bluuebunny/crossref_metadata_2025 huggingface dataset:
CD56+ AML Is Strongly Associated with AML1/ETO Rearrangement and CNS Involvement in Childhood AML.
Authors: Lee Hye Ryun , Lee Dong Soon , Kim Inho , Yoon Sung-Soo , Park Seonyang , Kim Byoung Kook , Kang Hyoung Jin , Shin Hee Young , Ahn Hyo Seop , Kim Hyun Kyung , Park Myoung Hee , Cho Han Ik
Published: October 2019

Introduction: To investigate the clinical difference between CD56+AML and CD56−AML, we examined the incidence of CD56+AML and analyzed several clinical and biological characteristics, cytogenetic features, immunophenotypic features, and clinical prognosis of CD56+AML.

Method: 213 patients (177 adults, 36 children) with de novo AML in Seoul National University Hospital were enrolled. FAB subtypes were 4 M0 (2.3%), 26 M1, (12.2%), 78 M2 (36.6%), 27 M3 (12.8%), 43 M4 (20.2%), 15 M5 (7.1%), 14 M6 (6.6%), and 5 M7 (2.4%). Immunophenotyping was performed by immunohistochemical stain or multiparameter flow cytometry. The association between CD 56 expression and variables (age, sex, WBC count, blast, cytogenetic features, extramedullary involvement, disease free survival, and overall survival) was analyzed by the fisher’s exact test, chi-square test and T test, and Kaplan-Meier method. All statistical calculation were performed using SPSS system.

Results: CD56 was detected in 6 of 177 adults (3.4%) and in 9 (25.0%) of children, showing significantly higher in children group (p = 0.000). The CD56 expression was significantly frequent in M7 subtype (p=0.003). The other clinical characteristics, such as sex, WBC count, % blasts in peripheral blood was not significantly associated with CD56 positivity. Frequency of extramedullary involvement did not differ between CD56+AML and CD56−AML. However, the frequency of CNS involvement at initial diagnosis or relapse were significantly higher in CD56+AML (p=0.018). (Table 1) Among cytogenetic changes, AML1/ETO rearrangement was significantly associated with CD56 expression (p=0.024). Aberrant expression of one or more lymphoid markers was observed in 42.9% (6/15 CD56+AML) and 45.2% (80/198 CD56+AML), showing no difference between CD56+AML and CD56−AML. Median disease free survival was 7 months in CD56+AML and 19 months in CD56−AML, showing no significant difference in two groups (p=0.2466). Median overall survival was not reached in CD56+AML and 25 months in CD56−AML (p=0.1591).

Conclusion: The incidence of CD56 positive AML was higher in childhood AML and association of CD56+AML with AML1/ETO rearrangement, CNS involvement and M7 subtype was observed, suggesting the different biologic behavior of CD56+AML. Furthermore, we suggest that 3rd lineage of leukemic cells, would be taken into consideration for the biphenotypic leukemia.

Extramedullary involvement of CD56+ vs. CD56− CD56+ CD56- p * chi-square test or fisher’s exact test (level of significance: p<0.05) n=15 (7.0%) n=198 (93.0%) Extramedullary involvement 3 (20.0%) 27 (13.6%) 0.450 Adult 0 19 Child 3 8 CNS involvement 3 (20.0%) 7 (3.5%) 0.025 Adult 0 4 Child 3 3
Hemangioblastic Activity of Infant Leukemia with t(4;11).
Authors: Hu Zhongbo , Li Xiaomiao , Slayton William B.
Published: October 2019

Background: Infant leukemia patients with t(4;11) have an extremely high risk for treatment failure. Hemangioblasts are cells that were initially described in the embryonic yolk sac, where they make both blood and blood vessels when these two systems are forming. It was demonstrated that hemangioblasts are present in the adult bone marrow and CML patients. Recently, subgroups of infant ALL patients with t(4;11) were found to have gene expression profiles similar to hemangioblasts by microarray. However, whether infant leukemia cells behave like hemangioblasts and produce their own blood vessels remains unknown.

Objective: We sought to determine whether infant leukemia cells with t(4;11) are derived from malignant hemangioblasts and can produce their own blood vessels.

Design/Methods: Three childhood leukemia cell lines with t(4;11): MV4-11, SEM-K2 and RS4-11, were used to analyze the expression pattern of key angiogenic receptors by flow cytometry and angiogenesis related proteins by protein array in comparison with benign endothelial cells. These cell lines were also cultured in vitro using Matrilgel, an in vitro angiogenesis assay system, in order to test their ability to produce vascular tubes. These cell lines were injected into the immune deficient NOD/SCID mice after sublethal irradiation to establish leukemia in vivo. Some of primary cells from MLL patients were obtained and subcutaneously injected into NOD/SCID mice mixed with BD Matrigel to observe their vessel development in vivo together with these three cell lines. The bone marrow, liver, spleen and tumor tissues together with Matrigel were collected to look for the evidence of t(4;11) in endothelial cells by immunohistochemical staining and fluorescent in situ hybridization (FISH).

Results: The leukemia cell lines expressed many angiogenetic cytokines, such as VEGF, VEGF-D, RANTES, PIGF, PDGF-BB, MCP-1, IGF-1, ENA-78, and angiogenin, at the same levels as HUVEC cells, a human umbilical vessel endothelial cell line. Different cell lines expressed some angiogenesis-related receptors, such as CD31, Tie-2, PDGFRalpha, CD141, CD146, and KDR. None of the cell lines formed tubes in Matrigel. When these three cell lines generated leukemia in NOD/SCID mice, the microvessel density level increased in the tumor areas. However, immunostaining for human and murine endothelial markers demonstrated that all the vessels came from the mouse, not from the human leukemia cells.

