scholarly journals ETV6-FLT3–positive myeloid/lymphoid neoplasm with eosinophilia presenting in an infant: an entity distinct from JMML

2021 ◽  
Vol 5 (7) ◽  
pp. 1899-1902
Author(s):  
Barbara Spitzer ◽  
Filemon S. Dela Cruz ◽  
Glorymar D. Ibanez Sanchez ◽  
Yanming Zhang ◽  
Wenbin Xiao ◽  
...  
Keyword(s):  
Drug Testing ◽  
Ex Vivo ◽  
Hematologic Malignancies ◽  
World Health ◽  
Juvenile Myelomonocytic Leukemia ◽  
Type I ◽  
Cell Transplant ◽  
Hematopoietic Stem ◽  
Lymphoid Neoplasm ◽  
Patient Reported

Abstract Myeloid/lymphoid neoplasm with eosinophilia (MLN-Eo) is a World Health Organization (WHO) established category of hematologic malignancies primarily arising in adults. We discuss an 8-month-old infant who presented with clinical features similar to those of juvenile myelomonocytic leukemia (JMML) but who was diagnosed with MLN-Eo driven by an ETV6-FLT3 fusion. Results of patient-derived leukemia ex vivo studies demonstrated increased sensitivity to type I FLT3 inhibitors as compared with type II inhibitors. Treatment with the type I inhibitor gilteritinib resulted in complete immunophenotypic and cytogenetic remission. This patient subsequently underwent a hematopoietic stem cell transplant and remains in complete remission 1 year later. This is the youngest patient reported with an ETV6-FLT3 fusion and adds to the mounting reports of FLT3-rearranged MLN-Eo, supporting its addition to the WHO classification. Furthermore, this case highlights the clinical utility of ex vivo drug testing of targeted therapies.

scholarly journals Patient-reported outcomes in survivors of childhood hematologic malignancies with hematopoietic stem cell transplant

Blood ◽  
2020 ◽  
Vol 135 (21) ◽  
pp. 1847-1858 ◽  
Author(s):  
Hsiu-Ju Yen ◽  
Hesham M. Eissa ◽  
Neel S. Bhatt ◽  
Sujuan Huang ◽  
Matthew J. Ehrhardt ◽  
...  
Keyword(s):  
Patient Reported Outcomes ◽  
Hematopoietic Stem Cell Transplant ◽  
Stem Cell Transplant ◽  
Adult Survivors ◽  
Hematologic Malignancies ◽  
Cell Transplant ◽  
Hematopoietic Stem ◽  
Patient Reported ◽  
Symptom Domains ◽  
Symptom Prevalence

Abstract Patient-reported outcomes among survivors of pediatric hematopoietic stem cell transplant (HSCT) are understudied. We compared symptom prevalence, health-related quality of life (HRQOL), and risk factors in adult survivors of childhood hematologic malignancies treated with HSCT to those treated with conventional therapy and noncancer controls. Survivors of childhood hematologic malignancies (HSCT N = 112 [70% allogeneic, 30% autologous]; conventionally treated N = 1106) and noncancer controls (N = 242) from the St. Jude Lifetime Cohort Study completed surveys assessing 10 symptom domains and SF-36 HRQOL summary scores. Chronic health conditions (CHCs) were validated by clinical assessment. Multivariable logistic regression reveals that compared with noncancer controls, HSCT survivors endorsed a significantly higher symptom prevalence in sensation (OR = 4.7, 95% confidence interval [CI], 2.6-8.4), motor/movement (OR = 4.3, 95% CI, 1.6-11.0), pulmonary (OR = 4.6, 95% CI, 1.8-11.8), and memory domains (OR = 4.8, 95% CI, 2.5-9.2), and poorer physical HRQOL (OR = 6.9, 95% CI, 2.8-17.0). HSCT and conventionally treated survivors had a similar prevalence of all symptom domains and HRQOL (all P > .05); however, HSCT survivors had a significantly higher cumulative prevalence for specific symptoms: double vision (P = .04), very dry eyes (P < .0001), and trouble seeing when wearing glasses (P < .0001). Occurrence of organ-specific CHCs, instead of transplant receipt, was significantly associated with a higher prevalence of all symptom domains (all P < .05) in adult survivors of childhood cancer, except for pain and anxiety domains. This study found that patient-reported outcomes were equally impaired between HSCT and conventionally treated survivors, but poorer in both groups compared with noncancer controls. Poor patient-reported outcomes in all survivors of childhood hematologic malignancies correlated with the presence of CHCs, whether treated with conventional therapy or HSCT.

