Therapeutic options for chronic myeloid leukemia following the failure of second-generation tyrosine kinase inhibitor therapy.

The management of chronic myeloid leukemia in the chronic phase (CML-CP) has witnessed significant advancements since the identification of a common chromosomal translocation anomaly involving chromosomes 9 and 22, which results in the formation of the Philadelphia chromosome driven by the BCR-ABL1 fusion protein. This discovery paved the way for the development of tyrosine kinase inhibitors (TKIs) that target the adenosine triphosphate (ATP) binding site of ABL1 through the BCR-ABL-1 fusion protein. Following the approval of Imatinib by the Food and Drug Administration (FDA) as the first TKI for CML treatment in 2001, the median overall survival (OS) for chronic phase CML (CML-CP) has significantly improved, approaching that of the general population. However, achieving this milestone crucially depends on reaching certain treatment response milestones. Since the introduction of imatinib, five additional TKIs have been approved for CML-CP treatment. Despite the availability of these treatments, many patients may experience treatment failure and require multiple lines of therapy due to factors such as the emergence of resistance, such as mutations in the ATP binding site of ABL, or intolerance to therapy. This review will primarily focus on exploring treatment options for patients who fail second-generation TKI therapy due to true resistance.

Middle Meningeal Artery Embolization in Acute Leukemia Patients Presenting With Subdural Hematoma.

Intracerebral hemorrhage is a potentially fatal complication in patients with acute leukemia and contributing factors include thrombocytopenia and coagulopathy. Patients with acute leukemia may develop subdural hematoma (SDH) spontaneously or secondary to trauma. In patients with acute leukemia and SDH, the surgical evacuation of the hematoma causes significant morbidity and mortality. New approaches and strategies to reduce the need for surgical evacuation are needed to improve outcomes in patients with acute leukemia and intracerebral hemorrhage. We report two cases of acute SDH in patients with acute leukemia successfully treated with middle meningeal artery embolization, a minimally invasive interventional radiology technique, obviating the need for a surgical intervention. The first patient with acute promyelocytic leukemia (APL) presented with coagulopathy and developed an acute SDH after a fall. The second patient with acute myeloid leukemia presented with gum bleeding and also sustained an acute SDH after a fall. Both patients underwent middle meningeal artery embolization for treating their SDHs while actively receiving induction chemotherapy for acute leukemia. Both patients had resolution of their acute SDH and are in remission from their acute leukemia. Middle meningeal artery embolization is a very effective, and within the context of this setting, a novel, minimally invasive technique for management of SDH in acute leukemia patients, which can prevent the need for surgical interventions with its associated comorbidities and high risk of fatal outcomes in patients with acute leukemia and acute SDH.

Reduced-Intensity Anthracycline-Free Chemoimmunotherapy in Elderly Patients With Newly Diagnosed or Relapsed Diffuse Large B-Cell Lymphoma.

Diffuse large B-cell lymphoma (DLBCL) is the most common type of non-Hodgkin lymphoma (NHL); it has a cure rate of approximately 50% with standard anthracycline-based chemoimmunotherapy. However, the clinical outcomes of elderly unfit/frail DLBCL patients remain suboptimal due to poor tolerance of anthracycline-containing regimens. Herein, we report a series of seven elderly unfit patients with DLBCL who were treated with a reduced-intensity anthracycline-free chemoimmunotherapy (rituximab, cyclophosphamide, vincristine, and prednisone) regimen combined with lenalidomide (R2-COP). Five patients received R2-COP as first-line therapy, and two patients were treated for relapsed DLBCL. Four patients with newly diagnosed DLBCL and two with relapsed disease achieved complete remission. The R2-COP regimen was well tolerated. Interim positron emission tomography (PET) scans in four patients after two to three cycles showed a complete metabolic response. At a median follow-up of 24 months, six patients remain in complete remission. R2-COP is an effective anthracycline-free regimen with encouraging clinical activity in elderly DLBCL patients who are unfit for standard anthracycline-containing regimens.