Conclusions: We conclude that infant leukemia cell lines with t(4;11) have proangiogenesic activity. However, these cells do not function as hemangioblasts, as they do not produce blood vessels in culture or in vivo in NOD/SCID mice. We plan to look further by examing bone marrow biopsies from patients with t(4;11) leukemia to determine whether the translocation is present in their blood vessels.
Intensification of Hyper-CVAD with L-Asparaginase, Vincristine, and Dexamethasone ("Augmented Hyper-CVAD") Has Activity in Adult Patients with Relapsed/Refractory Acute Lymphoblastic Leukemia (ALL).
Authors: Faderl Stefan , Thomas Deborah A. , Ravandi Farhad , Garcia-Manero Guillermo , Beran Miloslav , Rytting Michael , Koller Charles A. , Verstovsek Srdan , Borthakur Gautam , Andreeff Michael , Kornblau Steve , O’Brien Susan , Vu Khanh , Kwari Monica , Bretz Jennie , Kantarjian Hagop M.
Published: October 2019

Few treatment options exist for adults patients (pts) with relapsed/refractory ALL and prognosis for these pts remains poor. The hyper-CVAD program (fractionated cyclophosphamide, vincristine, doxorubicin, and dexamethasone) has been established as an active induction regimen with a 91% CR rate and 5-yr. survival of 39% (Kantarjian et al. JCO 18:547, 2000). Following this lead, we designed an “augmented” hyper-CVAD (AHCVAD) combination intensifying the doses of vincristine, L-asparaginase, and dexamethasone during induction and consolidation. In this phase II study, pts received up to 8 courses of HCVAD alternating with methotrexate and high-dose cytarabine. With each course, pts received L-asparaginase 20,000 units i.v. and vincristine 2 mg i.v. at days 1, 8, and 15 each, and dexamethasone 80 mg i.v./p.o. on days 1–4 and 15–18. From June 2003 to July 2007, 55 pts with relapsed/refractory ALL have been enrolled. Median age was 34 yrs (range 14–70). Forty-one pts (75%) had pre-B ALL (2 pts with isolated CNS disease and one with an isolated testicular mass), 12 (22%) T cell ALL (2 with isolated extramedullary disease), 1 (2%) pt mature B ALL, and 1 (2%) biphenotypic leukemia. Karyotype was diploid in 25 (45%) pts and abnormal in 27 (49%) pts (1 Ph+ ALL). Median number of prior regimens was 1 (1–6). Median remission duration to the initial induction regimen was 11.5 mos (1–68). Seven (13%) pts were primary refractory. Forty-nine pts are evaluable for response (1 too early, 5 off study for toxicity or pt choice). Twenty-two (45%) pts achieved CR, 3 (6%) PR, and 4 (8%) hematologic improvement (HI). Median remission duration following AHCVAD was 4.75 mos (range, 0.2–45.5+). Twelve (24%, 8 in CR, 1 in PR, 1 with HI) pts proceeded to receive a stem cell transplant. Eight (15%) died while on study from infectious complications. Uncomplicated neutropenic fever was common. Three pts (5%) were intolerant to L-asparaginase and had to be taken off study early. Intensification of hyper-CVAD with asparaginase, vincristine, and dexamethasone is active in ALL salvage producing a CR rate of 45%. Further improvements should include:

identification of salvage pts with maximum chance of response; combination with new drugs and attempts to prolong remission duration for these pts.
Induction of Oxidative Stress and Glutathione Depletion by ABT-737, a Novel Small Molecule Inhibitor of Bcl-2, Contributes to Cytotoxicity in Leukemia Cells.
Authors: Chandra Joya , Howard Adrienne , Jensen Kathleen , Meyn Ray
Published: October 2019

The Bcl-2 family of proteins regulate the process of cell death. Bcl-2 and Bcl-xL are potent anti-apoptotic members that are overexpressed in a number of malignancies, providing a means to evade cell death, which has been described as a characteristic hallmark of cancer. Several lines of evidence suggest that Bcl-2 and Bcl-xL possess anti-oxidant properties. Overexpression of Bcl-2 is protective against menadione and hydrogen peroxide induced cell death and causes an increase in intracellular levels of glutathione (GSH), the most abundant antioxidant defense. In the present study, we utilized a novel small molecule to test effects of Bcl-2 inhibition on intracellular redox status. ABT-737 is a first generation inhibitor of Bcl-2, Bcl-xL and Bcl-w and and acts as a mimic of the BH3-only antagonists of these family members. Exposure of acute lymphocytic leukemia (ALL) cells to ABT-737 caused a dose dependent increase in intracellular levels reactive oxygen species (ROS), namely superoxide and hydrogen peroxide. This dose dependent increase in intracellular oxidants was significantly less pronounced in cells treated with the less active enantiomer of ABT-737. A greater than 50% decrease in intracellular GSH levels was seen with similar doses of ABT-737 and the combination of buthionine sulfoximine, an agent that depletes GSH levels further, with ABT-737, caused synergistic cell death. These data were verified using cells transfected with a tetracycline repressable Bcl-2 expression plasmid. Taken together, our data identifies a novel sequelae for Bcl-2 inhibition: the induction of oxidative stress. Combination therapies utilizing ABT-737 or its analogs may be devised based on the observed effects on the redox environment.
Imatinib Plus Vincristin & Prednisolone Induces Complete Remission and Prolonged Survival in Elderly Philadelphia Chromosome Positive Acute Lymphoblastic Leukemia Patients.
Authors: Mukhopadhyay Ashis , Mukhopadhyay Soma , Gupta Pinaki Ranjan , Roy Ujjal Kanti , Sinha Ajoy
Published: October 2019

Introduction: Acute lymphoblastic Leukemia (ALL) in elderly patients (50yrs or older) carries a poor prognosis. In survival studies using in variety of therapeutic regimens. This may be because of relatively high frequency of the Philadelphia chromosome (Ph). With the advent of dose intensive chemotherapy regimen such as hyper CVAD (Fractionated Cyclophosphamide, Vincristin, Doxorubicin, Dexamethasone) overall survival has not improved. The aim of our study was to see the effectiveness of Imatinib plus Vincristin & Prednisolone in Philadelphia Chromosome positive in elderly acute lymphoblastic leukemia patients.

