Crisis Chronic Myeloid Leukemia Research Articles

Acquired hypofibrinogenemia in patients with leukemia during steroid therapy

Acquired hypofibrinogenemia is observed in patients with severe liver disease, disseminated intravascular coagulation, and high-volume perioperative fluid replacement. In lymphoblastic leukemia, hypofibrinogenemia is most frequently caused by the administration of L-asparaginase. Here we report the cases of two patients with acquired hypofibrinogenemia that occurred during steroid-containing chemotherapy treatment against lymphoblastic blast crisis of chronic myeloid leukemia in the first case and acute lymphoblastic leukemia in the second case. Administration of steroids repeatedly and promptly caused hypofibrinogenemia, irrespective of the products (prednisolone, dexamethasone, or methylprednisolone) or routes (oral or intravenous) that were used. Monitoring of the fibrinogen levels, especially during the first course of steroid therapy, would be useful for early diagnosis.

Analysis of Mechanisms of Blast Crisis in Chronic Myeloid Leukemia By Whole Genome Sequencing

Background: Thanks to tyrosine kinase inhibitors (TKIs) chronic myeloid leukemia (CML) has become a well manageable disease. This drastically changes once an individual progresses to blast crisis (BC), which carries a poor prognosis. Although progression to BC fortunately is a rare event, the mechanisms leading to transformation from chronic phase to BC are sparsely studied, which led us to perform in depth analyses of CML patients each at diagnosis (D), at molecular or hematological remission (REM) and at BC by whole genome sequencing (WGS). Aim: (1) Study chromosomal and mutational profiles at D, REM and BC (2) Identify chromosomal and molecular genetic mechanisms in progression to BC Patients and Methods: We performed in depth analyses of 11 CML patients with BC confirmed by cytomorphology. REM samples were available for 8 patients, in 1 patient 2 BC samples were sequenced. Median age at D was 59 years (range 31-70) and median time to BC was 2 years (range 0-6). Nine patients received only first line TKI and 2 patients had switched to second- or third line TKIs before or at time of BC. We sequenced DNA of bone marrow (n=17) or peripheral blood (n=14) by WGS at a median coverage of 106x and used Strelka2 for variant calling. Structural variations (SVs) were analyzed by Manta caller, copy number alterations (CNVs) were called using the GATK4 CNV calling pipeline. Results: None of the patients presented with known high risk additional chromosomal aberrations (ACA) at D (Hochhaus et al, Leukemia 2020). Using WGS at D, we found deletions in the breakpoint region of der(9)t(9;22) (n=2), der(22)t(9;22) (n=1) and a translocation involving 12p and der(22)t(9;22) (n=1). Mutations in known myeloid driver genes were found in 4 patients at D. In two patients (DNMT3A, ASXL1) mutations were present at D and BC, while in two patients three ASXL1 mutations were present at D (VAF 27%; 23% and 14%), but could not be detected at BC by WGS and more sensitive targeted sequencing. Both patients presented with complex ACAs detected both by chromosome banding analysis (CBA) and WGS at BC. Other known driver or resistance mutations were not detected in any other sample at D. We identified three mechanisms driving the transition from chronic phase to BC, the first being ABL1 resistance mutations which render one or several TKIs ineffective (n=6/11). All patients developed ABL1 mutations that conferred resistance to the TKI they were receiving. In BC we detected T315I, Y253H, F359V (n=2 each), E450K, Q252H and Q255K (n=1 each) mutations, one patient had T315I, Q255K and F259V mutation combined, all other patients had a single mutation. In one patient two BCs occurred which showed both an additional t(9;10) but differed in the ABL1 mutations: First Q252H was detected and after REM in second BC T315I was present whereas the Q252H was absent. Secondly, in 10/11 of all patients SVs or CNVs were identified in addition to t(9;22)(q34;q11) by WGS in BC. If CBA data was available it confirmed the WGS data. Patients showed an additional t(9;10) (n=1), t(10;11) (n=1), inv(16) (n=1) and CNVs involving virtually all chromosomes which were only detected in BC pointing towards a major role of chromosomal instability. Interestingly WGS detected de-novo leukemic driver mutations in BC that are described primarily in other myeloid malignancies, representing the third mechanism (n=7). Two patients gained truncating mutations in BCOR, one patient each gained a mutation in ASXL1 and CUX1, one patient 3 frameshift mutations in ETV6, another patient two mutations in WT1 and one case gained a CBFB-MYH11 rearrangement which is usually found in a subtype of AML. Conclusion: Using WGS we found three different contributing mechanisms to progression to BC in CML: 1) ABL1 resistance mutations, 2) gain of structural and copy number variations and 3) potentially rise of additional AML like mutations. Since none of these factors were identified at D and REM, a comprehensive screening is recommended to detect, at the earliest possible time point when molecular remission is lost, the drivers to BC and allow early clinical intervention such as allogeneic transplant. Disclosures No relevant conflicts of interest to declare.