Primary Diffuse Large B-Cell Lymphoma of the Bone.

Primary lymphoma of the bone (PLB) is a rare lymphoproliferative neoplasm that can present either as solitary or multiple bone lesions. We report four patients with PLB who were successfully treated with R-CHOP (rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone) followed by consolidative radiotherapy. All patients achieved a complete remission and had excellent long-term outcomes. PLB has a favorable response to combined modality treatment with chemoimmunotherapy and radiation. Long-term outcomes of PLB tend to be better than those of non-osseous diffuse large B-cell lymphoma.

T-Cell Prolymphocytic Leukemia With t(X;14)(q28;q11.2): A Clinicopathologic Study of 15 Cases.

OBJECTIVES: T-cell prolymphocytic leukemia (T-PLL) is a rare mature T-cell leukemia usually characterized by inv(14)(q11.2q32)/t(14;14)(q11.2;q32). In this study, we aimed to investigate the clinicopathologic features and molecular profile of T-PLL associated with t(X;14)(q28;q11.2). METHODS: The study group included 10 women and 5 men with a median age of 64 years. All 15 patients had a diagnosis of T-PLL with t(X;14)(q28;q11.2). RESULTS: All 15 patients had lymphocytosis at initial diagnosis. Morphologically, the leukemic cells had features of prolymphocytes in 11 patients, small cell variant in 3, and cerebriform variant in 1. All 15 patients had hypercellular bone marrow with an interstitial infiltrate in 12 (80%) cases. By flow cytometry, the leukemic cells were surface CD3+/CD5+/CD7+/CD26+/CD52+/TCR α/ß+ in 15 (100%) cases, CD2+ in 14 (93%) cases, CD4+/CD8+ in 8 (53%) cases, CD4+/CD8- in 6 (40%) cases, and CD4-/CD8 + in 1 (7%) case. At the cytogenetic level, complex karyotypes with t(X;14)(q28;q11.2) were seen in all 15 patients assessed. Mutational analysis showed mutations of JAK3 in 5 of 6 and STAT5B p.N642H in 2 of 6 patients. Patients received variable treatments, including 12 with alemtuzumab. After a median follow-up of 17.2 months, 8 of 15 (53%) patients died. CONCLUSIONS: T-PLL with t(X;14)(q28;q11.2) frequently shows a complex karyotype and mutations involving JAK/STAT pathway, and it is an aggressive disease with a poor outcome.

Antibody therapies for the treatment of acute myeloid leukemia: exploring current and emerging therapeutic targets.

INTRODUCTION: Acute myeloid leukemia (AML) is the most common and deadly type of leukemia affecting adults. It is typically managed with rounds of non-targeted chemotherapy followed by hematopoietic stem cell transplants, but this is only possible in patients who can tolerate these harsh treatments and many are elderly and frail. With the identification of novel tumor-specific cell surface receptors, there is great conviction that targeted antibody therapies will soon become available for these patients. AREAS COVERED: In this review, we describe the current landscape of known target receptors for monospecific and bispecific antibody-based therapeutics for AML. Here, we characterize each of the receptors and targeted antibody-based therapeutics in development, illustrating the rational design behind each therapeutic compound. We then discuss the bispecific antibodies in development and how they improve immune surveillance of AML. For each therapeutic, we also summarize the available pre-clinical and clinical data, including data from discontinued trials. EXPERT OPINION: One antibody-based therapeutic has already been approved for AML treatment, the CD33-targeting antibody-drug conjugate, gemtuzumab ozogamicin. Many more are currently in pre-clinical and clinical studies. These antibody-based therapeutics can perform tumor-specific, elaborate cytotoxic functions and there is growing confidence they will soon lead to personalized, safe AML treatment options that induce durable remissions.

Durable Remission in Hodgkin Lymphoma Treated With One Cycle of Bleomycin, Vinblastine, Dacarbazine and Two Doses of Nivolumab and Brentuximab Vedotin.

