Blast Crisis.

Factor VII (FVII) is an important, vitamin K-dependent clotting factor. Acquired FVII deficiency is a rare entity that is associated with serious bleeding complications. We report a case of acquired FVII deficiency in a patient with recurrent chronic myeloid leukemia in blast crisis who developed bilateral retinal hemorrhages. The coagulopathy was corrected with the initiation of chemotherapy and subsequent reduction in peripheral blast count.

Pediatric chronic myeloid leukemia in myeloid blast crisis

Chronic myeloid leukemia (CML) accounts for 2-3% of childhood leukemias. About 5% of cases present in a blastic phase of CML which clinically and morphologically mimics more common acute leukemias of childhood. We report a case of a 3-year-old male who presented with gradual onset swelling of the abdomen and extremities along with generalized weakness. Examination revealed massive splenomegaly, pallor, and pedal edema. Initial workup showed anemia, thrombocytopenia, and leukocytosis (120,000/uL) with a blast percentage of 35%. Blasts were positive for CD13, CD33, CD117, CD34 and HLA-DR, and stained negative for Myeloperoxidase and Periodic Acid Schiff. Fluorescence in situ hybridization was positive for b3a2/e14a2 junction BCR-ABL1 transcript and negative for RUNX1-RUNX1T1/t(8;21), clinching the diagnosis of CML in myeloid blast crisis. The patient expired within 17 days of diagnosis and initiation of therapy.

Blast crisis in chronic myeloid leukemia: An immunophenotypic analysis

Background and Aim of Study: There are two different phases of untreated chronic myeloid leukemia – chronic phase, and blast crisis – according to the World Health Organization classification of Hematolymphoid tumors. The blast cells in the chronic myeloid leukemia blast crisis can express myeloid, lymphoid, bi-phenotypic, monocytic, megakaryocytic, and erythroid phenotypes. The immunophenotype of blast population determines how chronic myeloid leukemia – blast crisis patients respond to treatment, hence flowcytometric examination is required. The aim of the study: to assess immunophenotyping outcomes of flowcytometry performed on the chronic myeloid leukemia – blast crisis. Material and Methods: A five-year retrospective descriptive analysis was carried out in Pathology Department at King George’s Medical University Lucknow, India (2017-2021). The patient’s peripheral blood and bone marrow aspirate samples were analyzed. Clinical, hematological, and immunophenotypic data were retrieved. The flow cytometry samples were prepared using the standardized “lyse-stain-wash” method. Results: A total of 43 cases of chronic myeloid leukemia – blast crisis were retrieved from the departmental archive in 5 years. The mean age of study population was 39.62±14.86 years. There were 24 males and 19 females. 27 patients were diagnosed with myeloid blast crisis, 14 cases of B-lymphoid blast crisis and 2 cases of mixed phenotypic acute leukemia. Conclusions: Identification of the blast lineage of patients with chronic myeloid leukemia – blast crisis is crucial since the existence of atypical blast phenotypes influences the disease treatment and prognosis.

Molecular genetic characterization of Philadelphia chromosome-positive acute myeloid leukemia

BackgroundPhiladelphia chromosome-positive acute myeloid leukemia (Ph+ AML) is a provisional disease entity in the 2016 WHO classification, while its genetic profile of Ph+ AML remains poorly defined. In addition, the differentiating features of Ph+ AML and chronic myeloid leukemia in myeloid blast crisis (CML-MBC) remain controversial. MethodsWe conducted a retrospective study of 15 Ph+ AML patients to compare their clinical and laboratory profiles with 27 CML-MBC patients. ResultsCompared to CML-MBC, Ph+ AML patients presented with significantly higher peripheral WBC count and bone marrow blast percentage. The immunophenotypic profiles were largely similar between Ph+ AML and CML-MBC, except for CD4 expression, which was significantly enriched in CML-MBC. Ph+ AML patients less frequently harboured co-occurring additional cytogenetic abnormalities (ACA) compared to CML-MBC, and trisomy 19 (23%) and IDH1/2 (46%) were the most common ACA and mutated genes in Ph+ AML, respectively. Overall survival (OS) did not significantly differ between Ph+ AML and CML-MBC. Ph+ AML without CML-like features appeared to have a better outcome compared to Ph+ AML with CML-like features; ACA in Ph+ AML may confer an even worse prognosis. ConclusionsOur results indicate that patients with Ph+ AML share similar genetic profiles and clinical outcomes with those with CML-MBC, thus should be classified as a high-risk entity.

