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Urinary symptoms are one of the most common reasons for emergency visits in females of pediatric age group and can be associated with various conditions like infections (most common), sexual trauma and rarely neoplastic processes. Here, we report a case of a 7-year-old female who presented in the emergency multiple times with the complaints of urinary symptoms and vaginal pain and was empirically treated with antibiotics and antifungals without symptomatic improvement. Her blood tests, physical examination during this time remained unrevealing. She was then transferred to our institution on her third emergency visit for further evaluation. On imaging studies, she was noted to have expansile lesions on her vertebral body at the L4 and T6 levels with compressive myelopathy with multiple bone and soft tissue lesions throughout her lower extremities. Patient developed saddle anesthesia requiring emergent decompression and biopsy of the epidural mass with the final pathology coming back as B-lymphoblastic leukemia/lymphoma. B-ALL/B-LBL is the most common pediatric hematologic malignancy and usually presents with fever, hepatosplenomegaly, lymphadenopathy, bone pain and bleeding. Occasionally, atypical presentations like bone and joint pain, osteoporosis, palpable paravertebral mass have been described. However, this is the first case report to describe a very unusual and unfamiliar presentation of this disease causing significant diagnostic difficulty resulting in delayed treatment. This case report can aid as a reminder that unusual pain or any nonspecific manifestations in pediatric patients, refractory to common treatment should be investigated with extreme diligence not to miss this neoplastic process. [ABSTRACT FROM AUTHOR]

Abstract Myeloperoxidase (MPO) is the most specific marker of the myeloid lineage, essential for diagnosing acute myeloid leukemia and mixed phenotype acute leukemia with myeloid components. In this regard, we present a unique case of B‐acute lymphoblastic leukemia (B‐ALL) with isolated MPO expression in bone marrow blasts detected by flow cytometry and immunohistochemistry, while peripheral blood blasts were negative for MPO expression. In this report, our discussion encompasses diagnostic pitfalls from a laboratory testing perspective in similar cases and includes a literature review. Furthermore, we emphasize the necessity of conducting a comprehensive analysis for the accurate diagnosis of MPO‐positive B‐ALL cases.

Relapsed or refractory (r/r) Philadelphia chromosome–positive (Ph+) acute lymphoblastic leukemia (ALL) still represent an unmet clinical need despite the new immune therapies available for these patients. We report the case of a Ph + ALL relapsed one year after allogeneic stem cell transplant. After one DLI was started CAR‐T program with brexucabtageneautoleucel, using as bridging treatment ponatinib, vincristine and prednisone. Brexu‐cel infusion was performed in 2023, without CRS or ICANS onset. One month after Brexu‐cel infusion BM aspirate and CT‐PET showed recovery of full donor chimerism, MRD negativity and complete metabolic remission. Subsequently was started maintenance with ponatinib: at last follow‐up, the patient persisted in leukemia‐free status. CAR‐T cells represent the most powerful treatment for r/r Ph + ALL but there is no consensus about the optimal bridging strategy and also regarding the management algorithm during "post CAR‐T phase". Here, we report the efficacy of ponatinib as a bridge to anti‐CD19 CAR‐T cell therapy and as post CAR‐T maintenance. Our experience suggests that a preserving approach with TKI associated to low‐dose chemotherapy can be the optimal bridging therapy prior to CAR‐T and that an "MRD‐guided" and "TKI‐based" maintenance strategy can represent the best choice for Ph + ALL which satisfactorily responds to CAR‐T. [ABSTRACT FROM AUTHOR]

CD30+ cells are typically part of lymphoproliferative disorders but can also be seen in inflammatory dermatoses. We present a case of 47‐year‐old man with a history of B‐lymphoblastic leukemia (B‐ALL) who presented with fever, leukocytosis, and papulonodular skin lesions, involving the extremities and trunk. A punch biopsy specimen demonstrated papillary dermal edema with a neutrophilic and histiocytic infiltrate extending into the subcutis. The infiltrate also harbored scattered large cells that were positive for CD30 and demonstrated the immunohistochemical profile of monocytes. A diagnosis of histiocytoid Sweet syndrome with CD30+ cells was made. The case is unique, demonstrating a combination of Sweet syndrome variants with subcutis involvement, histiocytoid morphology, and large CD30+ cells. A prior history of B‐ALL and immunohistochemical profile of monocytes with immature morphology broadened the differential diagnosis and added to the diagnostic challenge. [ABSTRACT FROM AUTHOR]

Objectives: Lineage switch in patients with B-ALL treated with blinatumomab has been previously reported. We present a case of blinatumomab-treated B-ALL with t(9;22)(q34.1;q11.2) (Ph + B-ALL) relapsing as a keratin-positive undifferentiated neoplasm with lack of B-cell, T-cell, or definitive myeloid antigens and persistent BCR::ABL1. Results: A 47-year-old male with Ph + B-ALL (p190 fusion transcript) experienced early relapse and received multi-agent therapy including blinatumomab and achieved complete remission. Eleven months after initiation of treatment, he presented with a chest wall mass. Biopsy showed an immature- appearing neoplasm without lineage-specific differentiation, but with expression of keratin and retention of the BCR::ABL1. Subsequently, bone marrow relapse with keratin positivity and BCR::ABL1 was identified. The findings were most compatible with dedifferentiation and aberrant keratin expression of Ph + B-ALL. Conclusions: We present, to our knowledge, the first reported case of an acute leukemia which relapsed as a dedifferentiated neoplasm and the second reported case of lymphoblastic leukemia with aberrant keratin expression in a patient with Ph + B-ALL and treatment including blinatumomab.