Isolated central nervous system blast crisis in chronic myeloid leukemia - Report of two cases

AbstractExtramedullary blast crisis (BC) presenting as the central nervous system (CNS) involvement in chronic myeloid leukemia (CML) is rare and usually accompanies systemic involvement. Imatinib has shown efficacy in treating patients with CML in accelerated or blastic phases. However, CNS penetration of Imatinib is poor due to the P-glycoprotein mediated efflux mechanisms. Therefore, patients on long-term Imatinib therapy with hematological and cytogenetic remission may rarely present with CNS BC. Isolated CNS BC is uncommon and the literature is limited to only a few case reports. Here, we present two cases of isolated CNS BC in patients with BCR ABL positive CML on treatment.

Clonal evolution of AML1-ETO coexisting with BCR-ABL and additional chromosome abnormalities in a blastic transformation of chronic myeloid leukemia

Blast crisis develops in a minority of patients with chronic myeloid leukemia even in the era of tyrosine kinase inhibitor (TKI) therapy. Reports suggest that we know little about the mechanism of BCR-ABL and AML1-ETO co-expression in blast crisis of chronic myeloid leukemia, and that other chromosomal abnormalities also coexist. Here, we document an unusual and interesting case of a 51-year-old female diagnosed in the chronic phase of chronic myeloid leukemia. After undergoing TKI treatment for 3 months, her bone marrow aspirates in the chronic phase had transformed to blast crisis. Molecular genetic testing indicated she was positive for p210 form of BCR-ABL (copy number decreased from 108.91% to 56.96%) and AML1-ETO fusion (copy number, 5.65%) genes and had additional chromosomal abnormalities of t(8; 21)(q22; q22)/t(9; 22)(q34; q11), t(2; 5)(p24; q13) and an additional +8 chromosome.

RUNX1-EVI1 disrupts lineage determination and the cell cycle by interfering with RUNX1 and EVI1 driven gene regulatory networks.

Hematological malignancies are characterized by a block in differentiation, which in many cases is caused by recurrent mutations affecting the activity of hematopoietic transcription factors. RUNX1-EVI1 is a fusion protein encoded by the t(3;21) translocation linking two transcription factors required for normal hematopoiesis. RUNX1-EVI1 expression is found in myelodysplastic syndrome, secondary acute my eloid leukemia, and blast crisis of chronic myeloid leukemia; with clinical outcomes being worse than in patients with RUNX1-ETO, RUNX1 or EVI1 mutations alone. RUNX1-EVI1 is usually found as a secondary mutation, therefore the molecular mechanisms underlying how RUNX1-EVI1 alone contributes to poor prognosis are unknown. In order to address this question, we induced expression of RUNX1-EVI1 in hematopoietic cells derived from an embryonic stem cell d i fferentiation model. Induction resulte d in disruption of t he RUNX1-dependent endothelial-hematopoietic transition, blocked the cell cycle and undermined cell fate decisions in multipotent hematopoietic progenitor cells. Integrative analyses of gene expression with chromatin and transcription factor binding data demonstrated that RUNX1- EVI1 binding caused a re-distribution of endogenous RUNX1 within the genome and interfered with both RUNX1 and EVI1 regulated gene expression programs. In summary, RUNX1-EVI1 expression alone leads to extensive epigenetic reprogramming which is incompatible with healthy blood production.