scholarly journals Bedside to bench in juvenile myelomonocytic leukemia: insights into leukemogenesis from a rare pediatric leukemia

Blood ◽  
2014 ◽  
Vol 124 (16) ◽  
pp. 2487-2497 ◽  
Author(s):  
Tiffany Y. Chang ◽  
Christopher C. Dvorak ◽  
Mignon L. Loh
Keyword(s):  
Myeloproliferative Neoplasm ◽  
World Health ◽  
Driver Mutations ◽  
Juvenile Myelomonocytic Leukemia ◽  
Ras Signaling ◽  
Cell Transplant ◽  
Pediatric Leukemia ◽  
Hematopoietic Stem ◽  
Molecular Features ◽  
Myelomonocytic Leukemia

AbstractJuvenile myelomonocytic leukemia (JMML) is a typically aggressive myeloid neoplasm of childhood that is clinically characterized by overproduction of monocytic cells that can infiltrate organs, including the spleen, liver, gastrointestinal tract, and lung. JMML is categorized as an overlap myelodysplastic syndrome/myeloproliferative neoplasm (MDS/MPN) by the World Health Organization and also shares some clinical and molecular features with chronic myelomonocytic leukemia, a similar disease in adults. Although the current standard of care for patients with JMML relies on allogeneic hematopoietic stem cell transplant, relapse is the most frequent cause of treatment failure. Tremendous progress has been made in defining the genomic landscape of JMML. Insights from cancer predisposition syndromes have led to the discovery of nearly 90% of driver mutations in JMML, all of which thus far converge on the Ras signaling pathway. This has improved our ability to accurately diagnose patients, develop molecular markers to measure disease burden, and choose therapeutic agents to test in clinical trials. This review emphasizes recent advances in the field, including mapping of the genomic and epigenome landscape, insights from new and existing disease models, targeted therapeutics, and future directions.

A Review of Evaluating Hematopoietic Stem Cells Derived from Umbilical Cord Blood's Expansion and Homing

2020 ◽  
Vol 15 (3) ◽  
pp. 250-262
Author(s):  
Maryam Islami ◽  
Fatemeh Soleimanifar
Keyword(s):  
Stem Cells ◽  
Hematopoietic Stem Cells ◽  
Umbilical Cord ◽  
Stromal Cells ◽  
Ex Vivo ◽  
Hematologic Malignancies ◽  
Future Directions ◽  
Hematopoietic Stem ◽  
Efficient Procedure ◽  
Hematopoietic Recovery

Transplantation of hematopoietic stem cells (HSCs) derived from umbilical cord blood (UCB) has been taken into account as a therapeutic approach in patients with hematologic malignancies. Unfortunately, there are limitations concerning HSC transplantation (HSCT), including (a) low contents of UCB-HSCs in a single unit of UCB and (b) defects in UCB-HSC homing to their niche. Therefore, delays are observed in hematopoietic and immunologic recovery and homing. Among numerous strategies proposed, ex vivo expansion of UCB-HSCs to enhance UCB-HSC dose without any differentiation into mature cells is known as an efficient procedure that is able to alter clinical treatments through adjusting transplantation-related results and making them available. Accordingly, culture type, cytokine combinations, O2 level, co-culture with mesenchymal stromal cells (MSCs), as well as gene manipulation of UCB-HSCs can have effects on their expansion and growth. Besides, defects in homing can be resolved by exposing UCB-HSCs to compounds aimed at improving homing. Fucosylation of HSCs before expansion, CXCR4-SDF-1 axis partnership and homing gene involvement are among strategies that all depend on efficiency, reasonable costs, and confirmation of clinical trials. In general, the present study reviewed factors improving the expansion and homing of UCB-HSCs aimed at advancing hematopoietic recovery and expansion in clinical applications and future directions.

scholarly journals Immune Therapies for Hematologic Malignancies

Cancers ◽  
2021 ◽  
Vol 13 (2) ◽  
pp. 295
Author(s):  
Matthew J. Olnes
Keyword(s):  
Stem Cell ◽  
Hematopoietic Stem Cell ◽  
Hematopoietic Stem Cell Transplant ◽  
Stem Cell Transplant ◽  
Hematologic Malignancies ◽  
Cell Transplant ◽  
Hematopoietic Stem ◽  
Immune Therapies

The era of immunotherapy for hematologic malignancies began with the first allogeneic hematopoietic stem cell transplant (HSCT) study published by E [...]