The updated International Consensus Classification (ICC) of B-acute lymphoblastic leukemia (B-ALL) and T-acute lymphoblastic leukemia (T-ALL) includes both revisions to subtypes previously outlined in the 2016 WHO classification and several newly described entities. The ICC classification incorporates recent clinical, cytogenetic, and molecular data, with a particular emphasis on whole transcriptome analysis and gene expression (GEX) clustering studies. B-ALL classification is modified to further subclassify BCR::ABL1-positive B-ALL and hypodiploid B-ALL. Additionally, nine new categories of B-ALL are defined, including seven that contain distinguishing gene rearrangements, as well as two new categories that are characterized by a specific single gene mutation. Four provisional entities are also included in the updated B-ALL classification, although definitive identification of these subtypes requires GEX studies. T-ALL classification is also updated to incorporate BCL11B-activating rearrangements into early T-precursor (ETP) ALL taxonomy. Additionally, eight new provisional entities are added to the T-ALL subclassification. The clinical implications of the new entities are discussed, as are practical approaches to the use of different technologies in diagnosis. The enhanced specificity of the new classification will allow for improved risk stratification and optimized treatment plans for patients with ALL. [ABSTRACT FROM AUTHOR]

BCR-ABL1-like B-acute lymphoblastic leukemia (B-ALL) is a genetically heterogeneous group of high-risk B-ALL that benefits from targeted tyrosine kinase inhibitor (TKI) therapy. The incidence of this high-risk B-ALL is relatively low and screening with surrogate markers will be useful to identify patients for further genetic testing. Here we demonstrate that widely available MUC4 protein immunohistochemistry (IHC) is predictive of a BCR-ABL1-like genotype for a subset of patients. Overall, MUC4 expression was observed in 36% (9/25) BCR-ABL1-like, 43% (3/7) BCR-ABL1+ and 9% (2/22) B-ALL other cases (p=.019 for BCR-ABL1 like and BCR-ABL1+ versus B-ALL others). Furthermore, 83% (5/6) of patients with ABL class fusions showed MUC4 expression when compared to 25% (4/16, p=.006) patients with JAK class fusions. Overall, the study demonstrates that MUC4 expression is highly specific (90.9%) for BCR-ABL1+ and BCR-ABL1-like B-ALL with high sensitivity for cases with ABL class fusions. [ABSTRACT FROM AUTHOR]

Objectives: New B-cell markers are needed for monitoring B lymphoblastic leukemia (B-ALL) in the era of immunotherapies directed against CD19 and CD22. The expression of leukocyte immunoglobulin-like receptor subfamily B member 1 (LILRB1) on hematogones in bone marrow (BM) and neoplastic B lymphoblasts has not yet been systematically investigated.Methods: We assessed LILRB1 expression pattern on B cells in 19 control BMs and 22 B-ALL cases by flow cytometry.Results: In all cases, mature B cells and hematogones exhibited a consistent pattern of LILRB1 expression with variable intensity over different stages of maturation, including a characteristic V-shaped pattern on hematogones. While neoplastic B lymphoblasts in all cases expressed LILRB1, the pattern of expression was distinctly abnormal relative to hematogones (loss of the dynamic pattern in all cases and abnormal expression levels in 83% of cases).Conclusions: LILRB1 is a novel diagnostic B-cell marker to aid in distinguishing neoplastic B lymphoblasts from hematogones. [ABSTRACT FROM AUTHOR]

Introduction: Infantile leukemia encompasses a heterogeneous group which needs stratifying for treatment selection. Methods: We collected 78 cases of infantile leukemia and retrospectively analyzed their clinicopathological data. Results: Infantile leukemia featured a ratio of acute myeloid leukemia (AML) to B‐lymphoblastic leukemia (B‐ALL) of 1:2, with a better survival for AML than B‐ALL (median survival 36 vs 24 months). When stratified by age, "early" infantile B‐ALL (2‐6 months) showed a high rate of KMT2A rearrangement (100%), similar to the rate seen in congenital B‐ALL (1 month) (100%) and higher than seen in "late" infantile B‐ALL (≥7 months) (68%). The three categories of infantile B‐ALL exhibited an age‐dependent increase in survival (median survival 8.5, 24, and >24 months, respectively). The age‐dependent survival benefit remained after excluding the cases negative for KMT2A rearrangement. Conversely, infantile AML lacked an age‐dependent pattern of survival. Conclusion: The clinical outcome of infantile leukemia depends on the type of leukemia. Given the age‐dependent survival, infantile B‐ALL can be divided into three subcategories. [ABSTRACT FROM AUTHOR]

Introduction: Minimal residual disease (MRD) is a cornerstone for stratification of upfront B‐lymphoblastic leukemia (B‐ALL) treatment protocols to decrease relapse risk. Although its detection by flow cytometry (FC) and real‐time quantitative polymerase has clinical usefulness, evidence suggests that methods with increased sensitivity could lead to improved outcomes. The aim of this study was to develop an amplicon‐based assay followed by high‐throughput sequencing of the immunoglobulin heavy chain variable region for MRD detection in B‐ALL. Methods: We analyzed 84 samples, 27 from diagnosis, 5 from relapse, 40 from post‐treatment samples, and 12 from healthy controls. Results: Our assay was able to identify more neoplastic clones at diagnosis than Sanger sequencing including incomplete DJ rearrangements. From the 40 MRD samples evaluated 21 were positive by our new approach on high‐throughput sequencing assay, but only 15 of these were positive by FC. The remaining 19 were negative by the two techniques. Conclusion: We have developed a novel approach on high‐sensitive assay for MRD detection in B‐ALL, which could add clinical value in the management of patients, especially in cases negative for MRD by FC. [ABSTRACT FROM AUTHOR]