Molecular Aberrations in Acute Myeloid Leukemia (AML) and Myelodysplastic Syndrome with Excess Blast II (MDS-EB II) in Kuwait

Introduction: AML is a heterogeneous disease. Different mutational profiles have been described and correlate with variable outcomes. Genetic abnormalities are not well-described in our region. Our aim is to describe the molecular aberrations observed in the first cohort of patients. We recently introduced DNA based Oncomine Myeloid Gene Panel testing 55 genes. Method: we collected clinical, cytogenetic and molecular data prospectively since we introduced the test in late 2020. We also reviewed medical charts to collect baseline clinical data. We included patients aged 16 yrs and above with AML or MDS-EB II treated at Kuwait Cancer Center. Results: fifty-seven patients were included in the study with median age of 51 yrs. Almost one third of the patients were Kuwaitis (36%). Baseline demographic described in (table 1). We have 53 patients with AML (92%), 3 patients with MDS-EB II (5%) and 1 pt with chronic myeloid leukemia in myeloid blast crisis (CML-MBC). Most of the patients had at least one mutation (91%) detected by the panel. The most common mutations (figure1) were FLT3 (ITD & D835) detected 26.3%, followed by NPM-1 detected in 21%. We have noticed an increased PTPN11 mutation, detected in 17.5% of the cases. Conclusion: This is an important study showing extensive molecular abnormalities in AML patients in the region. This will facilitate more understanding of the disease biology and potentially guide therapeutic options

AML-419 Molecular Aberrations in Acute Myeloid Leukemia (AML) and Myelodysplastic Syndrome With Excess Blast II (MDS-EB II) in Kuwait

AML is a heterogeneous disease. Different mutational profiles have been described and correlate with variable outcomes. Genetic abnormalities are not well-described in our region. Our aim is to describe the molecular aberrations observed in the first cohort of patients. We recently introduced DNA based Oncomine Myeloid Gene Panel, testing 55 genes. We collected clinical, cytogenetic and molecular data prospectively since we introduced the test in late 2020. We also reviewed medical charts to collect baseline clinical data. We included patients aged 16 yrs and above with AML or MDS-EB II treated at Kuwait Cancer Center. Fifty-seven patients were included in the study with median age of 51 yrs. Almost one third of the patients were Kuwaitis (36%). We have 53 patients with AML (92%), 3 patients with MDS-EB II (5%), and 1 patient with chronic myeloid leukemia in myeloid blast crisis (CML-MBC). Most of the patients had at least one mutation (91%) detected by the panel. The most common mutations were FLT3 (ITD & D835), detected 26.3%, followed by NPM-1, detected in 21%. We have noticed an increased PTPN11 mutation, detected in 17.5% of the cases. This is an important study showing extensive molecular abnormalities in AML patients in the region. This will facilitate more understanding of the disease biology.

A comparative experiment on the anti-chronic myeloid leukemia capacities of AgNO3, ‎Scrophularia striata leaf aqueous extract, and silver nanoparticles containing natural ‎compounds ‎