Investigating the role of the innate immune response in relapse or blast crisis in chronic myeloid leukemia

Chronic myeloid leukemia (CML) is characterized by expression of the tyrosine kinase oncogene, Bcr–abl. Tyrosine kinase inhibitors (TKI) induce prolonged remission in CML, and therapy discontinuation is an accepted approach to patients with reduction in Bcr–abl transcripts of four logs or greater. Half such individuals sustain a therapy free remission, but molecular mechanisms predicting relapse are undefined. We found relative calpain inhibition in CML cells with stabilization of calpain substrates, including βcatenin and Xiap1. Since the Survivin gene is activated by βcatenin, this identified two apoptosis-resistance mechanisms. We found that Survivin impaired apoptosis in leukemia stem cells (LSCs) and Xiap1 in CML granulocytes. Consistent with this, we determined treatment with an inhibitor of Survivin, but not Xiap1, prevented relapse during TKI treatment and after therapy discontinuation in a murine CML model. By transcriptome profiling, we identified activation of innate immune response pathways in murine CML bone marrow progenitors. This was increased by TKI treatment alone, but normalized with addition of a Survivin inhibitor. We found that activation of the innate immune response induced rapid blast crisis in untreated CML mice, and chronic phase relapse during a TKI discontinuation attempt. These results suggest that extrinsic stress exerts adverse effects on CML-LSCs.

Aberrant RAG-mediated recombination contributes to multiple structural rearrangements in lymphoid blast crisis of chronic myeloid leukemia.

Blast crisis of chronic myeloid leukemia is associated with poor survival and the accumulation of genomic lesions. Using whole-exome and/or RNA sequencing of patients at chronic phase (CP, n = 49), myeloid blast crisis (MBC, n = 19), and lymphoid blast crisis (LBC, n = 20), we found 25 focal gene deletions and 14 fusions in 24 patients in BC. Deletions predominated in LBC (83% of structural variants). Transcriptional analysis identified the upregulation of genes involved in V(D)J recombination, including RAG1/2 and DNTT in LBC. RAG recombination is a reported mediator of IKZF1 deletion. We investigated the extent of RAG-mediated genomic lesions in BC. Molecular hallmarks of RAG activity; DNTT-mediated nucleotide insertions and a RAG-binding motif at structural variants were exclusively found in patients with high RAG expression. Structural variants in 65% of patients in LBC displayed these hallmarks compared with only 5% in MBC. RAG-mediated events included focal deletion and novel fusion of genes associated with hematologic cancer: IKZF1, RUNX1, CDKN2A/B, and RB1. Importantly, 8/8 patients with elevated DNTT at CP diagnosis progressed to LBC by 12 months, potentially enabling early prediction of LBC. This work confirms the central mutagenic role of RAG in LBC and describes potential clinical utility in CML management.

Acquired Melanonychia and Mucocutaneous Hyper pigmentation with Hydroxyurea Therapy for the Treatment of Blast Crisis of Chronic Myeloid Leukaemia: A Case Report

Hydroxyurea is an antineoplastic agent used to treat chronic myeloid leukaemia (especially in accelerated phaseand blast crisis). We report this unique case of a 60 year old lady who was diagnosed case of chronic-phase ofchronic myeloid leukaemia was getting imatinib and well suited. As a consequence of imatinib noncompliance,she developed blast crisis and was subsequently hydroxyurea initiated. At her 3rdmonth follow-up she presentedwith blackening of her exposed parts of the body, all three mucocutaneous areas especially skin of her hands, feet,fingernails, toenails and oral mucosa in some extent.Hydroxyurea-induced melanonychia and mucocutaneous hyperpigmentation is rarely reported. To the best of ourknowledge, this is one of the few published reports of hydroxyurea induced mucocutaneous hyperpigmentationand melanonychia involving all 20 nails. The mainstays of treatment are withdrawal of the drug andsun-avoidance; laser therapy is a hope for cure in small percentage of permanent cases. A correct diagnosis isessential to prevent undue fears in the patient. Proper advice to the patient regarding adverse reactions ofparticular agent and close monitoring after prescribing should be ensured to prevent harm to patients. Alwaysshould remember, drugs not only save life, but can even take it.
 Bangladesh Crit Care J September 2019; 7(2): 106-108