Material & Methods: During period from January 2006 December 2006 we selected 10 consecutive elderly (more than 50yrs) Ph+ ALL patients in the haemato-oncology department Netaji Subhash Chandra Bose Cancer Research Institute. There were 4 males & 6 females. The median age of the patient was 64years (range 51 to 77yrs). All patients were started with Imatinib mesylate (Natco pharma) 400mg daily. Prednisolone was given 40mg /m2 over 6weeks & followed by 2weeks tapering dose. Vincristin was given 2mg/m2 weekly for 6weeks. All patients were evaluated by bone marrow and molecular testing done every 3monthly for 1year then 6monthly.

Result: All patients (100%) obtained complete haematological & partial molecular response at 3month. Three patient (30%) achieved complete molecular response at 9month. With median follow-up of 8months (range 6–15months) the disease free survival and overall survival were 80% & 90% respectively. Most of the induction treatment was done as OPD basis, no hospitalization required. The therapy was tolerated well.

Conclusion: We concluded that Imatinib plus Vincristin & Prednisolone is a feasible, highly active protocol for elderly Philadelphia Chromosome positive acute lymphoblastic leukemia patients. It is well tolerated & associated with good quality of life.
Histone Deacetylase Inhibitors as Adjuvants for the Differentiation of Dendritic Cell from Leukemic Blasts.
Authors: Moldenhauer Anja , Seeger Karl , Schmidt Kerstin , Kiesewetter Holger , Salama Abdulgabar
Published: October 2019

Purpose. Recurrent cytogenetic abnormalities in leukemic blasts make these cells an attractive source of dendritic cells (DC) for leukemia-specific immune therapies. The purpose of this study was the evaluation of different histone deacetylase inhibitors in their potential to enhance the immunogenicity of leukemic DCs.

Methods. Leukemic blasts from 96 patients with acute lymphoblastic leukemia were cultured in two different cytokine combinations and either SAHA, valproic acid, isobutyramide or trichostatin A. Immune phenotype, T-cell allostimulatory capacities and cytotoxic responses were determined in DC generated after culture for one and two weeks.

Results. 71 of 96 blasts developed a typical DC morphology with 55 showing an upregulation of CD83, HLA-DR and costimulatory molecules like CD80 and CD86. The allostimulatory potential of the leukemic DCs was not influenced by the addition of HdI. DCs generated with cytokines and SAHA or valproic acid from TEL/AML1-positive blasts of patients with a t(12;21) translocation induced blast-specific cytotoxic T-cell responses in HLA-A matched T cells. The DC differentiability of TEL/AML1-negative blasts was not diminished by the use of HdI.

Conclusion. Histone deacetylase inhibitors could be used for the development of a dendritic cell-based anti-leukemia vaccine.
Safety of Lumbar Puncture (LP) and Instillation of Intrathecal (IT) Chemotherapy during Thrombocytopenia in Adults with Acute Lymphocytic Leukemia (ALL).
Authors: Atallah Ehab , O’Brien Susan , Kaled Susan , Lynn Alice , Cortes Jorge , Kantarjian Hagop , Thomas Deborah A.
Published: October 2019

Background: The platelet (PLT) count at which LPs can safely be performed in adults has varied in practice. A few pediatric studies have suggested a threshold level of 10 K/μL above which prophylactic PLT transfusion is not required; however, this has not been systematically studied in adults with ALL. We therefore investigated the incidence of traumatic LPs (TLP >10 RBCs/μL), the incidence of complications, and the relationship to thrombocytopenia.

Methods: Adults with ALL undergoing frontline therapy with hyper-CVAD (fractionated cyclophosphamide, vincristine, doxorubicin, dexamethasone alternating with methotrexate and cytarabine) or variations incorporating rituximab and/or imatinib were reviewed. Patients (pts) were stratified to receive standard intrathecal treatment (IT) with methotrexate alternating with cytarabine based on CNS risk assessment (proliferative index ≥ 14% or serum lactate dehydrogenase ≥ 1400) [Cortes et al, Blood 86:2091, 1995]. Low risk pts received 6 IT, high or indeterminate risk 8 IT, and BLL 16 IT. Pts with PLT count ≤ 30 K/μL received PLT transfusions immediately prior to LP. Procedures were performed by trained practitioners.

Results: Outcome of 1998 LPs (282 pts) performed at our institution was reviewed. Median age was 42 years (range, 15–84). PLT count was ≤ 30 K/μL in 292 LPs (15%), 31–50 K/μL in 157 (8%), 51–80 K/μL in 211 (11%) and > 80 K/μL in 1338 (67%). Criteria for TLP was met in 910 (45%) of the LPs. The incidence of TLP was higher in patients with PLT count ≤ 50 K/μL (52% versus 44%, p=0.004). Four pts developed subdural hematomas. Of those, 3 had a history of CNS trauma, with only 1 considered possibly related to the LP. The latter occurred with PLT count of 28 K/μL prior to transfusion. Three pts developed diskitis or epidural abscesses after 3, 6 and 9 LPs, respectively, and were treated successfully with antibiotics.