B lymphoblastic leukemia (B-LL) is a clonal hematopoietic stem cell neoplasm derived from B-cell progenitors, which mainly occurs in children and adolescents and is one of the main causes of death from malignant tumors in this population. The surface marker CD19 is specifically expressed on the membrane of most malignant B-cells, which is widely used as a marker of B-LL antigen-specific immunotherapy. In this study, mesoporous titanium dioxide nanoparticles (MTNs)-based antibody drug delivery system was designed for B-LL treatment. Anti-CD19 monoclonal antibody was conjugated to PEGylated MTNs, and doxorubicin (DOX) was loaded in the nanoparticle. The CD19-PEG-MTN/DOX nanoparticle could recognize CD19+ B -LL cell lines and induced them apoptosis, but nontoxic for the normal cells. Further, after treated with CD19-PEG-MTN/DOX nanoparticle, pro-apoptotic proteins Bax and Caspase-3 in KOPN 8 and NALM-6 cells were significantly upregulated, but anti-apoptotic proteins Bcl2, MCL-1, HSP 70, and BAG 3 were downregulated, which indicated the activation of the apoptosis pathway by the nanodrug. By contrast, CD19-PEG-MTN/DOX didn't play a part on CD19−cell line U937. Besides, the cytotoxicity of CD19-PEG-MTN/DOX was low with good biocompatibility. Collectively, CD19-PEG-MTN/DOX is a promising antitumor nanodrug for the treatment of B-LL. [ABSTRACT FROM AUTHOR]

• We detected a novel type of KMT2A exon 8/EPS15 exon 12 fusion transcript in an adult B-ALL case with t(1;11)(p32;q23). • We also detected an uncommon type of FLT3 mutation (in-frame deletion and insertion) in the juxtamembrane domain. • The novel type of KMT2A/EPS15 fusion transcript and FLT3 mutation may cooperate in the pathogenesis of adult B-ALL. The t(1;11)(p32;q23) translocation is a rare but recurrent cytogenetic aberration in acute myeloid leukemia (AML) and B-cell acute lymphoblastic leukemia (B-ALL). This translocation was initially shown to form a fusion gene between KMT2A exon 8 at 11q23 and EPS15 exon 2 at 1p32 in AML. Activating mutations of FLT3 are frequently found in AML but are very rare in ALL. Here, we describe a 75-year-old woman who was diagnosed with B-ALL since her bone marrow was made up of 98.2% lymphoblasts. These blasts were positive for CD19, CD22, CD79a, CD13, and CD33 but negative for CD10 and myeloperoxidase. The karyotype by G-banding and spectral karyotyping was 46,XX,t(1;11)(p32;q23). Expression of KMT2A/EPS15 and reciprocal EPS15/KMT2A fusion transcripts were shown: KMT2A exon 8 was in-frame fused to EPS15 exon 12, indicating that this fusion transcript was a novel type. Considering three reported B-ALL cases, EPS15 breakpoints were markedly different between AML (exon 2) and B-ALL (exons 10-12). Furthermore, an uncommon type of FLT3 mutation in the juxtamembrane domain was detected: in-frame 4-bp deletion and 10-bp insertion. Accordingly, our results indicate that the novel type of KMT2A/EPS15 fusion transcript and FLT3 mutation may cooperate in the pathogenesis of adult B-ALL as class II and class I mutations, respectively. [ABSTRACT FROM AUTHOR]

A 15-year-old patient with B-lymphoblastic leukemia developed pulmonary mucormycosis. As severe immunosuppression due to chemotherapy was considered inevitable, emergency surgery was recommended. To minimize surgical invasiveness and reduce the risk of secondary infection, uniportal video-assisted thoracoscopic lobectomy was performed. Despite postoperative immunosuppression, the patient's postoperative course was favorable. There was no surgery-associated secondary infection or recurrence of pulmonary mucormycosis. Chemotherapy was administered, and he underwent hematopoietic stem cell transplantation. Follow-up computed tomography revealed no signs of mucormycosis recurrence at 15 months postoperatively. In conclusion, this type of lobectomy is relatively noninvasive and may be a useful surgical procedure for immunosuppressed patients.

Philadelphia chromosome-like B-lymphoblastic leukemia (Ph-like ALL) describes a group of genetically heterogeneous, Ph-negative entities with high relapse rates and poor prognoses. A Janus-kinase-2 (JAK2) rearrangement has been reported in approximately 7% of Ph-like ALL patients whose therapeutic responses to JAK inhibitors have been studied in clinical trials. Here, we report a novel STRBP-JAK2 fusion gene in a 21-year-old woman with Ph-like ALL. Although a normal karyotype was observed, a hitherto unreported JAK2 rearrangement was detected cytogenetically. STRBP-JAK2 fusion was identified by RNA sequencing and validated by Sanger sequencing. The Ph-like ALL proved refractory to traditional induction chemotherapy combined with ruxolitinib. The patient consented to infusion of autologous chimeric antigen receptor (CAR) T cells against both CD19 and CD22, which induced morphologic remission. Haplo-identical stem cell transplantation was then performed; however, she suffered relapse at just one month after transplantation. The patient subsequently received donor lymphocyte infusion after which she achieved and maintained a minimal residual disease negative remission. However, she succumbed to grade IV graft-versus-host disease 7 months post-transplant. In conclusion, this report describes a novel STRBP-JAK2 gene fusion in a Ph-like ALL patient with a very aggressive disease course, which proved resistant to chemotherapy combined with ruxolitinib but sensitive to immunotherapy. Our study suggests that CAR T-cell therapy may be a viable option for this type of leukemia.