A 49-year-old woman with systemic lupus erythematosus, lupus nephritis and chronic congestive heart failure presenting with "bulky" cervical lymphadenopathy was diagnosed with classic Hodgkin lymphoma (HL) stage IIIB (positron emission tomography-computed tomography (PET-CT) scan and bone marrow biopsy). She received one cycle of bleomycin, dacarbazine, and vinblastine to debulk the tumor. Given her advanced heart failure, doxorubicin was not administered. After the first cycle of chemotherapy, she was switched to nivolumab plus brentuximab vedotin (BV) and received two doses 4 weeks apart, finishing in July 2019. A restaging PET-CT in June 2019 showed a complete remission (CR). After the second course of treatment, she was unable to tolerate more treatments and hence was placed on a surveillance program. She remains in CR after a follow-up of 3 years. This case highlights the role of a tailored treatment approach to optimize clinical outcomes in uniquely complex clinical circumstances. BV in combination with nivolumab is a reasonable alternative regimen in HL ineligible for cytotoxic chemotherapy.

Mixed-Phenotype Acute Leukemia: Clinical Diagnosis and Therapeutic Strategies.

Mixed-phenotype acute leukemia (MPAL) comprises a heterogenous group of leukemias that are genetically, immunophenotypically, and clinically, diverse. Given the rarity of the disease, the diagnosis and treatment of MPAL is extremely challenging. Recent collaborative efforts have made significant progress in understanding the complex genomic landscape of MPAL. Some retrospective studies support starting ALL-type induction followed by an allogeneic stem cell transplant(allo-sct) in the first complete remission; however, due to the inherent bias of retrospective data and small case series, a prospective validation of AML- and ALL-based regimen, and the incorporation of targeted therapies based on genetics and immunophenotype are warranted. The prognosis of adults and children with MPAL varies; this justifies modulating the intensity of therapy, including the use of allo-sct as a consolidation strategy.

Durable remission with Bruton's tyrosine kinase inhibitor therapy in a patient with leptomeningeal disease secondary to relapsed mantle cell lymphoma.

Mantle cell lymphoma (MCL) is an incurable B cell non-Hodgkin's lymphoma with a variable clinical course. Central nervous system (CNS) involvement is a rare and dreaded complication in MCL. We report a case of leptomeningeal relapse of MCL that was successfully treated with a single-agent Bruton's tyrosine kinase inhibitor. A man in his 50s with MCL was treated with six cycles of bendamustine-rituximab, achieving a complete remission (CR) and was subsequently placed on rituximab maintenance for 2 years. Four years later, he was hospitalised with symptoms of organic brain syndrome. Brain MRI and cerebrospinal fluid analysis confirmed CNS relapse of MCL. He was treated with dexamethasone, ibrutinib 560 mg/day and intrathecal cytarabine with improvement in neurological symptoms, and a follow-up MRI showed CR. The patient was later switched to acalabrutinib due to intolerance to ibrutinib. The patient is tolerating this regimen well, remaining in CR 3 years later.

Synchronous Presentation of Autoimmune Hepatitis and Multiple Myeloma.

Autoimmune hepatitis (AIH) is a rare immune-mediated disease predominantly seen in women and triggered by various environmental factors. Rarely, AIH can be triggered by an underlying malignancy. We report a woman in her 60s who presented with markedly abnormal liver biochemical tests. Serology was positive for anti-smooth muscle antibodies and a liver biopsy confirmed AIH. During the hospital course, she developed sepsis and acute renal failure requiring dialysis support. Serum protein electrophoresis (SPEP) showed a monoclonal IgG kappa protein of 1.92 g/dL and a bone marrow biopsy revealed 7% clonal plasma cells. She had lytic lesions on skeletal survey confirming the diagnosis of a coexisting multiple myeloma (MM). Given her markedly abnormal liver chemistries, we decided to treat the AIH first and use the steroids (an important anti-myeloma therapy) as a bridge to the specific treatment of the MM once her clinical condition improved. She was treated with oral prednisone and azathioprine for AIH. One month later, a marked improvement in liver biochemical test results was noted and she was started on oral ixazomib, lenalidomide and dexamethasone. She received palliative radiotherapy to the lumbar spine (L2), left femur, and ischium lesions. This case highlights a rare co-occurrence of AIH and MM, the underlying mechanism of which is unknown.