IntroductionIn the current study, silver nanoparticles were prepared and synthesized in aqueous medium using Scrophularia ‎striata leaf extract as stabilizing and reducing agents. Also, we investigated the anti-chronic myeloid leukemia ‎potentials of silver nanoparticles against BV173 (chronic myeloid leukemia in blast crisis), CML-T1 (chronic ‎myeloid leukemia in lymphoid blast crisis), EM-2 (chronic myeloid leukemia in blast crisis; relapse after bone ‎marrow transplantation), and JOSK-M (chronic myeloid leukemia in myelomonocytic) cell lines. ‎Material and methodsSilver nanoparticles were characterized and analyzed using common nanotechnology techniques including UV-‎Vis.‎‏ ‏and FT-IR Spectroscopy, Field Emission-Scanning Electron Microscopy (FE-SEM), and Transmission ‎Electron Microscopy (TEM), and Energy Dispersive X‐ray Spectrometry (EDS). ‎ResultsFT-IR analysis offered antioxidant compounds in the nanoparticles were the sources of reducing power, ‎reducing silver ions to silver nanoparticles. FE-SEM and TEM images revealed a uniform spherical morphology ‎in size of 19.72 nm for the green synthesized nanoparticles. DPPH test revealed similar antioxidant potentials ‎for silver nanoparticles and butylated hydroxytoluene. Silver nanoparticles had very low cell viability and anti-‎chronic myeloid leukemia properties dose-dependently against JOSK-M, EM-2, CML-T1, and BV173 cell lines ‎without any cytotoxicity on the HUVEC cell line. The best result of cytotoxicity properties of silver ‎nanoparticles against the above cell lines was observed in the case of CML-T1 cell line. ‎ConclusionsAfter confirming in the in vivo and clinical trial studies, these nanoparticles can be administrated in humans for ‎the treatment of chronic myeloid leukemia.‎

Antineoplastic activity of free 4-nitrochalcone and encapsulated in poly(thioether-ester) nanoparticles obtained by thiol-ene polymerization in two human leukemia cell lines (Jurkat and K562)

Poly(thioether-ester) (PTEe), a polymer synthesized from renewable monomers, is a promising alternative for the encapsulation of antitumor drugs due to its biocompatibility and biodegradability. Therefore, the aim of this study was to synthesize, characterize and evaluate the cytotoxicity of free 4-nitrochalcone (4NC) and 4NC encapsulated in PTEe nanoparticles prepared by thiol-ene miniemulsion polymerization in chronic myeloid leukemia in blast crisis (K562) and acute lymphoblastic leukemia (Jurkat) and peripheral blood mononuclear cells. 4NC was successfully encapsulated in PTEe nanoparticles with an encapsulation efficiency >90%, a mean size of 110 nm, negative surface charge and extended-release profile. Free 4NC and encapsulated in PTEe nanoparticles presented a significant cytotoxicity on K562 and Jurkat cells. Also, 4NC encapsulated in PTEe nanoparticles presented lower damage to peripheral blood mononuclear cells, providing a higher selectivity index than free 4NC for chronic myeloid leukemia in blast crisis (K562) and acute lymphoblastic leukemia (Jurkat). Considering the difficulties involved in leukemia treatment and good results obtained with free 4NC and encapsulated in PTEe nanoparticles, these results can be a new tool for the treatment of neoplastic cells.

Disease-inducing potential of two leukemic cell lines in a xenografting model.

Cryopreserved ovarian tissue transplant restores ovarian function in young cancer patients after gonadotoxic treatment. However, leukemia is associated with increased risk of malignant cell transmission. We aimed to assess the tumor-inducing potential of two different leukemic cell lines when xenografted to immunodeficient mice. Fifty-four female immunodeficient mice were grafted with either 100, 200, 500, 1000, and 10,000 chronic myeloid leukemia in blast crisis (BV-173) cells or relapsed acute lymphoblastic leukemia (RCH-ACV) cells, embedded inside a fibrin scaffold along with 50,000 human ovarian stromal cells. Two mice per cell line received the fibrin matrix without leukemic cells as negative controls. Clinical signs of disease were monitored for 20 weeks. Grafts, liver tissue, and masses were collected for macroscopic analysis and gene expression of BCR-ABL1 and E2A-PBX fusion transcripts present in BV-173 and RCH-ACV respectively. BV-173 cells: Mice grafted with 100, 200, or 500 cells showed no sign of disease after and were negative for BCR-ABL1 expression. Three of the 5 animals grafted with 1000 cells and all mice with 10,000 cells developed disease and showed BCR-ABL1-positive expression. RCH-ACV cells: Two out of 4 mice grafted with 100 cells developed disease and were E2A-PBX1-positive. All the animals grafted with higher cell doses showed signs of disease and all but one were E2A-PBX1-positive. The present work proves that the disease-inducing potential of BV-173 and RCH-ACV leukemic cells xenografted to SCID mouse peritoneum differs between cell lines, depending on cell number, type, status, and cytogenetic disease profile when ovarian tissue is harvested.