Philadelphia chromosome-like B-lymphoblastic leukemia (Ph-like ALL) describes a group of genetically heterogeneous, Ph-negative entities with high relapse rates and poor prognoses. A Janus-kinase-2 (JAK 2) rearrangement has been reported in approximately 7% of Ph-like ALL patients whose therapeutic responses to JAK inhibitors have been studied in clinical trials. Here, we report a novel STRBP-JAK2 fusion gene in a 21-year-old woman with Ph-like ALL. Although a normal karyotype was observed, a hitherto unreported JAK2 rearrangement was detected cytogenetically. STRBP-JAK2 fusion was identified by RNA sequencing and validated by Sanger sequencing. The Ph-like ALL proved refractory to traditional induction chemotherapy combined with ruxolitinib. The patient consented to infusion of autologous chimeric antigen receptor (CAR) T cells against both CD19 and CD22, which induced morphologic remission. Haplo-identical stem cell transplantation was then performed; however, she suffered relapse at just one month after transplantation. The patient subsequently received donor lymphocyte infusion after which she achieved and maintained a minimal residual disease negative remission. However, she succumbed to grade IV graft- versus -host disease 7 months post-transplant. In conclusion, this report describes a novel STRBP-JAK2 gene fusion in a Ph-like ALL patient with a very aggressive disease course, which proved resistant to chemotherapy combined with ruxolitinib but sensitive to immunotherapy. Our study suggests that CAR T-cell therapy may be a viable option for this type of leukemia. [ABSTRACT FROM AUTHOR]

Rare patients with chronic myeloid leukemia (CML) can present initially in lymphoblastic crisis (LBC) mimicking Ph + B-lymphoblastic leukemia (B-ALL). We retrospectively reviewed 275 adults who diagnosed initially as Ph + B-ALL and identified 28 patients with at least one of three features supporting the diagnosis of CML-LBC: 1) a large discrepancy between the blast count and Ph + clone; 2) Ph + clone persistent when B-ALL in remission; 3) BCR/ABL1 fusion detected in segmented cells. BCR-ABL1 fusions were p210 in 25 patients and p190 in 3 patients. In comparison to patients with Ph + B-ALL, patients with CML-LBC were older; had higher leukocyte and absolute neutrophil counts; higher immature myeloid cells in peripheral blood; lower blast counts; and inferior outcomes. In addition, we prospectively analyzed 26 patients with Ph + B-lymphoblastic leukemia and identified 8 patients with features more consistent with CML-LBC. These findings highlight the importance of distinguishing CML-LBC from de novo Ph + B-ALL. [ABSTRACT FROM AUTHOR]

Objectives: Autologous stem cell transplant with lenalidomide maintenance therapy has greatly improved the relapse-free and overall survival rates of patients with multiple myeloma but also has been associated with an increased risk of secondary B-lymphoblastic leukemia/lymphoma (B-ALL).Methods: We report a comprehensive review of the clinicopathologic features of 2 patients with multiple myeloma who developed secondary B-ALL during lenalidomide maintenance.Results: Our observations showed that the disease may initially present with subtle clinical, morphologic, and flow-cytometric findings. The flow cytometry findings in such cases may initially mimic an expansion of hematogones with minimal immunophenotypic variation. Both patients achieved complete remission of secondary B-ALL after standard chemotherapy; however, one patient continues to have minimal residual disease, and the other experienced relapse. Next-generation sequencing of the relapse specimen showed numerous, complex abnormalities, suggesting clonal evolution.Conclusions: Our findings suggest the need for increased awareness and further study of this unique form of secondary B-ALL. [ABSTRACT FROM AUTHOR]

Objectives: To improve diagnostic accuracy in differentiating hematogones from leukemic blasts in cases of precursor B-lymphoblastic leukemia/lymphoma (B-ALL), particularly those that are posttreatment or after bone marrow transplant, and to provide an algorithmic approach to this diagnostic challenge.Methods: A seven-color antibody panel including CD10, CD19, CD45, CD38, CD34, CD58, and CD81 was generated to assess the feasibility of a single tube panel and provide an algorithmic approach to distinguish hematogones from B-ALL. Fifty-three cases were analyzed, and results were correlated with histology and ancillary studies.Results: There was a significant difference in mean fluorescent intensity (MFI) for CD81 and CD58 when comparing hematogones and B-ALL populations (P < .001). B-ALL cases had a mean (SD) MFI of 24.6 (27.5; range, 2-125) for CD81 and 135.6 (72.6; range, 48-328) for CD58. Hematogones cases had a mean (SD) MFI of 70.2 (19.2; range, 42-123) for CD81 and 38.8 (9.4; range, 23-58) for CD58.Conclusions: The flow cytometry panel with the above markers and utilization of the proposed algorithmic approach provide differentiation of hematogones from B-ALL. This includes rare cases of hematogones and B-ALL overlap where additional ancillary studies are necessary. [ABSTRACT FROM AUTHOR]

Objective: To determine frequency of post induction and post consolidation minimal residual disease (MRD) in pediatric B-lymphoblastic leukemia (B-ALL) patients and its association with clinical risk factors. Methods: This is a retrospective, cross sectional study carried out at the Indus Hospital on paediatric patients (1-17 years) was performed from May 2015 to January 2018. On day 35, MRD testing was done on bone marrow aspirate using four color flow cytometer with 0.01% cut off. Positive cases were retested at post consolidation. Data was collected for demographics, total leukocyte count (TLC), central nervous system status (CNS), Cytogenetics for BCR-ABL, MLL, TEL-AML by FISH and prophase response then analyzed in association to MRD status. Results: Out of 362 patients, 133 (37%) were post induction MRD positive, with no statistically significant association to age, gender, TLC, CNS status, prophase response, BCR-ABL and TEL-AML1. However, MLL showed closely significant association (p-value=0.05). Post consolidation, 49 (44%) were MRD positive; age, National cancer institute (NCI) risk groups and CNS status showed statistical significance (p-value <0.05). Conclusion: Despite high frequency of MRD positivity, significant association is not observed between post induction MRD and risk factors. However, post consolidation MRD has a significant association with NCI risk groups, age and CNS status. [ABSTRACT FROM AUTHOR]