TP53 in Acute Myeloid Leukemia: Molecular Aspects and Patterns of Mutation.

Mutation of the tumor suppressor gene, TP53, is associated with abysmal survival outcomes in acute myeloid leukemia (AML). Although it is the most commonly mutated gene in cancer, its occurrence is observed in only 5-10% of de novo AML, and in 30% of therapy related AML (t-AML). TP53 mutation serves as a prognostic marker of poor response to standard-of-care chemotherapy, particularly in t-AML and AML with complex cytogenetics. In light of a poor response to traditional chemotherapy and only a modest improvement in outcome with hypomethylation-based interventions, allogenic stem cell transplant is routinely recommended in these cases, albeit with a response that is often short lived. Despite being frequently mutated across the cancer spectrum, progress and enthusiasm for the development of p53 targeted therapeutic interventions is lacking and to date there is no approved drug that mitigates the effects of TP53 mutation. There is a mounting body of evidence indicating that p53 mutants differ in functionality and form from typical AML cases and subsequently display inconsistent responses to therapy at the cellular level. Understanding this pathobiological activity is imperative to the development of effective therapeutic strategies. This review aims to provide a comprehensive understanding of the effects of TP53 on the hematopoietic system, to describe its varying degree of functionality in tumor suppression, and to illustrate the need for the adoption of personalized therapeutic strategies to target distinct classes of the p53 mutation in AML management.

Primary Effusion Lymphoma: A Clinicopathological Study of 70 Cases.

Primary effusion lymphoma (PEL) is a rare type of large B-cell lymphoma associated with human herpesvirus 8 (HHV8) infection. Patients with PEL usually present with an effusion, but occasionally with an extracavitary mass. In this study, we reported a cohort of 70 patients with PEL: 67 men and 3 women with a median age of 46 years (range 26-91). Of these, 56 (80%) patients had human immunodeficiency virus (HIV) infection, eight were HIV-negative, and six had unknown HIV status. Nineteen (27%) patients had Kaposi sarcoma. Thirty-five (50%) patients presented with effusion only, 27 (39%) had an extracavitary mass or masses only, and eight (11%) had both effusion and extracavitary disease. The lymphoma cells showed plasmablastic, immunoblastic, or anaplastic morphology. All 70 (100%) cases were positive for HHV8. Compared with effusion-only PEL, patients with extracavitary-only PEL were younger (median age, 42 vs. 52 years, p = 0.001), more likely to be HIV-positive (88.9% vs. 68.6%, p = 0.06) and EBV-positive (76.9% vs. 51.9%, p = 0.06), and less often positive for CD45 (69.2% vs. 96.2%, p = 0.01), EMA (26.7% vs. 100%, p = 0.0005), and CD30 (60% vs. 81.5%, p = 0.09). Of 52 (50%) patients with clinical follow-up, 26 died after a median follow-up time of 40.0 months (range 0-96), and the median overall survival was 42.5 months. The median OS for patients with effusion-only and with extracavitary-only PEL were 30.0 and 37.9 months, respectively (p = 0.34), and patients with extracavitary-only PEL had a lower mortality rate at the time of last follow-up (35% vs. 61.5%, p = 0.07). The median OS for HIV-positive and HIV-negative patients were 42.5 and 6.8 months, respectively (p = 0.57), and they had a similar mortality rate of 50% at last follow-up. In conclusion, patients presenting with effusion-only versus extracavitary-only disease are associated with different clinicopathologic features. PEL is an aggressive lymphoma with a poor prognosis, regardless of extracavitary presentation or HIV status.