Histone demethylase RBP2 mediates the blast crisis of chronic myeloid leukemia through an RBP2/PTEN/BCR-ABL cascade

Epigenetic disorders play a key role in tumorigenesis and development, among which histone methylation abnormalities are common. While patients living with chronic myeloid leukemia in the chronic phase (CML-CP) have a good response to TKI, blastic phase (CML-BP) patients demonstrate poor efficacy and high fatality rates. However, while the mechanism of blast crisis of chronic myeloid leukemia remains unclear, high expression and activation of BCR-ABL are usually related to CML blast crisis transition. We found that histone H3 lysine 4 (H3K4) demethylase RBP2 expression is negatively correlated with BCR-ABL expression, which suggests a regulatory link between these two genes. We also discovered that RBP2 mediates the dephosphorylation of BCR-ABL by directly downregulating PTEN expression, depending on histone demethylase activity, while PTEN targets protein phosphatase activity of BCR-ABL, a phosphatase which directly dephosphorylates BCR-ABL. In clinical specimens, the mRNA expression of RBP2 was found to be positively correlated with that of PTEN. These data suggest that the under-expression of RBP2 promotes blast crisis transition by activating an RBP2/PTEN/BCR-ABL cascade.

PS946 BLINATUMOMAB + PONATINIB FOR RELAPSED PH1‐POSITIVE ACUTE LYMPHOBLASTIC LEUKEMIA: THE FRENCH EXPERIENCE

Background:Despite the progress achieved with the combination of BCR‐ABL1 tyrosine kinase inhibitors (TKI) and chemotherapy, the prognosis of patients with a refractory/relapsed Philadelphia chromosome‐positive acute lymphoblastic leukemia (Ph1+ ALL) is still very dismal. However, new drugs have recently improved outcomes of these patients: ponatinib has shown some efficacy in this context and a recent study has reported very encouraging results of the anti‐CD3/CD19 monoclonal antibody blinatumomab as single‐agent. Data regarding the efficacy and tolerance of a combination of blinatumomab+ponatinib (blina/pona) are still scarce.Aims:Methods:This was a retrospective study in 12 French centers: 23 patients with a relapsed/refractory Ph1+ ALL have concomitantly received blinatumomab (28 mg/day by continuous infusion for 28 days every 6 weeks) and daily orally ponatinib.Results:There were 13 males and 10 females, with a median age of 58 years (range:17–72). All patients, but 3 with blast crisis of chronic myeloid leukemia, had de novo Ph1+ ALL. Seven cases (30.4%) had BCR‐ABL1 T315I mutation. Patients received the blina/pona combination, either after a first (n = 10) or a second or more (n = 11) cytologic relapse. There was one refractory patient. One patient received blina/pona in consolidation, after serious side effects from front‐line chemotherapy. Previous allograft and autograft has been performed in 9 and 4 patients, respectively. The majority of patients (n = 15) had previously received 3 2 or more lines of TKI. The median number of blinatumomab cycle administered per patient was 3 (range: 1–5) while ponatinib was administered continuously at an initial dose of 45 mg once daily in 17 pts (74%) and 30 mg in 6 pts (26%) during a median time of 5 months (range: 1–41) from first blinatumomab cycle. The toxicity profile was safe: blinatumomab was stopped in 48% of cases because of neurologic events in 4, infections in 4 and cytokine release syndrome in 3 patients; ponatinib was stopped in 22% of cases because of neurologic events in 3, hepatobiliary disorder in 1 and severe arteriopathy in 1 patient who had others vascular disease risk factors. All neurologic events resolved after stopping involved drug. All but one patient (95.6%) obtained a cytologic complete remission (CR), of whom 19/22 (86%) achieved a complete molecular response (CMR). However, 2 patients were documented with CNS relapse, treated with intrathecal infusion of chemotherapy. Then, 7 patients underwent allogeneic transplant (including 3 patients already allotransplanted before blina/pona). With a median follow‐up of 29 months (range: 17.5–66.7) for the alive patients (74%), median overall survival from first cycle of blina/pona was not reached and leukemia‐free survival was 18.2 months (range: 1.3–41). At last follow‐up (February 2019), 7 relapses had occurred at a median of 7 months (range: 1.3–41) from first blina/pona cycle and 1 patient had refractory disease. 6 patients (26%) had died of 2 bacterial infections, 2 fungal infections, 1 secondary cancer and 1 progressive refractory ALL. Among the 17 patients alive, one had relapsed and 16 are still in CMR, but 2 with CNS relapse. Twelve patients are still under ponatinib medication.Summary/Conclusion:The combination of blinatumomab+ponatinib appears effective and tolerable in relapsed Ph1+ALL patients. It could replace chemotherapy salvage regimens and allow a brigde to allogeneic transplantation, or may be tested in first‐line therapy in the future. Our results have to be confirmed prospectively on a larger cohort of patients.