Conclusions: Although the incidence of TLP appears to be higher with a lower PLT, it appears safe to perform LPs in thrombocytopenic pts with a threshold of 30 K/μL for prophylactic PLT transfusion as per our standard practice. However, this study does not address whether a lower threshold for PLT count (e.g., 20 K/μL) would yield similar findings.
Arsenic Trioxide Induce the Upregulation of β1-Subunit of Proteasome in NB4 Cell.
Authors: Wang Huaiyu , Zhang Mei , He Pengcheng , Chen Ying , Chen Limei , Lu Xiaohong
Published: October 2019

Arsenic trioxide has proven efficacy in inducing molecular remission in patients with acute promyelocytic leukemia (APL). The degradation of PML-RARα fusion protein induced by arsenic trioxide is related to its clinical efficacy in APL. The ubiquitin (Ub)/ proteasome pathway may involved in the degradation, but the mechanism in detail is unclear. In our previous study, we found that PSMB6 gene which encoded the β1-subunit of 26s proteasome was up-regulated after the treatment of arsenic trioxide (0.5 mmol/L). In current study, by western-blot analysis, we investigated the expression of β1-subunit of 26s proteasome after As2O3 exposure. We found that β1-subunit of 26s proteasome was upregulated after 24h treatment of As2O3(0.5 mmol/L). But the expression of β1-subunit of 26s proteasome return to baseline after 48h treatment. These findings are consistent with the results of the degradation of PML-RARα fusion protein. It is well known that the differentiation and apoptosis of NB4 cells are associated with the degradation of PML-RARα fusion protein and the reconstitution of the nuclear bodys (NBs). These results indicate that increase of β1-subunit of 26s may be associated with the degradation of fusion protein and the NB reorganization and play roles in the differentiation and apoptosis of NB4 cells. This pathway employs a complex enzymatic system to degrade proteins and whether other subunits are involved in the process is still unclear.
Gemtuzumab Ozagamicin Is Well Tolerated as Post-Consolidation Therapy in Childhood AML.
Authors: Hasle Henrik , Abrahamsson Jonas , Clausen Niels , Forestier Erik , Gustafsson Göran , Heldrup Jesper , Hovi Liisa , Jahnukainen Kirsi , Jonmundsson Gudmundur , Palle Josefine , Zeller Bernward
Published: October 2019

The NOPHO-AML 2004 protocol includes a post-consolidation randomization to Gemtuzumab ozagamicin, (GO, Mylotarg) or no further therapy. Randomization is offered to all standard-risk patients and to high-risk patients without a donor for SCT. GO is administered as a 2-hour infusion of 5 mg/m2 at least four weeks after the last consolidation including high-dose cytarabine and etoposide (HA2E). GO is repeated following a scheduled interval of three weeks. By August 2007 a total of 45 patients have been randomized (39 with standard-risk and 6 with high-risk AML). An additional nine patients were eligible but not randomized due to clinical decision (n=2), parental refusal (n=6), or administrative error (n=1). Twenty-three were randomized to receive GO. Detailed toxicity data were available from 21 of these patients. The median age was 3 years (six patients less than 2 years of age) at the time of GO. The median interval from HA2E to first GO was 32 days (range 27 – 43). The median interval from first to second GO was 22 days (range 20 – 28). All randomized patients received the second GO except one who relapsed shortly after the first infusion. No major events were reported in relation to the infusion. ALAT showed a slight elevation from a median baseline of 64 U/L to a median peak of 82 U/L and bilirubin increased from a median baseline of 5 μmol/L to a median peak of 8 μmol/L; highest value 25 μmol/L. No patients showed signs of VOD. No significant decrease in hemoglobin was observed whereas all patients became severely leukopenic (median nadir WBC 0.6) and neutropenic (median nadir ANC 0.1). Recovery to ANC > 0.5 lasted a median of 14 days (range 0 – 21). Fever needing antibiotic treatment occurred following 8 of 40 GO courses. None of the infectious episodes were life-threatening. Only a modest decline in platelet count was noted, median nadir 77 (range 10 – 239). Platelet transfusion was given following 5 of 40 GO courses. In conclusion GO infusion was well tolerated without clinical liver toxicity. Severe neutropenia was common but antibiotics were necessary following only 20% of the courses. Thrombocytopenia was modest.
Evaluation of the Expression of MDM2 & CD44v6 in Hodgkin’s Lymphoma.
Authors: El-Sebaaie Amr Farag , Youssef Samya Ahmed , Hassan Osama Abed El-Fatah , Aggina Hala Adel , Zafer Nehal Saad , El-Slam Mahmoud Slah Abed
Published: October 2019

Owing to the advances made in the fields of immunology and molecular biology, identification of biological factors with potential factors with potential prognostic signficance in HL were tried aiming to prevent primary resistance or relapse with as efficient first-line of treatment as possible . biological markers as cell cycle molecules (MDM) and adhesion molecules (CD44V6) were studied in current research on 100 cases of already diagnosed HL of different subtypes using specific monclonal antibodies and Envision detection kit as a staining system. The 100 cases studied comprised 70 males and 30 females, in a ratio of 7:3. The cases were retrived from files of pathology department, El-Maddi Hospital, cairo, Egypt from 1990–2000. The age ranged between 11–68 years with mean age in males of 40.8+/− 13.39 years in males and 35.8 +/− 18.9 in females. Cases were reclassified according to WHO classfication, 2002. Follow up period of 5 years was obtained from files of all patients including 2-years free disease and 5 years overall survival. In 53% of cases studied (53/100) a variable proprtion of H&RS cells expressed MDM2 that was strictly confined to the nuclei, particularly the nucleoplasm, while 30% (30/100)of the studied cases expressed CD44V6 as membranous staining with a variable proprtion In H&RS cells. A significant staistical correlation between expression of MDM2& CD44v6 with both age groups (P<0.05 & P<0.001) and subtypes of HL (P>0.05 & P>0.001) respectively were found. An inverse signficant stastical correlation between MDM2 expression and both 2 years free and 5-years free survival (P> 0.001 & P<0.001) was detcted. also a same relation was seen and both prognostic parameters (P>0.001 & P< 0.001) respectively. A strong signficant correlation between MDM2 and CD44V6 immunoreasctivites was expressed (P< 0.001). Our findings suggest that combined use of MDM2 and CD44v6 could be powerful prognostic factor in both presdiction of relapse and overall survival.
High Prevalence of Chronic Health Conditions in Survivors of Hodgkin Lymphoma Treated during Adulthood.
Authors: Matasar Matthew J. , Butos John N. , Riedel Elyn R. , Ford Jennifer S. , Weinstock David M. , Oeffinger Kevin C. , Straus David J.
Published: October 2019

Background: An increased risk of morbidity, including second primary malignancies and cardiovascular disease, has been reported in survivors of Hodgkin lymphoma (HL) diagnosed during adulthood. However, in contrast to our understanding of the late effects of treatment of children with HL, the global burden of chronic morbidity among long-term survivors of adult-onset HL is poorly characterized.