The present study aimed to investigate the expression and significance of microRNA-31 (miR-31) in children with acute B-lymphoblastic leukemia (B-ALL). Bone marrow specimens and peripheral blood were collected from children with B-ALL (n=38) and healthy controls (n=18). Total RNA was extracted and the expression levels of miR-31 were measured using quantitative PCR. In addition, a receiver operating characteristic curve was generated, and the area under the curve (AUC) was calculated to evaluate the diagnostic value of miR-31 for the development of B-ALL. miR-31 expression was significantly lower in the B-ALL group compared with in the control group (P<0.05). Additionally, the expression levels of miR-31 in the B-ALL group before treatment were markedly lower than in the B-ALL group after treatment, and miR-31 expression was significantly lower after 30 days of treatment compared with after 12 weeks of treatment. Furthermore, miR-31 expression in the group of children ≥10 years of age was higher than that in the group of children <10 years of age. Furthermore, the expression levels of miR-31 were higher in the low-risk group compared with in the medium- and high-risk groups (P<0.05). When the cutoff value was set at 1.8, the AUC of miR-31 for B-ALL diagnosis was 0.915 (95% CI, 0.828–1.000; P<0.0001), with a sensitivity and specificity of 80.8 and 100%, respectively. In conclusion, miR-31 may exert an anticancer role in B-ALL in children and may be a potential marker to assist in diagnosis and prognostic prediction. [ABSTRACT FROM AUTHOR]

Acute lymphoblastic leukemia (ALL) in infants <1-year-old is biologically different from ALL in older children. Although KMT2A rearrangement is the predominant genetic signature in infantile B-ALL, disease course is heterogenous, behaving more aggressively in younger infants. We investigated clinicopathological differences throughout the first year to understand the transition to pediatric B-ALL. In a multi-institutional review involving four medical institutions, 54 cases of infantile B-ALL were identified. Patients were divided into congenital and non-congenital groups with multiple age subgroups. Male predominance was seen in congenital cases compared to female in non-congenital cases. There were decreasing trends of hyperleukocytosis, central nervous system involvement, KMT2A rearrangements, lineage switch, and mortality, versus increasing trends of CD10 expression and non-KMT2A abnormalities. Statistically significant differences emerged at 3 and 9 months, the latter was not previously described. Poor-prognostic risk factors decreased with age, the last trimester of infantile B-ALL essentially merging with pediatric B-ALL. [ABSTRACT FROM AUTHOR]

Loss of chromosome Y (LOY) in the bone marrow has long been considered as an age-related phenomenon with an incidence of more than 25% in males beyond the age of 80 years. Though reported as an acquired abnormality in myeloid neoplasms, it has rarely been described in B-lymphoblastic leukemia which primarily is a disease of the young. We describe here in three cases of pediatric B-lymphoblastic leukemia with LOY. Conventional cytogenetic studies and fluorescence in situ hybridization studies using centromeric probes for chromosome X and Y on peripheral blood samples ruled out constitutional LOY in all the three cases favoring it to be a neoplastic phenomenon.

Objectives: Lineage switch occurs in rare leukemias, and the mechanism is unclear. We report two cases of B-lymphoblastic leukemia (B-ALL) relapsed as acute myeloid leukemia (AML).Methods: Retrospective review of clinical and laboratory data.Results: Complex cytogenetic abnormalities were detected in B-ALL for both cases with subclone heterogeneity. Postchemotherapy marrow biopsies showed trilineage hematopoiesis without detectable B-ALL. Cytogenetics in both showed stemline abnormalities. The cases were considered "occult" myelodysplastic syndrome (MDS) preceding B-ALL. The patients relapsed 6.5 and 9 months following induction, respectively. Case 1 relapsed as AML-M5 initially, was treated as such, and then relapsed again as B-ALL. Case 2 relapsed as AML-M6. Cytogenetics demonstrated persistent abnormalities. Both patients died soon after relapse.Conclusions: Lineage switch between B-ALL and AML could be intermediated by occult MDS. A pluripotent progenitor likely undergoes neoplastic transformation, resulting in a genomically unstable clone. This leads to a repertoire of heterogeneous subclones that may be selected by chemotherapy. Lineage switch heralds a dismal clinical outcome. [ABSTRACT FROM AUTHOR]

Minimal residual disease (MRD) following B-lymphoblastic leukemia (B-ALL) treatment has gained prognostic importance. Clonal immunoglobulin heavy chain (IGH) gene rearrangement is a useful follow-up marker in B-ALL owing to its high positivity rate. We evaluated the performance and clinical applicability of a next-generation sequencing (NGS) assay for IGH rearrangement in B-ALL MRD monitoring. IGH rearrangement was tested by using fluorescence PCR-fragment analysis and the NGS assay in eight B-ALL patients. The NGS assay was run on two platforms: the Ion Torrent PGM (Thermo Fisher Scientific, USA) (18 samples from 1st to 7th patients) and the MiSeq system (Illumina, USA) (four samples from 8th patient). All initial diagnostic samples and four follow-up samples were positive for clonal IGH rearrangement with fluorescence PCR-fragment analysis and the NGS assay, and six follow-up samples were positive only with NGS. In one case with BCR-ABL1 translocation, BCR-ABL1 quantitative PCR was negative but the NGS IGH assay was positive just prior to full-blown relapse, suggesting the high sensitivity and clinical utility of the NGS assay. The NGS assay is proposed for MRD monitoring in B-ALL Additional studies are needed to confirm the clinical implications of cases showing positive results only in NGS. [ABSTRACT FROM AUTHOR]