Blinatumomab + Ponatinib for Relapsed Ph1-Positive Acute Lymphoblastic Leukemia: The French Experience

Prognosis of Philadelphia chromosome-positive acute lymphoblastic leukemia (Ph1+ ALL) has been considerably improved since the beginning of the BCR-ABL1 tyrosine kinase inhibitors (TKI) era 20 years ago. However, the prognosis of patients with a refractory/relapsed (including molecular relapse) disease is still very dismal. New drugs or combination of new drugs may improve outcomes of these patients. For example, ponatinib, a 3rd-generation oral TKI, known to have activity against BCR-ABL1 T315I mutations, has shown some efficacy in this context. Similarly, a recent study has reported very encouraging results of the bispecific anti-CD3/CD19 monoclonal antibody blinatumomab as single-agent in refractory/relapsed Ph1+ ALL. Data regarding the efficacy and tolerance of a combination of blinatumomab+ponatinib (blina/pona) are still scarce.This was a retrospective study with the aim to report outcomes of patients receiving a combination of blina/pona for refractory/relapsed Ph1+ ALL in France. Fifteen adults from 8 French centers were identified and data were collected by physicians of each centers, then gathered for the purpose of this study.There were 9 males and 6 females, with a median age of 53 years (range:17-72). All patients, but 2 with blast crisis of chronic myeloid leukemia, had de novo Ph1+ ALL. Four cases had BCR-ABL1 T315I mutation. Patients received the blina/pona combination, either after a first (n=8) or a second (n=7) cytologic relapse. There was no refractory patient in theses series. Previous allograft and autograft has been performed in 7 and 2 patients, respectively. The majority of patients (n=12) had previously received 2 or more lines of TKI. The median time between the first cycle of blina/pona and diagnosis was 14 months (range: 8-40). The median number of blinatumomab cycle (28 mg/day by continuous infusion for 28 days every 6 weeks) administered per patient was 3 (range: 1-6) while ponatinib was concomittantly administered continuously at an initial dose of 45 mg once daily in 11 pts (73%) and 30 mg in 4 pts (27%). Median duration of ponatinib administration was 4 months (range: 1.1-10.9) from first blinatumomab cycle. The toxicity profile was safe: all patients received a complete first cycle without grade 3-4 adverse events. After cycle 1, blinatumomab was stopped in 47% of cases because of neurologic events in 4 and infections in 3; ponatinib was stopped in 33% of cases because of neurologic events in 3, fluid retention in 1 and severe arteriopathy in 1 patient with other vascular disease risk factors. All neurologic events resolved after stopping blinatumomab or ponatinib.The majority of patients were evaluated after one cycle (n=11, after cycle 2 n=3, after cycle 3 n=1). All but one patients (93%) obtained a cytologic complete remission (CR), of whom 12/14 (86%) achieved a complete molecular response. However, 2 patients were documented with CNS relapse at the time of blina/pona evaluation although in bone marrow molecular remission. Both obtained clearance of leukemic blasts after intrathecal infusion of chemotherapy. Then, 5 patients underwent allogeneic transplant (including 2 patients already allotransplanted before blina/pona) and 1 patient received donor lymphocyte infusion. Seven cases pursued maintenance therapy with ponatinib as single agent after stopping blinatumomab. With a median follow-up of 8 months (range: 2.6-30.2) for alive patients, median overall and leukemia-free survivals from first cycle of blina/pona were 8.5 months (range: 1.7-30.2) and 8 months (range: 1.3-30.2), respectively.At last follow-up (July 2018), only 4 relapses had occurred at a median of 3.3 months (range: 1.3-8.3) from first blina/pona cycle and 6 patients had died (3 bacterial infections, 1 fungal infection, 1 secondary cancer and 1 ALL relapse). All alive patients (n=9) but one (cytologic CR but detectable minimal residual disease) are in complete molecular response. Four patients are still under ponatinib medication at last follow-up.The combination of blinatumomab+ponatinib appears effective and tolerable in relapsed Ph1+ALL patients and may replace chemotherapy salvage regimens. The combination should be tested in first-line therapy in the future. Our results have also to be confirmed prospectively on a larger cohort of patients. DisclosuresNo relevant conflicts of interest to declare.