Methods: We conducted a survey-based cohort study of patients treated as adults with protocol-based first-line therapy for HL at our center from 1975 to 2000. The protocols included 6 combined modality trials (CMT) of chemotherapy (CT) + radiation therapy (RT), with the exception of a single CT-only arm in 1 trial. Chronic health conditions were assigned severity scores based on a modification of the Common Terminology Criteria for Adverse Events, version 3 (grades 1 through 4, ranging from mild to life-threatening or disabling).

Results: Of 707 patients for whom follow-up was available, 517 were alive. Median survival was 29 years. Survey data were available from 169 patients, with a median time from last treatment to interview date of 21 years. Of responders, median age at interview was 48 years (range, 25–88) and median age at treatment was 29 years (range, 16–66). Fifty percent were women, and 96% were white, non-Hispanic. Self-reported chronic health conditions were very common in our cohort: 94% of respondents reported any chronic health condition, and 60% described chronic health conditions that were grades 3 or 4 in severity (Table 1). Frequently reported conditions included cardiovascular, musculoskeletal, endocrine, and psychiatric disorders. Sixty percent of patients reported grade ≥1 cardiovascular dysfunction (20% ≥grade 3), 40% grade ≥1 musculoskeletal (7% ≥grade 3), 71% ≥grade 1 endocrine (17% ≥grade 3), and 23% ≥grade 1 psychiatric (21% ≥grade 3). Second primary malignancies were reported by 23%, and infectious conditions by 34%. Additional data collection on surviving and deceased patients is ongoing.

Conclusions: These results document the high prevalence of chronic illness among survivors of HL treated as adults. Evidence-based guidelines built upon such data are needed to aid clinicians in the management of the late morbidities associated with HL treatment.

Table 1. Chronic health conditions among adult-onset Hodgkin lymphoma survivors, according to severity score. Health Condition Frequency (%) Conditions by grade No condition 10 (6%) Grade 1 17 (10%) Grade 2 41 (24%) Grade 3 67 (40%) Grade 4 34 (20%) Any condition Grades 1–4 159 (94%) Grade 3 or 4 101 (60%) Multiple health conditions ≥Grade 1 ≥2 conditions 142 (84%) ≥3 conditions 120 (71%) ≥Grade 2 ≥2 conditions 111 (66%) ≥3 conditions 72 (43%) ≥Grade 3 ≥2 conditions 50 (30%) ≥3 conditions 19 (11%)
Coexistence of Two Distinct Histological Subtypes of Follicular Lymphoma and Burkitt’s-Like Lymphoma in the Single Lymph Node: A Case Report and Literature Review.
Authors: Nagoshi Haruhisa , Miyamoto Kou , Sano Fumiaki , Kyou Aki , Nishio Yuji , Miura Ikuo , Koike Junki
Published: October 2019

Transformation to a high-grade lymphoma occurs in approximately 20% to 30% of cases of follicular lymphoma, usually to diffuse large B-cell lymphoma and small cases to Burkitt’s or Burkitt-like lymphoma, are reported. This transformation from follicular lymphoma to Burkitt’s lymphoma, namely the mechanism of the acquisition of c-MYC gene to tumor cells already immortalized by BCL2, are not completely understood. Case: A 49-year-old man visited our hospital because of high fever and generalized lymph node swelling for several weeks. The WBC count was 20x109/l including 60% of Burkitt-like blasts. Immunophenotype was positive for CD10, CD19 and CD20. FISH analysis with IGH/BCL2 probe set and sprit signal of 5′c-MYC /3′c-MYC showed positive for 79.3% and 3.9%, respectively. Needle biopsy of the bone marrow (BM) consisted of cells large non-cleaved lymphocytes arranged diffusely. Immunophenotype was positive for CD10, CD20, CD45LCA, CD79a, and strongly positive for MIB-1 by immunohistochemistry. FISH analysis of BM cells was performed as same way of peripheral blood (PB), and the result showed similar findings with peripheral blast cells. Excision biopsy of the neck lymph node showed effacement of architecture with the presence of 2 distinctive components in absolutory separated with each other. The first component consisted of follicles, some showing predominance of small-to medium-sized cells, termed centrocyte. The second consisted of large non-cleaved cells, known as centroblasts. The follicular lesion was positive for CD10, CD20, CD79a and BCL2 by immunohistochemistry. On the other hand, the diffuse component, the Burkitt-like lesion, was positive for CD10, p53 and strongly positive for MIB-1, but negative for CD20, CD79a and BCL2. The diagnosis was interpreted as a follicular lymphoma, grade 2, composite a Burkitt-like lymphoma in a diffuse pattern in the single lymph node. After he underwent 2 courses of chemotherapy, he relapsed in the cerebrospinal fluid. Inverted cells showed positive for CD10, CD19 but negative for CD20 and CD79a. FISH analysis of inverted cell was strongly positive for IGH/BCL2 and sprit signal of c-MYC, 98.8% and 98.5% respectively. Mukhopadhyay et al. reported the first case of the transformation of follicular lymphoma to Burkitt-like lymphoma within a single lymph node (Human Pathol. 2005, 36, 571). One study of transformed follicular lymphoma, 8% harbored c-MYC translocations (Blood 1992, 80, 756). We estimated that major gene expression was IGH/BCL2 with harbored c-MYC translocations in lymphoma cells and in a subset of follicular lymphoma, the gain of a c-MYC translocation confers an additive oncogenic stimulus and gain the inhibition of apoptosis by BCL2 combined with the cell growth activity by c-MYC.
High-Dose Dexamethasone Reduces Bortezomib-Induced Thrombocytopenia.
Authors: Quach Hang , Prince Miles H. , Honemann Dirk , Westerman David , Milner Alvin D. , Barron Austin , Harrison Simon
Published: October 2019

Introduction: Bortezomib (B)-induced thrombocytopenia is a well documented adverse event; platelet nadir occur typically around day 10–12 of B therapy. The exact mechanism remains unknown but is not associated with reduced/abnormal marrow megakaryocytes. We postulated that corticosteroids could modulate the impact of B on the platelet budding, release or survival.