Involvement of the AML1 Gene in the t(3;21) in Therapy-Related Leukemia and in Chronic Myeloid Leukemia in Blast Crisis

AbstractA nonrandom translocation between chromosomes 3 and 21, t(3;21)(q26.2;q22) has been detected in patients with a myelodysplastic syndrome or acute myeloid leukemia after treatment (t-MDS/t-AML) for a primary malignant disease and in chronic myelogenous leukemia in blast crisis (CML-BC). In these patients, the breakpoint on chromosome 21 is at band 21q22. This band is also involved in the t(8;21)(q22;q22) detected in 40% of the patients with acute myeloid leukemia subtype M2 (AML-M2) de novo who have an abnormal karyotype. In the t(8;21), the AML1 gene is the site of the breakpoint on chromosome 21. The AML1 gene is transcribed from telomere to centromere, and in the t(8;21) the 5′ part of AML1 is fused to the ETO gene on chromosome 8 to produce the chimeric AML1/ETO on the der(8) chromosome. We found that AML1 is also rearranged in two t-AML patients and in one CML-BC patient with the t(3;21), but the breakpoints are approximately 40 to 60 kb downstream to those of AML-M2 patients. This region contains at least one additional exon of AML1, as determined by using an AML1 cDNA as a probe in Southern blot analysis. The t(3;21) breakpoints for the remaining patients could not be determined because, by fluorescence in situ hybridization analysis, the breaks are outside of the region covered by the available probes.

Dasatinib monotherapy for chronic myeloid leukemia in blast crisis: report of one case and review of literature

目的 观察达沙替尼单药治疗慢性粒细胞白血病（CML）急髓变的疗效及安全性。 方法 回顾性分析东莞市人民医院1例应用达沙替尼单药治疗的CML急髓变患者的临床经过，并复习相关文献。 结果 患者骨髓检查提示CML急髓变，同时伴随附加染色体核型异常，但BCR-ABL1激酶区突变阴性，坚持服用达沙替尼（100 mg/d）靶向治疗，并每月动态监测BCR-ABLIS基因水平。患者BCR-ABLIS基因水平逐渐下降，骨髓细胞学提示完全缓解，流式免疫微小残留转阴。治疗期间除可控的骨髓抑制及轻度肝损伤外，未出现其他严重不良反应。 结论 CML急髓变后可根据患者激酶区突变情况选取不同的治疗策略，如无激酶区突变，达沙替尼单药治疗患者易耐受、安全有效，可作为优先治疗方案，但治疗期间需密切监测BCR-ABLIS基因水平，符合移植条件的患者仍应争取异基因造血干细胞移植以改善长期预后。

Efficacy of Hyper-CVAD/MA and CHALL-01 regimens in the treatment of Philadelphia chromosome-positive adult acute lymphoblastic leukemia patients under 60 years old

目的比较传统Hyper-CVAD/MA方案及借鉴儿童急性淋巴细胞白血病（ALL）的新化疗方案CHALL-01在≤60岁成人Ph阳性ALL（Ph+ ALL）中的临床疗效。方法回顾性分析2007年1月至2017年12月第二军医大学附属长海医院及长征医院收治的158例Ph+ ALL患者（除外慢性髓性白血病急变期患者），其中Hyper-CVAD/MA组63例，CHALL-01组95例，诱导及巩固化疗期间联合酪氨酸激酶抑制剂（TKI）治疗，有合适供者的患者进行造血干细胞移植，并用TKI进行维持治疗。结果经过1~2个疗程的诱导治疗，91.1%（144/158）患者获得完全缓解（CR），其中Hyper-CVAD/MA组CR率为90.5%（57/63），CHALL-01组CR率为91.6%（87/95），两组间差异无统计学意义（χ2=0.057，P=0.811）。随访截止于2018年6月，共134例CR患者可进一步分析，其中Hyper-CVAD/MA组53例，CHALL-01组81例。CHALL-01组达到分子学缓解的比例显著高于Hyper-CVAD/MA组（完全分子学反应率：44.4%对22.6%，主要分子学反应率：9.9%对18.9%）（χ2=7.216，P=0.027）。Hyper-CVAD/MA组和CHALL-01组4年总生存率分别为44.81%（95%CI 30.80%~57.86%）和55.63%（95%CI 39.07%~69.36%）（P=0.037），4年无病生存率分别为37.95%（95%CI 24.87%~50.93%）和49.06%（95%CI 34.24%~62.29%）（P=0.015）。两组在4年累积复发率（P=0.328）及无复发死亡率（P=0.138）上差异无统计学意义。CHALL-01组肺部感染发生率较Hyper-CVAD/MA组明显减低（43.4%对67.9%，χ2=7.908，P=0.005）。结论CHALL-01方案治疗成人Ph+ ALL疗效优于Hyper-CVAD/MA方案，肺部感染发生率低，分子学缓解率高，可以提高Ph+ ALL患者的生存率。