Objective: We observed that pediatric patients with B lymphoblastic leukemia which expressed CD36 at diagnosis seemed to have worse outcome than patients whose blasts did not. Here, we describe the patient, disease characteristics, pathological, molecular, and genetic features and outcomes of patients with CD36 + B-LL compared to patients with CD36 - B-LL. Methods: We retrospectively reviewed all flow cytometry reports from September 2008 to December 2015 to identify patients diagnosed at our institution with CD36 expression on B lymphoblasts. CD36-control patients were chosen from our leukemia database and matched 2:1 to CD36 + patients for National Cancer Institute (NCI) risk group at diagnosis. We reviewed diagnostic marrow slides for cytoplasmic granules and abstracted clinical data from patient charts. To identify underlying genetic abnormalities, clinical FISH testing and RNA sequencing was performed on 5 of our CD36 + patients, and RNA-seq data from the NIH Therapeutically Applicable Research to Generate Effective Treatments (TARGET) ALL Expansion Phase 2 data set were examined. Results: Twenty-five of 366 (6.83%) patients diagnosed at our institution in the study period had CD36 + blasts. With a median follow-up of 5.32 years, 5-year event-free survival (EFS) and overall survival (OS) were significantly worse for CD36 + patients compared to CD36- patients who were NCI Standard Risk at diagnosis (EFS: 60% ± 15.49 vs 95% ± 4.87, P=.016; OS: 90% ± 9.5 vs 100%, P=.019). NCI Standard Risk patients whose blasts were both CD36+ and had granules had the worst survival compared to CD36- patients without granules (EFS 25%±21.65 vs 95%±4.87, P=.0004). From our CD36+ patients and the TARGET database, we found 2 ABL2 mutations, 1 PDGFRB mutation, and 2 NRAS mutations. Conclusions: For NCI Standard Risk patients, CD36 expression on B-lymphoblasts identifies patients with B-LL who have especially poor outcome. This may be due to underlying genetic abnormalities that may be amenable to targeted therapy. [ABSTRACT FROM AUTHOR]

Chronic lymphocytic leukemia (CLL) is an indolent mature B-cell neoplasm. During a prolonged disease course, a secondary B-cell neoplasm may arise in some patients, the most common example being the clonal evolution of CLL to diffuse large B-cell lymphoma, which is referred to as Richter transformation. Secondary de novo mature B-cell neoplasms arising in a patient with pre-existing CLL have been described; however, B-lymphoblastic leukemia (B-ALL) developing in untreated CLL is rare, and its clonal relationship to the primary neoplasm has been an interesting issue. Herein, we report an unusual case of the sequential development of CLL and B-ALL over a 23-year period in a 64-year-old male. Examination of the peripheral blood smear and bone marrow biopsy demonstrated dual neoplastic populations: small mature lymphocytes consistent with those seen in CLL and a population of blasts that were confirmed to be B-ALL by immunophenotyping. The biclonality of these two B-cell neoplasms was supported by cytogenetic studies. While an intrinsic immunodeficiency in patients with CLL may predispose them to the development of other malignancies, the pathogenesis of this unusual phenomenon remains to be further investigated. [ABSTRACT FROM AUTHOR]

Objectives: B-lymphoblastic leukemia (B-LBL) arising in patients with chronic lymphocytic leukemia (CLL) is exceedingly rare and poorly characterized. Methods: We describe four patients with CLL and concurrent or subsequent B-LBL diagnosed by morphologic, immunophenotypic, cytogenetic, and molecular analysis and reviewed the literature. Results: In three patients, B-LBL followed CLL by 5 to 15 years, and in one patient, B-LBL was diagnosed simultaneously with CLL. In all cases, the CLL had a typical immunophenotype, and the B-LBL blasts showed an immature B-cell immunophenotype with expression of CD10, CD19, and TdT and absence of surface immunoglobulin. In two patients, B-LBL blasts harbored t(9;22)(q34;q11.2)/BCR-ABL1. We sequenced the IGHV genes in both CLL and B-LBL in two patients and showed that IGHV usage differed. Conclusions: Our data suggest that at least some cases of B-LBL arising in patients with CLL are independent, secondary neoplasms rather than a manifestation of histologic transformation. [ABSTRACT FROM AUTHOR]

Objectives: Study to date suggests that BCL6 protein expression in B-cell neoplasia predominates in germinal center-derived tumors, but less is known regarding its expression in B-lymphoblastic leukemia. Therefore, we designed a comprehensive study of BCL6 expression in B-lymphoblastic leukemia. Methods: BCL6, LMO, and HGAL protein expression in B-lymphoblastic leukemia was investigated using immunohistochemical staining of paraffin-embedded bone marrow specimens. Cryptic TCF3(E2A)-PBX1 rearrangements were investigated using interphase fluorescence in situ hybridization. Results: Six (12%) of 52 B-lymphoblastic leukemias demonstrated BCL6 protein expression, with B-cell lymphoblastic leukemias containing a t(1;19) translocation demonstrating the strongest staining (three of three). Additional t(1;19) cases beyond the screening study showed similar results. Public microarray expression database mining showed that BCL6 messenger RNA expression levels in B-lymphoblastic leukemia correlated with the protein expression findings. Finally, other markers of B-cell development correlated with BCL6 expression in t(1;19) B-lymphoblastic leukemia cases, with LMO2 and HGAL proteins expressed in six (67%) of nine and eight (89%) of nine cases, respectively. Conclusions: BCL6 expression is present in a subset of B-lymphoblastic leukemias, especially in cases containing the 1;19 translocation. Investigation for TCF3(E2A)-PBX1 rearrangements may be useful in BCL6-positive B-lymphoblastic leukemia. [ABSTRACT FROM AUTHOR]