Method: A retrospective analysis was performed on patients with relapsed or refractory multiple myeloma, treated with B (1.3mg/m2 IV bi-weekly q3 weeks) ± Dex (20mg/d on day of, and day after, bortezomib) at our Institute between February 2005 to February 2007. Data was abstracted regarding patients’ baseline characteristics, platelet count at the beginning, at nadir, and the percentage of platelet reduction as well as the number of platelet transfusions with each treatment cycle. Comparisons of these parameters between the two groups were performed using the two-sample t-test.

Results: Forty one patients received a median of 4 cycles (range 1–10) of B ± D. Seven patients had dex only episodically with different cycles of B, and were excluded from analysis. Of the remaining 34 patients, 16 pts had a total of 75 cycles with dex, and 18 pts had a total of 65 cycles without dex. Baseline characteristics were similar in both groups including age, stage of disease, percentage of bone marrow plasma cell infiltration and mean platelet count prior to cycle 1 (196 × 109/l in the B+Dex group vs.160 × 109/l in the B without Dex group; p=0.27). Patients who received dexamethasone had a higher mean platelet count at the start of each new cycle (217 × 109/l vs. 171 × 109/l; p=0.002), a higher nadir platelet count (149 × 109/l vs. 88 × 109/l; p<0.001) and a lower mean platelet reduction (33% vs. 51%; p<0.001) per treatment cycle. Patients who did not receive dex required more platelet transfusions (p=0.004); on average 1 adult pool platelet per treatment cycle. Those who required transfusions had lower baseline platelets at the beginning of cycle 1.

Conclusion: Bortezomib induces a reduction of platelets by approximately 50% and concurrent Dex administration reduces both the incidence and depth of bortezomib-associated thrombocytopenia, resulting in a subsequent reduction in platelet transfusion requirements. We believe that dexamethasone is likely having an effect on either platelet release or survival through anti-apoptotic mechanisms at the megakaryocyte or platelet level, or by enhancing platelet survival. Clearly further studies are required to investigate the underlying mechanisms. We recommend the concurrent use of dexamethasone for patients with low baseline platelets being treated with bortezomib.
Neuropathy in Multiple Myeloma Patients Treated with Bortezomib: A Multicenter Experience.
Authors: Caravita Tommaso , Petrucci Maria Teresa , Spagnoli Alessandra , Siniscalchi Agostina , Offidani Massimo , Federico Vincenzo , Falco Patrizia , Rizzo Manuela , Palumbo Antonio , de Fabritiis Paolo
Published: October 2019

INTRODUCTION: Bortezomib (B) is the first proteasome inhibitor to be used in clinical practice and has been recently approved for second line treatment of multiple myeloma (MM) patients(pts). Several trials demonstrated that Bortezomib is relatively well tolerated; however, manageable non-hematologic and hematologic toxicity has been reported. The dose limiting toxicity is peripheral neuropathy (PN), reported up to 35% of the patient population.

AIM: We evaluated the incidence and severity of PN in 179 MM patients that received B as single agent or in combination.

MATERIAL AND METHODS: Patients characteristics were as follows: median age was 66.7 years (range: 32–82) with 52% male; 55 patients were at the onset of the disease, 124 were pre-treated. Median time from diagnosis to treatment with B was 25.4 months (range 0–111), median value of β2-microglobulin was 3.02 (0.2–20). Risk factors for PN included prior use of thalidomide in 68 patients (38%), vincristine in 75 patients (41.8%) and 15 patients (8.8%) had diabetes mellitus.

RESULTS: Patients received bortezomib alone (?) or in combination with either dexamethasone (n=52), or chemotherapy (n=114) or thalidomide (n=38). Overall, the response rate (≥PR) was 86%. PN of grade ≥2 was observed in 73 pts (41%); grade 3–4 occurred in 32 (18%). Median time to the onset of bortezomib-related PN was 84 days (range, 10–449) after bortezomib initiation. In most cases (93%), patients had sensory symptoms, while 5 patients (7%) experienced both sensory and motor symptoms. Bortezomib-related PN led to therapy discontinuation in 31 pts (17%). For PN treatment, pts received mostly supportive therapy (analgesics, gabapentin, pregabalin, amitriptyline and vitamin supplements). Of the 31 patients with bortezomib-related PN that required discontinuation, resolution or improvement occurred in 16 (51.6%), at a median time of 140 days (range, 27–346) from B discontinuation. Data analysis of the PN risk factors (age, diabetes, sex, β2M, neurotoxic pre-treatment) showed a significant association with age >75 years (p<0.013) and a trend with thalidomde pre-treatment (p=0.07); noteworthy, PN risk was not increased in pts treated with bortezomib and thalidomide in combination. Furthermore, responses were independent to PN.