scholarly journals 205. Rectal Stool Surveillance Cultures to Guide Empiric Antibiotic Therapy in Patients with Hematologic Malignancies with or without Hematopoietic Stem Cell Transplantation

2020 ◽  
Vol 7 (Supplement_1) ◽  
pp. S106-S106
Author(s):  
Afrah S Sait ◽  
Shalom S Patole ◽  
Kathryn Dzintars ◽  
Sara E Cosgrove ◽  
Seema Mehta Steinke
Keyword(s):  
Stem Cell ◽  
Hematopoietic Stem Cell ◽  
Broad Spectrum ◽  
Hematologic Malignancies ◽  
Adult Patients ◽  
Empiric Antibiotic Therapy ◽  
Lower Probability ◽  
Cell Transplant ◽  
Hematopoietic Stem ◽  
Surveillance Cultures

Abstract Background Patients with hematologic malignancies (HM) or hematopoietic stem cell transplant (HSCT) commonly receive broad-spectrum antimicrobials, often leading to the development of multidrug resistant organisms (MDRO). At our institution, rectal stool surveillance cultures (SSC) are done weekly on admitted adult patients with HMs or HSCT. The objective of this study is to determine the role of SSCs in predicting the development of a sterile site infection (StSI) with the same MDRO as identified in the SSC. Methods We retrospectively evaluated StSIs (blood, CSF, sputum/respiratory, pleural fluid, and urine) and SSC data from 242 adult patients admitted to the adult oncology ward at a large academic tertiary care center from 6/1/2017 to 2/28/2019. Demographics, SSC data, and StSIs in a 3-month period following the last SSC for each patient were collected from electronic medical records. SSCs were cultured on HardyCHROM ESBL™ media. MDRO similarity between SSC and StSI was determined by comparing susceptibility profiles. JMPÒ Pro 14.3.0 and RStudio were used for statistical analyses. Results Two hundred forty-two patients yielded 732 SSCs. We eliminated SSCs with incomplete (< 3 months of follow up) data. Thus, 579 SSCs were included in the analyses. 64% of patients were male. Leukemias (55.4%), lymphomas (21.9%), and multiple myeloma (10.3%) were the most common HMs. HSCT recipients comprised 50.4%. SSCs were positive for a MDRO in 251 cases (vancomycin-resistant enterococci, 52.2%; extended-spectrum beta-lactamase (ESBL) producing organisms, 22.2%; and carbapenamase producing organisms, 4.4%). There were 54 StSIs documented where the MDRO was the same as the SSC MDRO. The NPV of the SSC was 95.1% (95%CI 0.93,0.97). The positive likelihood ratio of the SSC was 2.5 (95%CI 2.07,3.02). Conclusion Our results suggest that a negative SSC is associated with a lower probability of identifying a StSI with an MDRO. Clinically, this can be useful in providing the opportunity to judiciously guide antimicrobial therapy, thereby avoiding the unnecessary usage of broad-spectrum antimicrobials when no MDRO is identified in the SSC. Disclosures All Authors: No reported disclosures

scholarly journals Combining Immunocytokine and Ex Vivo Activated NK Cells as a Platform for Enhancing Graft-Versus-Tumor Effects Against GD2+ Murine Neuroblastoma

2021 ◽  
Vol 12 ◽  
Author(s):  
Paul D. Bates ◽  
Alexander L. Rakhmilevich ◽  
Monica M. Cho ◽  
Myriam N. Bouchlaka ◽  
Seema L. Rao ◽  
...  
Keyword(s):  
Tumor Growth ◽  
Nk Cells ◽  
Nk Cell ◽  
Ex Vivo ◽  
Cell Transplant ◽  
Hematopoietic Stem ◽  
Allogeneic Hsct ◽  
Tnf Α