Acute myeloid leukemia with mutated NPM1 mimics acute promyelocytic leukemia presentation.

OBJECTIVES: To investigate clinicopathological and molecular features of NPM1-mutated acute myeloid leukemia that presented with infrequent acute promyelocytic leukemia (APL)-like phenotype and clinical presentation. METHODS: Cases with both de novo or secondary Acute Myeloid Leukemia (AML) were retrieved. Data from flow cytometry immunophenotyping, cytogenetics, molecular studies, and clinical presentation were analyzed. RESULTS: Cases presented with abnormal coagulation parameters and low platelets count; four of them showed a DIC index compatible with overt DIC. Two cases showed Auer rods. In all cases, immunophenotypes mimicked APL: blasts expressed CD33, CD13, and cytoplasmic MPO but did not express CD34, HLA-DR, or CD11b. Notably, CD4 expression was observed in all cases. Neither t(15;17) nor PML/RARα gene rearrangement was detected. NPM1 gene mutation was identified in all cases. In four cases, TET2 or IDH2 co-mutations were identified. CONCLUSIONS: Our findings provide additional evidence of association between NPM1-mutated AML with TET2 or IDH2 co-mutations and the APL-like immunophenotype. This AML subset was found to exist in both de novo and secondary AML. High WBC count and blasts with low to moderate side scatter and significant expression of CD4 are observed features that could assist in the differential diagnosis with APL. The occurrence of significant elevated D-dimer levels, or even overt DIC observed at diagnosis in these cases could be relevant for this AML subtype.

Variable expression of CXCR4 in molecular subtypes of infiltrating gliomas.

AIM: Glioblastomas (GBMs) and diffuse intrinsic pontine gliomas (DIPGs) are infiltrating gliomas with poor prognosis. CXCR4 has been linked to glioma cell invasion, survival, proliferation, and angiogenesis. This study aimed to evaluate the expression of CXCR4 in molecular subtypes of adult and pediatric infiltrating gliomas. MATERIALS AND METHODS: We evaluated the expression of CXCR4 in 21 DIPGs and 44 adult infiltrating gliomas (25 GBM, 8 astrocytomas, and 11 oligodendrogliomas) by immunohistochemistry. Mutations in 315 cancer genes and rearrangements in 28 genes were evaluated by next-generation sequencing. RESULTS: CXCR4 was expressed in -DIPGs and adult infiltrating gliomas in tumor cells (28.6% and 5.6%, respectively) and endothelial cells (14.3% and 19.4%?, respectively). In adult gliomas, there was a correlation between CXCR4 expression and mutations in EGFR, PIK3CA, TERT promoter, and CDKN2A/B loss. In contrast, CXCR4 expression was not detected in IDH1/IDH2 mutant gliomas. These associations were confirmed using The Cancer Genome Atlas (TCGA) database. CONCLUSION: CXCR4 is expressed in a subset of DIPGs and GBMs, but it is not expressed in astrocytomas or oligodendrogliomas. CXCR4 expression is variable and it is influenced by tumor genomic alterations. It is important to consider CXCR4 expression in clinical trials that evaluate the efficacy of CXCR4 inhibitors in the treatment of gliomas.

High Prevalence of Sexually Transmitted Infections, and High-Risk Sexual Behaviors Among Indigenous Adolescents of the Comarca Ngäbe-Buglé, Panama.