Successful Salvage with Inotuzumab Ozogamicin in Relapsed/Refractory Lymphoid Blast Crisis of Chronic Myeloid Leukemia after Failure of Multiple Lines of Therapy Including Blinatumomab

Background: Lymphoid blast crisis, one of the two major forms of chronic myeloid leukemia (CML) blast crisis (BC), is comprised of lymphoblasts and occurs in about 30% of BC patients. These individuals often respond to the same treatment strategies used in Philadelphia chromosome positive acute lymphoblastic leukemia (Ph+ ALL). Blinatumomab, a bispecific T engager, or BiTE, is an antibody with dual specificity against both CD3 and CD19, and is approved for use in relapsed/refractory ALL. We present the first known case of relapsed/refractory lymphoid blast phase CML, including treatment failure with blinatumomab, who achieved a complete response to inotuzumab ozogamicin.Case report: In 2004, the patient was initially diagnosed with CML and received treatment with hydroxyurea followed by imatinib. He was intermittently compliant, later changed to nilotinib, and was ultimately lost to follow-up. Approximately 11 years after diagnosis, he returned with pancytopenia. Bone marrow aspiration and biopsy showed a hypercellular bone marrow with 10-15% lymphoid blasts that expressed CD34, CD19, cCD79a, HLA-Dr, CD10 and nTdt. Testing for the BCR-ABL translocation (at breakpoint P210) was positive confirming lymphoid blast phase CML. He received hyperCVAD + dasatinib, responded, and was referred for allogeneic hematopoietic cell transplantation (HCT) but deferred for social reasons. He was ultimately lost to follow-up.The patient returned with relapsed disease in February 2017 and bone marrow aspiration and biopsy was consistent with CD19+ lymphoid blast phase CML with BCR-ABL major breakpoint p210 and new F317L mutation of ABL kinase domain. He received salvage therapy with vincristine/prednisone/bosutinib, however, repeat bone marrow testing confirmed persistent CD19+ lymphoid blasts (20%). He was treated with blinatumomab, entered a minimal residual disease (MRD)-positive morphologic remission with 1.9% abnormal B lymphoblasts by flow cytometry. A second cycle of blinatumomab was complicated by bone pain and repeat bone marrow testing showed progressive disease with 50-60% CD19+, CD22+ lymphoblasts. Salvage therapy with fludarabine, cytarabine, and idarubicin (FLAG-Ida) in September 2017 was unsuccessful and palliative treatment with vincristine, prednisone, and methotrexate was initiated. He developed new onset neurologic symptoms in March 2018 and lumbar puncture showed evidence of disease in his central nervous system (CNS) The patient received concurrent intrathecal methotrexate and inotuzumab ozogamicin which led to clearance of CNS disease and a morphologic remission in his marrow. He continues with MRD-positivity with 0.15% B lymphoblasts and is on ponatinib maintenance while allogeneic HCT evaluation is underway.Discussion: This is the first reported patient with lymphoid blast phase CML, refractory to BiTE therapy, that was successfully salvaged with inotuzumab ozogamycin. Recent data from acute lymphoblastic leukemia (ALL) reported that the majority of BiTE failures remained CD19+ and the mechanisms of CD19 immunotherapy failure are poorly understood (Jabbour E, et al, AJH 2017). These patients may be successfully salvaged by CD19-directed chimeric antigen receptor (CAR) T cells or other directed therapies such as inotuzumab ozogamycin.Conclusion: Patients with relapsed/refractory lymphoid blast phase CML should receive directed salvage therapies. This case report demonstrates that failure of one line of directed therapy does not predict for future failures. DisclosuresNo relevant conflicts of interest to declare.