CONCLUSIONS: In our experience, PN is a relatively frequent side effect of bortezomib treatment, generally manegeable by dose reduction or discontinuation and reversible in the majority of pts. Patients with advanced age can be considered at higher risk, while the combination of thalidomide and bortezomib did not increase the risk of PN. Further studies are needed to better define the PN pathogenesis and develop optimal strategies to improve the B related PN management.
Non-Myeloablative Allogeneic Stem Cell Transplantation (NMT) Overcomes the Adverse Effects of Treatment Resistance and High Beta-2-Microglobulin in Patients with Mantle Cell Lymphoma (MCL): An Analysis of 123 Transplantations at the MD Anderson Cancer Center.
Authors: Tam Constantine S. , Ledesma Celina , Korbling Martin , Fayad Luis E. , Wang Michael , Alousi Amin , Hosing Chitra , Kebriaei Partow , Rondon Gabriela , Giralt Sergio A. , Anderlini Paolo , Popat Uday , Couriel Daniel , Pro Barbara , Samuels Barry , Hagemeister Frederick , Champlin Richard E. , Khouri Issa F.
Published: October 2019

BACKGROUND: MCL remains incurable with cytotoxic therapy, but may be susceptible to immune-based modalities. Since the availability of NMT(1997) and rituximab(1999), we have employed the following risk-adapted strategy: patients (pts) in first remission after one chemotherapy (REM1) were offered autologous SCT (ASCT) with high-dose rituximab (R), and pts beyond REM1 were offered NMT if a donor was available, and ASCT+R if not. In order to assess the success of this strategy, we analyzed the results of 17 years of MCL transplantation at our center, including ASCT pts transplanted without R as historical controls.

METHODS: 52 pts in REM1 (ASCT1) and 36 pts beyond REM1 (ASCT2) received ASCT with (43%) or without (57%) R, and 35 pts beyond REM1 received NMT with fludarabine, cyclophosphamide & R. ASCT1, ASCT2 and NMT pts were balanced for age, Ann-Arbor stage, B-symptoms, LDH and B2m, but NMT pts were more heavily pretreated (p=0.01) and were further from initial diagnosis (p=0.02) than ASCT2 pts.

RESULTS {ASCT}: 96% & 91% of ASCT1 & ASCT2 pts were in CR following transplantation. Chemoresistance was an important determinant of ASCT outcome, with ASCT1 pts experiencing superior median PFS (42 v 27 months, p=0.009) and OS (94 v 52 months p=0.01) than ASCT2. B-symptoms and B2m≥3.0mg/L adversely affected OS in both ASCT groups. There was a trend to improved PFS for the 20 ASCT1 pts who received R, with no events in 10 pts followed between 24 to 94 months, compared with a continuous pattern of progression in non-R pts (p=0.06). {NMT}: 94% of pts were in CR after transplantation, and the 42 month current-PFS was 57%. In contrast to the ASCT pts, OS following NMT was not affected by high B2m, although B-symptoms remained significant (p=0.03). Despite all pts being transplanted beyond REM1, a plateau in survival was evident with no deaths occurring among 11 pts followed between 46 to 98 months (figure). Actuarial non-relapse mortality (NRM) at 90 days, 12 months and 2 years were 0%, 13% and 20% respectively. Neither the stem cell source (related 69% v unrelated 31%) nor a history of previous autologous transplantation (n=6) had a significant impact on NMT outcome (p>0.30 for PFS, OS and NRM).

CONCLUSIONS: These results suggest that ASCT is most effective in pts transplanted in REM1, in whom the addition of R may have improved PFS. NMT is effective in overcoming the adverse impact of prior chemotherapy and high B2m, and remains the modality of choice for pts beyond first remission.

Figure Figure
Organ-Specific T Cell Receptor Repertoire in Target Organs of Murine Graft-Versus-Host after Haploidentical Bone Marrow Transplantation.
Authors: Fu Yue Wen , Wu De Pei , Chen Feng , Feng Yu Feng , Chong Wei Rong , Zhu Zi Ling , Zhu Ping
Published: October 2019

Objective Haploidentical bone marrow transplantation (Haploidentical-BMT) usually has high morbidity and mortality associated with the early complication of SCT and severe GVHD. GVHD-associated T-cell clones can be identified in GVHD-affected tissues. In our study, Murine CB6F1(H-2b/d, [male]) and C57BL/6(H-2b, [female]) haploidentical-BMT GVHD model was established and proved a novel method to study the characteristics of T cell receptor repertoire in target organs of murine GVHD and research the molecular characteristics of T cell receptor BV complementarity determining region3 (TCRBV CDR3) repertoires of these monoclonal T cells in liver, skin and ileum.

Methods Murine haploidentical BMT model was established, RT-PCR was used to amplify 24 subfamily genes of TCRBV from liver, skin, ileum, spleen and kidney, PCR products were further analyzed by genescan to evaluate the clonality of BV subfamily and characteristics of CDR3, monoclonal bands were obtained thorough denaturation polyacrylamide gel electrophoresis and sequenced. A group of CDR3 molecules were obtained from GVHD-target tissues.

Results GVHD occurred as early as days 14 and was proven by histology in liver, skin and ileum. After BMT, it emerged a number of new monoclonal and oligoclonal T cells in GVHD-target tissues, while kidney was not affected by GVHD and infiltrated by polycolnal T cell. 48 TCRBV CDR3 molecules of monoclonal T cells which obtained from liver, skin, ileum in different times after BMT have six C’-terminal motifs(TEVFF, DTQYF, YEQYF, A EQ (Y F/FF), QNTLY F, AE T L Y F)and use restricted JB genes(JB1.1, JB2.5, JB2.7, JB2.1, JB2.4, JB2.3).

Conclusion Through murine haploidentical BMT GVHD model, TCRBV CDR3 was detected in GVHD-target tissues (liver, skin, ileum) and found that it emerged a number of monoclonal or oligoclonal T cells which associated with the development of GVHD and existed conserved CDR3 motifs.
Reduced Intensity Allogeneic Transplantation Provides High Disease-Free and Overall Survival in Patients (Pts) with Advanced Indolent NHL and CLL: CALGB 109901.
Authors: Shea Thomas C. , Johnston Jeffrey , Walsh William , Farag Sherif , McCarty John , Bashey Asad , Isola Luis , Stewart Marc , Kelly Michael , Owzar Kouros , Linker Charles
Published: October 2019

Reduced intensity allogeneic stem cell transplantation has been used increasingly to treat patients with both aggressive and indolent diseases such as low grade NHL and CLL. Most reports have consisted of single institution or registry data. We report here a prospective Cooperative Group study by CALGB in which 45 patients were treated at 11 CALGB institutions.