Clinical Retrospective Analysis of Chronic Myeloid Leukemia in Myeloid Blast Crisis

To retrospectively analyze the clinical manifestation, laboratorial test features and prognosis of patients with CML in myeloid blast crisis. The clinical data of 10 patients with CML in myeloid blast crisis admitted in Chinese PLA General Hospital from June 2011 to May 2018 were collected, and their clinical features, laboratorial data and long-term survival were analyzed. The median age of these 10 cases was 32.5 (23-73) years old. Nine cases had chronic phase history. The median chronic phase was 17(4-84) months. All the 10 cases had splenomegaly; B-ultrasonography showed that the median spleen size was 5.2 (4-7.8) cm in thickness, and 14.6 (11.4-19.8) in length. When chronic myeloid leukemia was in blast crisis, the median WBC count was 41.705（11.9-344.41）×109 /L and the median platelet count was 159 (13-2326) ×109 /L. The Ph+ chromosome and BCR-ABL1 fusion gene coulld be detected in all the cases. The chromosome karyotyping showed that additional chromosome abnormalities were found in 5 cases. One case was of low diploid, and two cases were with complex karyotype. ABL1 mutation was detected in 6 out of these 10 cases. ABL1 T315I mutation was detected in 2 of them and one was with deletion of combined P53 in genetic tests. The median follow-up time was 10.5(0.2-78) months. There were 5 cases treated sequentially by chemotheraphy with or without TKI and allo-HSCT. Three cases reached CP2 before transplantation. Among them, two cases still survived without progression for 67 months and 69 months after the transplantation respectively. One case died of transplantation-related mortality (suffered from cerebral hemorrhage 7 months after the transplantation). Two cases were NR before the transplantation, and both died of disease relapse or progression at the time points of one or three months after the transplantation. Five cases treated by TKI ± chemotheraphy and without HSCT succumbed to disease progression. The median time was 6(0.2-22) months. CML patients in myeloid blast crisis treated by chemotheraphy combined with TKI gain CP2, the survival time of patients treated by sequential allo-HSCT is prolonged.

Spectrum and Immunophenotypic Profile of Acute Leukemia: A Tertiary Center Flow Cytometry Experience.

BackgroundFor diagnosis, sub-categorization and follow up of Acute Leukemia (AL), phenotypic analysis using flow cytometry is mandatory.Material and methodsWe retrospectively analyzed immunophenotypic data along with cytogenetics/molecular genetics data (wherever available) from 631 consecutive cases of AL diagnosed at our flow cytometry laboratory from January 2014 to August 2017.ResultsOf the total 631 cases, 52.9% (n=334) were acute lymphoblastic leukemia (ALL), 43.9% (n=277) acute myeloid leukemia (AML), 2.2% (n=14) mixed phenotypic acute leukemia (MPAL), 0.5% (n=3) acute undifferentiated leukemia (AUL) and 0.5% (n=3) chronic myeloid leukemia in blast crisis (CML-BC). ALL cases comprised of 81.7% (n=273/334) B-cell ALLs (95.2%, n=260/273 common B-ALLs and 4.8%, n=13/273 Pro B-ALLs). CD13 was the commonest cross lineage antigen, expressed in B-ALL (25.6%, n=70/273), followed by CD33 (17.9%, n=49) and combined CD13/CD33 (11.3%, n=31/273) expression. T-ALLs constituted 18.3% (n=61/334) of total ALLs and included 27.9% (n=17/61) cortical T- ALLs. CD13 was commonest (32.7%, n=20/61) aberrantly expressed antigen in T-ALLs, followed by CD117 (19.1%, n=9/47). AML cases included 32.1% (n=89/277) AML with recurrent genetic abnormalities, 9.0% (n=25/277) with FLT3/NPM1c mutation and 58.9% (n=163/277) AML NOS including 14.7% (n=24/163) AML M4/M5, 1.8% (n=3/163) AML M6 and 3.7% (n=6/163) AML M7. In AMLs, CD19 aberrancy was the most common (20.2%, n=56/277) followed by CD56 (15.8%, n=42/265).ConclusionsIn this study, we document the spectrum, correlate the immunophenotype with genetic data of all leukemias, especially concerning T-ALL where the data from India is scarce.