BACKGROUND: There is scant information on sexually transmitted infection (STI) prevalence and risk factors among Latin American indigenous populations. We investigated STI prevalence and risk factors among adolescents of the Comarca Ngäbe-Buglé indigenous region of Panama. METHODS: A population-based cross-sectional study was conducted among school-going adolescents aged 14 to 19 years. Eligible consenting participants self-completed a questionnaire and provided blood and urine samples. Female participants provided additional self-administered genital swabs. Seroprevalences of human immunodeficiency virus (HIV), syphilis, hepatitis B (HBsAg, anti-HBc), and herpes simplex virus type 2 (HSV-2) were determined in all participants; genital Chlamydia trachomatis (CT) and Neisseria gonorrhoeae (NG) by PCR among participants who reported sexual experience or were seropositive for HIV/syphilis/HSV2/HBsAg; high-risk human papillomavirus (HPV) by qualitative DNA assay and bacterial vaginosis (BV) by Gram-stain among female participants. Risk factors were identified by estimating adjusted odds ratios (AOR) using random-effects logistic regression. RESULTS: We enrolled 700 participants (median age, 17 years [female participants]; 18 years [male participants]) from 20 schools. Sexual experience was reported by 536 participants (76.6%). The HIV/STI prevalences among females and males were: HIV 0.4% and 1.0%, high-titer active syphilis 1.3% and 6.6%, HSV-2 16.1% and 16.1%, HBsAg 1.3% and 1.4%, anti-HBc 3.2% and 1.4%, NG 1.8% and 1.7%, CT 17.5% and 10.7%; among females: BV 42.9% and HPV 33.2%. CT was independently associated with being female (AOR, 2.02; 95% confidence interval [CI], 1.20-3.41); high-titer active syphilis with being male (AOR, 4.51; 95% CI, 1.17-17.40). Bacterial vaginosis was associated with sexual behavior (≥3 lifetime sex partners: AOR, 3.81; 95% CI, 1.29-11.26), HPV with sexual experience (AOR, 4.05; 95% CI, 1.62-10.09). CONCLUSIONS: School-going indigenous adolescents in rural Panama have substantial STI burden. Targeted STI screening is required.

Automated Diagnosis of Lymphoma with Digital Pathology Images Using Deep Learning.

Recent studies have shown promising results in using Deep Learning to detect malignancy in whole slide imaging, however, they were limited to just predicting a positive or negative finding for a specific neoplasm. We attempted to use Deep Learning with a convolutional neural network (CNN) algorithm to build a lymphoma diagnostic model for four diagnostic categories: (1) benign lymph node, (2) diffuse large B-cell lymphoma, (3) Burkitt lymphoma, and (4) small lymphocytic lymphoma. Our software was written in Python language. We obtained digital whole-slide images of Hematoxylin and Eosin stained slides of 128 cases including 32 cases for each diagnostic category. Four sets of 5 representative images, 40x40 pixels in dimension, were taken for each case. A total of 2,560 images were obtained from which 1,856 were used for training, 464 for validation, and 240 for testing. For each test set of 5 images, the predicted diagnosis was combined from the prediction of five images. The test results showed excellent diagnostic accuracy at 95% for image-by-image prediction and at 100% for set-by-set prediction. This preliminary study provided a proof of concept for incorporating automated lymphoma diagnostic screen into future pathology work-flow to augment the pathologists' productivity.

Human endotrophin as a driver of malignant tumor growth.

We have previously reported that the carboxy-terminal proteolytic cleavage product of the COL6α3 chain that we refer to as "endotrophin" has potent effects on transformed mammary ductal epithelial cells in rodents. Endotrophin (ETP) is abundantly expressed in adipose tissue. It is a chemoattractant for macrophages, exerts effects on endothelial cells and through epithelial-mesenchymal transition (EMT) enhances progression of tumor cells. In a recombinant form, human endotrophin exerts similar effects on human macrophages and endothelial cells as its rodent counterpart. It enhances EMT in human breast cancer cells and upon overexpression in tumor cells, the cells become chemoresistant. Here, we report the identification of endotrophin from human plasma. It is circulating at higher levels in breast cancer patients. We have developed neutralizing monoclonal antibodies against human endotrophin and provide evidence for the effectiveness of these antibodies to curb tumor growth and enhance chemosensitivity in a nude mouse model carrying human tumor cell lesions. Combined, the data validate endotrophin as a viable target for anti-tumor therapy for human breast cancer and opens the possibility for further use of these new reagents for anti-fibrotic approaches in liver, kidney, bone marrow and adipose tissue.