Methods: Patients < 70 years of age with a matched sibling donor and recurrent or refractory low grade NHL or CLL, high-risk CLL in first remission, mantle cell lymphoma or prolymphocytic leukemia were eligible. Patients were required to have CrCl > 40, DLCO > 40%, RNEF > 30% and LFTs < 3 × ULN. Disease must have been stable or responsive to the most recent previous therapy. The preparative regimen included 30 mg/m2 fludarabine × 5, and 1 gm/m2 cyclophosphamide × 3. The graft was G-CSF mobilized PBSC, and tacrolimus and low-dose MTX (5 mg/m2) on days 1,3,and 6 was used for GVHD prevention. Tacrolimus was tapered from day +90 to +150 in the absence of GVHD. Standard infectious disease prophylaxis, supportive care, and G-CSF from day +5 to engraftment were employed. DLI was given for stable or progressive disease, not loss of chimerism alone.

Results: 47 pts were enrolled with 44 eligible and evaluable; median age 53; 23 NHL, 14 CLL, 2 PLL, 4 mantle cell and one unknown. 27% developed ≥ grade 2 acute GVHD and 47% (18% extensive) chronic GVHD. TRM at 6 months was 2% and was 7% overall. Mortality at 2.6 year f/u is 25% due to GVH, sepsis, or 2nd malignancy (9%) and progressive disease (7 pts,16%). Estimated 2 yr DFS is 71% (CI 54–82) and OS is 76% (CI 60–87). Grade 4 AEs included 4 pneumonia/ pneumonitis, 1 PE, 1 VOD and 1 second malignancy (pancreatic CA). Documented infectious events included 32% viral, 41% bacterial, and 20% fugal. For T cell (CD3), the median chimerism at day 180 was 98% and 99% in peripheral blood and bone marrow; > 90% chimerism was present in 64% and 66% respectively. For unfractionated, the median chimerism at day 180 was 99% and 98% in peripheral blood and bone marrow; > 90% chimerism was present in 65% and 70% respectively.

Conclusion: These encouraging results indicate that a high CR and DFS rate can be obtained with low TRM without use of anti-CD20 therapy in a Cooperative Group trial of matched related allogeneic transplant in patients with low grade NHL or CLL. Appropriate patients should be considered for such therapy when standard treatments are no longer capable of achieving prolonged remissions.

Overall and Disease-Free Survival Overall and Disease-Free Survival
Marked Improvement of Skin Involvement in Severe Progressive Systemic Sclerosis after Transplantation of Mesenchymal Stem Cells from an Allogeneic Haploidentical Related Donor.
Authors: Christopeit Maximilian , Schendel Marit , Mueller Lutz Peter , Keyszer Gernot , Behre Gerhard
Published: October 2019

Introduction. Mesenchymal stem cells (MSC) show immunosuppressive capacity in an allogeneic host. Severe progressive systemic sclerosis (SSc) is an autoimmune disease in which prognosis is worsened in individuals presenting with diffuse cutaneous, lung and renal involvement. Immunosuppression can improve the course of the disease.

Methods. We transplanted a 41 year old female patient suffering from diffuse cutaneous systemic sclerosis with MSC from her father after in vitro expansion of the MSC.

Results. The patient presented with a remarkable clinical response. Her ulcer surface decreased, the 17 Site Modified Rodnan Skin Score, vascular ultrasound, mouth aperture, the Visual Analogue Scale for pain (VAS), the Valentini Activity Score and the Hannover Functional Questionnaire showed encouraging improvements. The patient did not experience any adverse events during the first 300 days after transplantation.

Conclusions. The transplantation of MSC from a haploidentical donor into a patient with systemic sclerosis is feasible, safe and effective. Furthermore is the transplantation of MSC from a haploidentical donor into an adult without severe pharmacological immunosuppression at the time of transplantation feasible and safe.
Bone Marrow Sinusoidal Endothelium Undergoes DNA Damage and Repair Following Lethal Irradiation.
Authors: Li Xiao-Miao , Hu Zhongbo , Jorgenson Marda L. , Wingard John R. , Slayton William B.
Published: October 2019

In the light of the possibility that adult bone marrow cells possess hemangioblast ability, work from our laboratory demonstrates that the bone marrow sinusoids remain predominantly host-derived following bone marrow transplant when ionizing irradiation is used as the conditioning regimen. To determine the effect of lethal irradiation to the host sinusoidal endothelial cells, we performed four apoptosis related assays and two cell proliferation assays on bone marrow sections at various time points during the first two weeks post-irradiation. We found:

Phosphorylated H2AX was present in both hematopoietic and sinusoidal endothelial cells. However, only hematopoietic cells showed caspase-3 dependent apoptosis. Three days after radiation, some sinusoidal endothelial cells became TUNEL (Terminal deoxynucleotidyl transferase-mediated dUTP nick end labeling assay) positive, but were activated caspase-3 and ISOL (in situ oligo ligation assay) negative, suggesting non-apoptotic DNA fragmentation. TUNEL positive endothelial cells were present in non-transplanted irradiated bone marrow 7–13 days post-irradiation while after 7 days, there were almost no TUNEL positive endothelial cells in transplanted animal, demonstrating that donor cells support sinusoidal endothelial survival. In some endothelial cells, TUNEL signal was concentrated in discrete areas of the nucleus, suggesting a repair process that involves the localization and removal of damaged DNA fragments. Very few sinusoidal endothelial cells were Ki67 positive and even fewer were BrdU positive, demonstrating that endothelial cell division is not a major mechanism for the survival of bone marrow sinusoidal system after irradiation on the short term.

These results demonstrate that sinusoidal endothelial cells undergo DNA damage and repair after lethal irradiation for bone marrow transplant. These results may explain, in part, why patients with impaired DNA damage/repair mechanisms have engraftment defects.