Quinoline and ferrocene conjugates: Synthesis, computational study and biological evaluations

Novel O‐alkylated quinoline and N‐alkylated 4‐quinolone derivatives attached to the ferrocene moiety through 4,1‐ (7a–d, 8a–d and 12a–d) and 1,4‐disubstituted (9a, 9b, 10a and 10b) 1,2,3‐triazole moiety were synthesized. The observed regioselectivity of O‐ vs. N‐alkylation was explored by the use of NMR and computational techniques. Among the N‐alkylated derivatives, the quinolone‐ferrocene conjugate 9a displayed marked activities against chronic myeloid leukemia in blast crisis (K562) and Burkitt lymphoma (Raji). The 6‐chloroquinolone‐ferrocene conjugate 12c, with selective inhibitory activity on Raji cells and no cytostatic effect on normal MDCK1 cells was highlighted as the most promising anticancer organometallic complex in a group of O‐alkylated quinolines.

Safety and Efficacy of Blinatumomab in Combination With a Tyrosine Kinase Inhibitor for the Treatment of Relapsed Philadelphia Chromosome-positive Leukemia.

The treatment of Philadelphia chromosome-positive (Ph+) acute lymphoblastic leukemia has been revolutionized with the introduction of tyrosine kinase inhibitors (TKIs) and the combination of these agents with chemotherapy. Blinatumomab is a bispecific anti-CD3/CD19 monoclonal antibody with clinical activity as single-agent in the relapsed setting and independent of BCR-ABL1 mutational status, including T315I. The combination of blinatumomab with a TKI may further improve outcomes for this high-risk population, including higher eradication of minimal residual disease and minimize the use of chemotherapy. We retrospectively studied 12 adults with relapsed/refractory Ph+ acute lymphoblastic leukemia (n= 9) and chronic myeloid leukemia in blast crisis (n= 3), treated with the combination blinatumomab and a TKI (ponatinib, n= 8; dasatinib, n= 3; bosutinib, n=1). All patients have previously failed at least 1 line of chemotherapy, including allogeneic stem cell transplantation, and 1 class of TKIs. Patients were treated for either overt hematologic relapse (n= 6) or persistent minimal residual disease following other regimens (n= 6). The complete hematologic, cytogenetic, and molecular response rates were 50% (3/6), 71% (5/7), and 75% (9/12), respectively. Two cases of grade 2 cytokine release syndrome were observed, all of which resolved with steroids and tocilizumab. No cardiovascular adverse events were encountered. With a median follow-up of 8 months, the median survival was not reached; the 6-month and 1-year overall survival rates were 73%. The combination of blinatumomab with TKI is safe and effective in patients with relapsed/refractory Ph+ disease. Prospective studies are warranted.

Unrelated Allogeneic Stem Cell Transplantation in a Patient with Chronic Myeloid Leukemia in Blast Crisis

Abstract Chronic myeloid leukemia (CML) is a clonal myeloproliferative disorder, which can involve the hematopoietic stem cell or early progenitor cells, without the loss of their capacity to differentiate. Typically, CML has three clinical phases: a chronic phase, an accelerated phase, and an aggressive transformation in blast crisis, analogous to acute leukemia. The following article presents the case of a 49-year-old patient diagnosed with Philadelphia-negative CML in blastic transformation, where after multiple conventional acute leukemia induction chemotherapy regimens an unrelated allogeneic hematopoietic stem cell transplant was performed.