Blinatumumab Induces Responses in Extramedulary B-Cell Acute Lymphoid Leukemia (B-ALL) and Lymphoid Blast Crisis Chronic Myelogenous Leukemia (CML), and Rarely Results in CD19 Negative Relapse

Blinatumumab Induces Responses in Extramedulary B-Cell Acute Lymphoid Leukemia (B-ALL) and Lymphoid Blast Crisis Chronic Myelogenous Leukemia (CML), and Rarely Results in CD19 Negative Relapse

Precursor B cell lymphoid blast crisis of chronic myeloid leukemia with novel chromosomal abnormalities: A case report.

Chronic myeloid leukemia (CML) is a clonal hematopoietic stem cell disorder. It is characterized by the presence of the Philadelphia (Ph) chromosome, t(9;22)(q34.1;q11.2), which carries the BCR-ABL1 fusion gene. Tyrosine kinase inhibitors (TKIs) have markedly changed the treatment approach of CML and have become the first-line agents for almost all CML patients. However, certain patients experience resistance to these medications, which occurs through several mechanisms, including the accumulation of TKI-resistant chromosomal abnormalities. The present study reports a case of a 27-year-old Saudi male with CML receiving TKI treatment, who presented with precursor B-cell lymphoblastic crisis demonstrating the presence of the novel combined chromosomal abnormalities; non-Ph der(22), i(9) and der(20), carrying the BCR-ABL1 fusion gene. This case report adds to the literature on novel TKI-resistance-conferring chromosomal abnormalities and links them to precursor B-cell lymphoblastic crisis.

Utility of simultaneous assessment of bone marrow aspirates and trephine biopsy sections in various haematological disorders

Background: Bone marrow examination is crucial diagnostic modality for evaluation of various hematological and nonhematological disorders. However, marrow aspirate smears and biopsy sections, even though performed simultaneously, are often assessed at different points of time due to different processing methods. This sometimes results in discordance in diagnosis which adds to the diagnostic dilemma and delays the treatment. aim: This study aims to compare the diagnostic accuracy and the rate of concordance between the two modalities of bone marrow examination. Materials and Methods: Three hundred simultaneously performed bone marrow aspirates and BM trephine biopsies were retrospectively analyzed over a period of 1 year. The presence or absence of concordance was recorded. The reasons for inconclusive reports were also recorded. The concordance rates for different hematological disorders were calculated and recorded as high for >80%, moderate for 50%–80%, and low for Results: A high concordance was found in cases of megaloblastic anemia, leukemias, non-Hodgkin's lymphoma, and multiple myeloma; moderate concordance was found in hypoplastic marrow and concordance was low in Hodgkin's lymphoma, chronic myeloid leukemia (CML) in blast phase, metastatic, and granulomatous involvement of bone marrow. Conclusion: Bone marrow aspiration alone is sufficient for the diagnosis of megaloblastic anemia and most of the hematological malignancies. Bone marrow biopsy is more appropriate for detection of disorders with focal marrow involvement such as lymphoproliferative disorders, metastatic cancer, focal blast crisis in CML, granulomatous lesions, and hypoplastic marrow. However, it is strongly recommended that both should be reviewed simultaneously to ensure maximum diagnostic accuracy.