Mantle cell lymphoma is a mature B-cell neoplasm composed of small to medium-sized atypical lymphocytes and has a characteristic t(11;14)(q13;q32) translocation, with a variably aggressive and overall incurable course. More aggressive histologic variants have been described, as well as rare cases of transformation to other large cell lymphomas. Here, we describe a novel case of large cell blastic transformation of mantle cell lymphoma/leukemia at presentation with unusual immunophenotypic and cytogenetic features, most consistent with B-lymphoblastic leukemia. Morphologic findings include sheets of large blasts replacing the bone marrow, as well as occasional small to medium-sized atypical lymphocytes in the background. The blasts express CD19, PAX5, CD10, Cyclin D1, and TdT but are negative for CD5, CD20, and BCL2 by immunophenotyping. Cytogenetic studies show a complex karyotype with t(11;14), monosomy 13, gains of 8q, and MYC gene rearrangement and amplification among other changes. This unique case of blastic TdT-positive B-cell leukemia arising from mantle cell lymphoma may represent transformation with complex cytogenetic abnormalities including 'double hit' changes. This distinctive presentation may expand our understanding of the biology behind mantle cell lymphoma progression. [ABSTRACT FROM AUTHOR]

B-lymphoblastic leukemia/lymphoma (B-LL) is the most common childhood cancer. Circulating blasts in the peripheral blood may be rare (<1%) and missed, even when flow cytometric immunophenotyping is performed, leading to a false-negative report. The records from all patients with a new diagnosis of B-LL between January 2009 and December 2011 at our institution were reviewed. Of 130 cases with peripheral blood flow cytometry, 15 had a blast count of <1%, with 14 having electronic files for gating monocytes. The percentage of monocytes by flow cytometry and absolute monocyte counts (AMCs) were compared with peripheral blood samples that were negative by flow cytometry, sent due to cytopenia of at least 1 lineage (n 39). The monocytes from the patients with leukemia averaged 0.8% and were statistically fewer than the negative controls, which averaged 7.1% (P < 0.001). Eleven of the 14 (79%) patients with leukemia had monocytes <1%, compared to only 3 (8%) of the negative controls. The AMCs were also significantly lower (P < 0.001), with 93% of the leukemia group having an AMC <100 cells/jiL, com- pared to only 28% of the negative controls. In patients with cytopenias, percentage of monocytes may be an important diagnostic clue in determining the presence of occult leukemia. If flow cytometry is performed, acquisition of more than the standard 10 000 events is necessary to adequately assess for leukemia. If monocytes are <1% by flow cytometry in the setting of cytopenias, bone marrow examination is recommended, even with negative peripheral blood flow cytometry. [ABSTRACT FROM AUTHOR]

Follicular lymphoma (FL) is a common form of non-Hodgkin lymphoma with an ability to transform into a more aggressive disease, albeit infrequently to B-lymphoblastic leukemia/lymphoma. While t(14;18)(q32;q21) has been associated with approximately 90% cases of FL, that alteration alone is insufficient to cause FL and associated mutations are still being elucidated. The transformation of FL to B-lymphoblastic leukemia generally includes the dysregulation of MYC gene expression, typically through IGH rearrangement. Such cases of "double-hit" leukemia/ lymphoma with both BCL2 and MYC translocations warrant further study as they are often not identified early, are associated with a poor prognosis, and are incompletely understood in molecular terms. Here we describe a patient with a diagnosis of FL that transformed to B-lymphoblastic leukemia. Detailed cytogenetic characterization of the transformed specimen using karyotype, fluorescence in situ hybridization, microarray and gene rearrangement analyses revealed a complex karyotype comprised principally of whole chromosome or whole arm copy number gains or losses. Smaller, single-gene copy number alterations identified by microarray were limited in number, but included amplification of a truncated EP300 gene and alterations in NEIL1 and GPHN. Analyses defined the presence of an IGH/BCL2 fusion due to a translocation as well as a MYC/IGH fusion due to an insertion, with both rearrangements involving the same IGH allele. The data illustrate the value in characterizing double-hit lymphoma cases with both traditional and novel technologies in the detailed cytogenetic workup. [ABSTRACT FROM AUTHOR]

The effector activity of thiazine and thiourea derivatives towards various forms of NO-synthase (NOS) in vitro and ex vivo was compared with their cytotoxic effect on human lymphocytes and leukemic cells. A thiazine derivative was revealed that exhibits a selective effect only on malignant cells and is an inhibitor of inducible and neuronal NOS. [ABSTRACT FROM AUTHOR]