Synthesis, Cytostatic and Antibacterial Evaluations of Novel 1,2,3-Triazolyl-tagged Pyrimidine and Furo[2,3-d]pyrimidine Derivatives

C-5 alkynylated and N-1 alkylated pyrimidine derivatives were synthesized by N-alkylation reaction of 5-iodouracil in the presence of NaH, as a base, followed by Pd-catalyzed Sonogashira cross-coupling reaction of N-alkyl-5-iodouracil derivatives (1 and 2) with corresponding terminal alkynes. Intramolecular in situ O- heteroannulation ring closure of N-1- alkyl-C-5- alkynylpyrimidine derivatives (3 and 5) generated novel 6-substituted furo[2, 3-d]pyrimidine derivatives (7 and 8). 1, 4-Disubstituted 1, 2, 3- triazole tethered 5- alkynylpyrimidines (14– 19) and 6-substituted furo[2, 3- d]pyrimidines (20–22) were successfully prepared by the copper(I)- catalyzed click reaction of 5-iodo-N- 1- propargylpyrimidine (2) using microwave irradiation, followed by Sonogashira cross- coupling reaction with corresponding terminal alkynes. In vitro antiproliferative activity of prepared compounds evaluated on human cancer cell lines cervix adenocarcinoma (HeLa), colon adenocarcinoma (CaCo- 2), chronic myeloid leukemia in blast crisis (K562), Burkitt lymphoma (Raji) revealed that pyrimidine (19) and furo[2, 3- d]pyrimidine (22) derivatives with 3, 5- difluorophenyl at pyrimidine and furo[2, 3- d]pyrimidine as well as p- (trifluoromethyl)phenyl at 1, 2, 3-triazole exhibited marked and selective inhibitory effects on the growth of K562 and Raji tumor cells. Antibacterial evaluations showed that pyrimidine derivative 14 substituted with p- tolylethynyl at C-5 of pyrimidine and benzyl at 1, 2, 3-triazole moiety was the most active of all evaluated compounds on the Gram positive bacterial strains Enterococcus faecalis. Further structure optimization of compounds 14, 19 and 22 is foreseen in order to obtain lead structural analogs with efficient and selective antitumoral and antibacterial activities.

High Rates of Minimal Residual Disease-Negative (MRD−) Complete Responses (CR) in Adult and Pediatric and Patients With Relapsed/Refractory Acute Lymphoblastic Leukemia (R/R ALL) Treated With KTE-C19 (Anti-CD19 Chimeric Antigen Receptor [CAR] T Cells): Preliminary Results of the ZUMA-3 and ZUMA-4 Trials