Incidental Finding of Microfilaria in Blast Crisis of Chronic Myeloid Leukemia– A Rare Entity

Incidental Finding of Microfilaria in Blast Crisis of Chronic Myeloid Leukemia– A Rare Entity

Successful Third Hematopoietic Stem Cell Transplantation for Blast Crisis of Chronic Myeloid Leukemia After Two Times of Graft Failure

Successful Third Hematopoietic Stem Cell Transplantation for Blast Crisis of Chronic Myeloid Leukemia After Two Times of Graft Failure

A feedback loop that regulates the expression of polycomb group protein Suz12 via non-canonical WNT signaling pathway in blast crisis of chronic myeloid leukemia

Abstract The importance of Kaiso, Wnt5, Wnt11 and PcG proteins in tumorigenesis has been widely discussed in the scientific literature, in recent years. However, until now, there has been no exploration of the relationship of these sets

Activation of EVI1 transcription by the LEF1/β-catenin complex with p53-alteration in myeloid blast crisis of chronic myeloid leukemia

The presence of a BCR-ABL1 fusion gene is necessary for the pathogenesis of chronic myeloid leukemia (CML) through t(9;22)(q34;q11) translocation. Imatinib, an ABL tyrosine kinase inhibitor, is dramatically effective in CML patients; however, 30% of CML patients will need further treatment due to progression of CML to blast crisis (BC). Aberrant high expression of ecotropic viral integration site 1 (EVI1) is frequently observed in CML during myeloid-BC as a potent driver with a CML stem cell signature; however, the precise molecular mechanism of EVI1 transcriptional regulation during CML progression is poorly defined. Here, we demonstrate the transcriptional activity of EVI1 is dependent on activation of lymphoid enhancer-binding factor 1 (LEF1)/β-catenin complex by BCR-ABL with loss of p53 function during CML-BC. The activation of β-catenin is partly dependent on BCR-ABL expression through enhanced GSK3β phosphorylation, and EVI1 expression is directly enhanced by the LEF1/β-catenin complex bound to the EVI1 promoter region. Moreover, the loss of p53 expression is inversely correlated with high expression of EVI1 in CML leukemia cells with an aggressive phase of CML, and a portion of the activation mechanism of EVI1 expression is dependent on β-catenin activation through GSK3β phosphorylation by loss of p53. Therefore, we found that the EVI1 activation in CML-BC is dependent on LEF1/β-catenin activation by BCR-ABL expression with loss of p53 function, representing a novel selective therapeutic approach targeting myeloid blast crisis progression.

A vicious cycle of metabolic interaction between leukemia stem cells and adipose tissues: implications in cachexia and drug resistance

Compelling evidences from recent studies suggest that leukemia stem cells (LSCs), a small subpopulation of malignant cells with long-term self-renewal capacity, play a key role in leukemia development, drug resistance, and disease relapse and recurrence (1). It has also been known for some time that tumor microenvironment or tissue niches may exert profound effect on the fates and viability of LSCs. A recent study by Ye et al . revealed a metabolic interaction between LSCs and adipose tissues, and showed that LSCs could be segregated into two metabolically and functionally distinct subgroups by their expression of the fatty acid (FA) transporter CD36 (2). The authors also suggested that gonadal adipose tissue (GAT) might provide a preferred niche to support CD36 + LSCs and promote drug resistance in a mouse model of blast crisis chronic myeloid leukemia (CML).