Management for high-risk neuroblastoma (NBL) has included autologous hematopoietic stem cell transplant (HSCT) and anti-GD2 immunotherapy, but survival remains around 50%. The aim of this study was to determine if allogeneic HSCT could serve as a platform for inducing a graft-versus-tumor (GVT) effect against NBL with combination immunocytokine and NK cells in a murine model. Lethally irradiated C57BL/6 (B6) x A/J recipients were transplanted with B6 bone marrow on Day +0. On day +10, allogeneic HSCT recipients were challenged with NXS2, a GD2+ NBL. On days +14-16, mice were treated with the anti-GD2 immunocytokine hu14.18-IL2. In select groups, hu14.18-IL2 was combined with infusions of B6 NK cells activated with IL-15/IL-15Rα and CD137L ex vivo. Allogeneic HSCT alone was insufficient to control NXS2 tumor growth, but the addition of hu14.18-IL2 controlled tumor growth and improved survival. Adoptive transfer of ex vivo CD137L/IL-15/IL-15Rα activated NK cells with or without hu14.18-IL2 exacerbated lethality. CD137L/IL-15/IL-15Rα activated NK cells showed enhanced cytotoxicity and produced high levels of TNF-α in vitro, but induced cytokine release syndrome (CRS) in vivo. Infusing Perforin-/- CD137L/IL-15/IL-15Rα activated NK cells had no impact on GVT, whereas TNF-α-/- CD137L/IL-15/IL-15Rα activated NK cells improved GVT by decreasing peripheral effector cell subsets while preserving tumor-infiltrating lymphocytes. Depletion of Ly49H+ NK cells also improved GVT. Using allogeneic HSCT for NBL is a viable platform for immunocytokines and ex vivo activated NK cell infusions, but must be balanced with induction of CRS. Regulation of TNFα or activating NK subsets may be needed to improve GVT effects.

Manipulation of Oxygen Tension and Medium Composition To Enhance CD34+ Cell Numbers and Megakaryocytic Potential of Cord Blood Progenitors.

Blood ◽  
2007 ◽  
Vol 110 (11) ◽  
pp. 772-772
Author(s):  
Shannon M. Kidd ◽  
Nathalie Brouard ◽  
Kevin Cao ◽  
Simon N. Robinson ◽  
Michael Thomas ◽  
...  
Keyword(s):  
Stem Cell ◽  
Cord Blood ◽  
Oxygen Tension ◽  
Ex Vivo ◽  
Ex Vivo Expansion ◽  
Medium Composition ◽  
Bleeding Complications ◽  
Striking Difference ◽  
Cell Transplant ◽  
Hematopoietic Stem

Abstract A major disadvantage of cord blood (CB) hematopoietic stem cell transplant is delayed engraftment. Cell dose has been identified as the key variable limiting neutrophil and platelet reconstitution. This has lead to the development of culture systems promoting the ex-vivo expansion of CB hematopoietic stem and progenitor cells (HSC/HPC). Typically such systems involve suspension cultures with cytokine supplementation, where the selected media supplies differing essential nutrients. Physiologically, HSCs are regulated by their interactions with the osteoblastic stem cell niche, a region characterized by low oxygen tension. We therefore investigated the effects of oxygen tension as well as differing medium composition on the ex-vivo expansion of CB HSC/HPC. METHODS: Replilcate cultures of fresh CB CD34+ (3,000 cells/mL) cells were established at 5% (hypoxia) or 20% O2 (normoxia) in αMEM medium supplemented with 20% fetal bovine serum (FBS) or in CellGro serum-free medium. 100ng/mL stem cell factor (SCF), Fms-like tyrosine kinase 3 ligand (Flt3-L), thrombopoietin (Tpo) and granulocyte- colony stimulating factor (G-CSF) were added to each medium. The cellular output was evaluated after 7 and 14 days by counting total nucleated cells (TNC) and flow cytometric analysis measuring HSC/HPC (CD34), myeloid (CD11b), and megakaryocytic (CD41) cell progeny. RESULTS: Cultures established under hypoxic conditions demonstrated a consistent increase in TNC (range 1.15 to 2.27-fold; N=8, p= 0.02) compared to those grown in normoxia. In addition, six of eight CB CD34+ samples showed equivalent or greater TNC production in CellGro versus αMEM/FBS. In accord with this, cultures initiated in CellGro at 5% O2 demonstrated a nearly 2-fold higher incidence (10.1% vs. 5.5%) and content (2.5 ± 0.5 x104vs. 1.3 + 0.3 x104, p=0.001) of CD34+ cells at day 7 than in αMEM/FBS. However the most striking difference between the two culture media was their capacity to support megakaryocyte differentiation in 5% O2. At day 14, a mean of 4.3% of cells cultured in CellGro expressed CD41 corresponding to a mean of 1.8± 0.3 x105 CD41+ cells/culture compared to only 0.12 ± 0.08 x105 CD41 cells (0.03% of cells) in αMEM/FBS cultures (p =0.0001). This reveals a 15-fold difference in megakaryocytic cell production. These data demonstrate that significant increases in TNC, CD34+ and CD41+ fractions can be gained by modifying oxygen tension and medium composition for ex-vivo expansion of CB progenitors. The increase in megakaryocytic cells may be of particular importance in ameliorating bleeding complications and the need for extensive platelet transfusions as a consequence of thrombocytopenia following CB transplant. Figure Figure

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