Background:Acute lymphoblastic leukemia (ALL) exhibits a bimodal age distribution with 60% of cases occurring in children and adolescents (<20 y) and 25% in older adults (>45 y; Howlader SEER Cancer Statistics 2015). Most adults and 15-20% of children will relapse following initial therapy with subsequent poor outcomes. (Bassan, JCO 2012; Locatelli, Blood 2012). Promising results have been observed in studies of anti-CD19 CAR T cells in patients with B cell malignancies, including those treated with KTE-C19, a CD28/CD3ζ anti-CD19 CAR T cell studied in the multicenter ZUMA-1 trial (Neelapu ASCO 2016). However, studies of anti-CD19 CAR T cell therapy in R/R ALL have also observed high incidences of severe CRS in patients with high leukemic burden (Lee, Lancet 2015; Maude NEJM 2014). We present a preliminary analysis of the phase 1 portions of ZUMA-3 and ZUMA-4 which to date have enrolled adult and pediatric patients, respectively with high leukemic burden (M3 marrow).Methods:The primary objective of phase 1 of these multicenter trials is to evaluate the safety of KTE-C19. Eligible patients with R/R ALL are aged ≥18 y (ZUMA-3) or 2-21 y (ZUMA-4) with ≥25% marrow blasts, and adequate renal, hepatic, and cardiac function. Patients are required to have an Eastern Cooperative Oncology Group performance score 0-1 (ZUMA-3) or a Lansky or Karnofsky performance status of >80% (ZUMA-4). Patients with Ph+ ALL and low-burden central nervous system disease are eligible. Patients with Burkitt lymphoma or chronic myeloid leukemia in blast crisis, extramedullary disease only, active graft-versus-host disease, or clinically significant infection are not eligible. KTE-C19 is administered at a target dose of either 1 or 2 × 106 anti-CD19 CAR T cells/kg after low-dose conditioning with fludarabine (25 mg/m2/day for 3 days) and cyclophosphamide (900 mg/m2/day [CyFlu]; Wayne ASCO 2016; Shah ESMO 2016).Results:As of July 8, 2016, 6 patients have enrolled and 5 patients (3 adult and 2 pediatric) have been treated with KTE-C19. KTE-C19 was successfully manufactured in a centralized, streamlined 6-8-day process for 5 patients with approximately a 2-week turnaround time from the time of apheresis to delivery of KTE-C19 to site for patient infusion (Choi, ASGCT 2016). In one 2-year-old patient with peripheral white blood cells >150,000/μL and >99% leukemic blasts in the apheresis collection, KTE-C19 could not be manufactured. All 5 treated patients had high burden disease with a median 85% of marrow blasts (range, 48%-100%) at screening. All 5 patients received bridging chemotherapy prior to dosing with KTE-C19. No patient experienced a dose-limiting toxicity. Cytokine release syndrome (CRS) was reported in all adult (grade 1, n=1; grade 2, n=2) and pediatric (grade 2, n=2) patients; neurotoxicity (NT) was reported in adults only (grade 3, n=2; grade 4, n=1). CRS and NT were successfully managed to resolution with either tocilizumab, corticosteroids, and/or siltuximab in addition to other supportive care for all 5 patients. MRD- remission has been observed in all 5 patients who received KTE-C19 by day 28, with some remissions occurring as early as day 7. Four of 5 patients have had a CR/CR with partial hematologic recovery to date, and 1 of 5 patients with MRD- remission was showing recovering counts. CAR T cells expanded in blood within 2 weeks after infusion and were also detected in bone marrow and/or cerebrospinal fluid. Additional patients and clinical and correlative biomarker data will be presented.Conclusions:The administered dose of KTE-C19 after low-dose CyFlu conditioning has been tolerable and to date appears safe for further analysis in adult and pediatric patients with high leukemic burden R/R ALL. Initial results demonstrate promising efficacy, and the central manufacturing process is deemed feasible. The phase 1 portions of ZUMA-3 and ZUMA-4 are ongoing with planned expansion to phase 2. Clinical trial information: NCT02614066 (ZUMA-3); NCT02625480 (ZUMA-4). DisclosuresShah:Pfizer: Consultancy, Speakers Bureau; Bayer: Honoraria, Speakers Bureau; Plexus Communications: Honoraria; Rosetta Genomics: Research Funding; Celgene: Honoraria, Membership on an entity’s Board of Directors or advisory committees, Speakers Bureau; Baxalta: Honoraria, Speakers Bureau. Lee:Juno: Honoraria. Wierda:Novartis: Research Funding; Abbvie: Research Funding; Acerta: Research Funding; Gilead: Research Funding; Genentech: Research Funding. Schiller:Incyte Corporation: Research Funding. Gökbuget:Pfizer: Honoraria, Research Funding; Amgen: Honoraria, Research Funding. Sabatino:Kite: Employment, Equity Ownership. Bot:Kite Pharma: Employment, Equity Ownership. Rossi:Kite Pharma: Employment, Equity Ownership. Jiang:Kite Pharma: Employment, Equity Ownership. Navale:Kite Pharma: Employment, Equity Ownership. Stout:Kite Pharma: Employment, Equity Ownership. Aycock:Kite Pharma: Employment, Equity Ownership. Wiezorek:Kite Pharma: Employment, Equity Ownership. Jain:Kite Pharma: Employment, Equity Ownership. Wayne:Spectrum Pharmaceuticals: Honoraria, Other: Travel Support, Research Funding; Kite Pharma: Honoraria, Other: Travel support, Research Funding; Pfizer: Consultancy, Honoraria, Other: Travel Support; Medimmune: Honoraria, Other: Travel Support, Research Funding; NIH: Patents & Royalties.