Summary: B-lymphoblastic leukemia/lymphoma, also known as B-acute lymphoblastic leukemia, is derived from B-cell progenitors. B-acute lymphoblastic leukemia occurs predominantly in children, but can occur at any age. Risk-adapted intensive chemotherapy is effective in treating most children with B-acute lymphoblastic leukemia, but this approach is less successful in adults. Recent developments in genome-wide genetic analysis in B-acute lymphoblastic leukemia have provided insights into disease pathogenesis and prognosis. B-acute lymphoblastic leukemia cases usually carry a primary genetic event, often a chromosome translocation, and a constellation of secondary genetic alterations that are acquired and selected dynamically in a nonlinear fashion. These genetic changes commonly affect cellular mechanisms that control B-cell differentiation and proliferation. The cooperative interaction between inactivation of hematopoietic transcription factors involved in differentiation (class II mutation) and activating mutations involved in cell proliferation (class I mutation) is reminiscent of the pathogenic model of acute myeloid leukemia. The resulting improved molecular understanding of B-acute lymphoblastic leukemia is helping to refine disease risk stratification and discover new therapeutic approaches for patients with refractory disease. In this review, we first summarize the clinicopathologic and immunophenotypic features of B-acute lymphoblastic leukemia and introduce current understanding of B-cell development and B-acute lymphoblastic leukemia leukemogenesis. We then focus on recent advances in genetic analysis and gene expression profiling of B-acute lymphoblastic leukemia and discuss the implications of these findings for disease evolution, risk prediction, and possible novel therapeutic approaches. [ABSTRACT FROM AUTHOR]

We herein present the case of a pediatric patient with B-lymphoblastic leukemia (B-ALL) with MLL gene rearrangement associated with the t(4;ll)(q21;q23). Complete remission was achieved with standard B-ALL-directed chemotherapy and whole brain radiation. The patient subsequently relapsed and cytogenetic assessment revealed an additional acquired t(l;19)(q23;pl3) associated with the TCF3-PBX1 fusion. After reinduction chemotherapy with a relapse B-ALL protocol the patient achieved disease remission; however, he developed respiratory complications and died. This represents a unique case as these two translocations have never been described concurrently in pediatric acute leukemia patients. [ABSTRACT FROM AUTHOR]

Abstract: Rearrangements of JAK2 are rare and have been described in various hematological neoplasms. We report a novel JAK2 rearrangement resulting from a t(9;22)(p24;q11.2) in a 14-year-old male with a diagnosis of B lymphoblastic leukemia. He was treated with Children''s Oncology Group''s protocol (AALL0232) but failed to achieve remission by day 29. He underwent a second induction and entered remission. His clinical course suggested that this JAK2 rearrangement might portend an unfavorable prognosis. This case brings the total number of JAK2 rearranged lymphoblastic leukemia cases in the literature to seven. The molecular genetic and clinicopathologic features of these cases were reviewed. [Copyright &y& Elsevier]

A 15-year-old patient with B-lymphoblastic leukemia developed pulmonary mucormycosis. As severe immunosuppression due to chemotherapy was considered inevitable, emergency surgery was recommended. To minimize surgical invasiveness and reduce the risk of secondary infection, uniportal video-assisted thoracoscopic lobectomy was performed. Despite postoperative immunosuppression, the patient's postoperative course was favorable. There was no surgery-associated secondary infection or recurrence of pulmonary mucormycosis. Chemotherapy was administered, and he underwent hematopoietic stem cell transplantation. Follow-up computed tomography revealed no signs of mucormycosis recurrence at 15 months postoperatively. In conclusion, this type of lobectomy is relatively noninvasive and may be a useful surgical procedure for immunosuppressed patients. [ABSTRACT FROM AUTHOR]

• Ph-like B-ALL shows a gene expression profile similar to BCR-ABL1 + B-ALL in the absence of BCR-ABL1 fusion. • Ph-like B-ALL cannot be distinguished from other types of B-ALL without ancillary studies. • EPOR rearrangements represent is identified in 4–9% of Ph-like B-ALL. • IGH/EPOR fusion is often undetected by conventional cytogenetic and FISH analysis and could only be revealed by molecular fusion transcripts. [ABSTRACT FROM AUTHOR]

Myocardial calcification, a rare disease that leads to chronic or acute heart failure and with a poor prognosis, occurs in patients with abnormal calcium-phosphorus metabolism. The association between myocardial calcification and tumor lysis syndrome has not been reported to date. A 50-year-old man with hyperthermia and general malaise presented to our hospital and was clinically diagnosed with B-lymphoblastic leukemia (B-ALL) and febrile neutropenia accompanied by septic shock. Prednisolone was administered for tumor reduction. Two to three hours later, electrocardiography demonstrated ST elevation in V4–6, and blood tests showed elevated levels of cardiac enzymes. Transthoracic echocardiogram revealed diffuse severe hypokinesis with decreased left ventricular ejection fraction. Additionally, blood tests showed that serum phosphorus level increased to 8.0 mg/dl, which was likely due to tumor lysis syndrome. Circulatory and respiratory failure due to left heart failure progressed, and he died 3 days after administration of prednisolone. Pathological autopsy revealed diffuse proliferation of atypical B-lymphoblasts in the bone marrow, which led to the pathological diagnosis of B-ALL, accompanied by necrosis. On the cut surface of the heart, the left ventricle was dilated, and patchy yellowish-brown areas were present in the epicardial-side of the myocardium and spread through the circumferential wall of the left ventricle and interventricular septum. Microscopically, myocardial fibers were granularly basophilic in that area and were revealed as calcium deposits by Von Kossa staining. He was diagnosed with myocardial calcification. The drastic increase in the serum phosphorus level caused by tumor lysis syndrome seemed to be associated with myocardial calcification. • A 50-year-old man was diagnosed with B-lymphoblastic leukemia • Hyperphosphatemia developed after prednisolone administration • He was diagnosed with myocardial calcification on autopsy • Myocardial calcification seemed to develop in association with tumor lysis syndrome • This is the first case of myocardial calcification caused by tumor lysis syndrome [ABSTRACT FROM AUTHOR]