bluuebunny/crossref_metadata_2025_split huggingface dataset:
Complete Cytogenetic Response in a Case of T-PLL with a Complex Karyotype after Treatment with Alemtuzumab.
Authors: Marinato André F. , de Oliveira Fábio Morato , Jácomo Rafael H. , Rizzatti Edgar G. , Falcão Roberto P. , Rego Eduardo M. , Tone Luiz G. , Simões Belinda P. 
Published: October 2019

Abstract
T-prolymphocytic leukemia (T-PLL) is an aggressive T-cell leukemia characterized by the proliferation of prolymphocytes with a mature postthymic T-cell phenotype and commonly involves the blood, bone marrow, lymph nodes, liver, spleen, and skin. Leukemic cells appear as small to medium-sized prolymphocytes or small variant cells, occasionally with cerebriform nuclei. T prolymphocytes are CD2+, CD3+, and CD7+ and may express CD4+CD8−, CD4+CD8+, or CD4−CD8+ markers. The most frequent chromosomal abnormalities are t(14;14)(q11;q32), inv(14)(q11q32), t(X;14)(q28;q11), i(8)(q10), and t(8;8)(p12;q11). Although patients treated with conventional chemotherapy generally have a poor prognosis, alemtuzumab (Campath®) has been associated with good clinical responses in patients with T-PLL. Routine cytogenetic analysis to determine the response to alemtuzumab has not been performed in patients with T-PLL. This study reports the complete cytogenetic remission achieved following alemtuzumab treatment in a single patient with T-PLL. The 41-year old male patient presented with weight loss, night sweats, diffuse lymphadenopathy and hepatosplenomegaly, in the absence of any skin rash. Peripheral blood counts were: platelets 128 x 109/L and leukocytes 93.6 x 109/L, and hemoglobin values were 12.5 g/dL. The lymphocytes were mostly medium-sized with round to irregular nuclei; some cerebriform cells were also observed, with intermediate chromatin, single evident nucleoli, and a basophilic cytoplasm. Human T-cell lymphotrophic virus-1 serology was negative. Immunophenotypic studies showed CD2+, CD3+, CD5+, CD7+, CD4−, CD8+, CD1−, terminal deoxynucleotidyl transferase-negative (TdT-), and T-cell receptor a/b+. Classic cytogenetics and spectral karyotyping (SKY) were performed and an abnormal karyotype was observed in 18 metaphases analyzed: 46, t(X;14)(q28;q11), t(Y;14)(q12;q11), r[i(8)(q10)]. These abnormalities have not been previously reported in cases of T-PLL. The patient then underwent chemotherapy with CHOP, and subsequent therapy with fludarabine. The patient was then treated with alemtuzumab, 30 mg twice a week, for a total of 7 doses. The patient achieved complete clinical, hematological, and cytogenetic remission, characterized by lack of symptoms, reduction of lymph nodes, liver, and spleen size to normal volumes, and the disappearance of prolymphocytes from peripheral blood. Cytogenetic studies performed 7 months after treatment by classic cytogenetics and SKY revealed a karyotype of 46,XY[20]. This study is the first to demonstrate a complete cytogenetic remission following treatment with alemtuzumab in a patient with T-PLL that was refractory to standard chemotherapy. This is especially impressive in a patient with a complex karyotype and with different cytogenetic alterations not previously described.
Acquired Extramedullary Resistance to Dasatinib Due to Selection of Philadelphia-Positive Lymphoblast Clone Harboring a T315I BCR-ABL Gene Mutation: Reversal by Dose Escalation and Hydroxyurea.
Authors: Lundan Tuija , Gruber Franz , Hoglund Martin , Simonsson Bengt , Knuutila Sakari , Porkka Kimmo 
Published: October 2019

Abstract
Most patients with advanced Philadelphia-positive (Ph+) hematologic malignancies develop resistance to imatinib. Acquired resistance to imatinib is commonly a result of selection for subclones bearing point-mutations in the catalytic kinase domain of BCR-ABL. Dasatinib (BMS-354825), a dual-specific SRC/ABL kinase inhibitor, has shown activity in imatinib-resistant Ph+ diseases both in vitro and in vivo. Preliminary data also indicate efficacy in patients. Based on laboratory evidence, dasatinib appears to inhibit all known BCR-ABL mutant clones, with the exception of T315I, a gatekeeper mutation conferring resistance to several kinase inhibitors. Here we describe a Ph+ ALL patient, who initially developed imatinib resistance (hematologic) possibly due to BCR-ABL amplification (FISH). His disease relapsed as extensive extramedullary tumors bearing wild-type BCR-ABL. He received dasatinib 70 mg BID as part of the BMS CA180–015 study and achieved a very good partial remission. After 5 months of therapy, the disease relapsed as a solitary axillary tumor and several small palmar skin lesions. He also had blasts in the CSF indicative of neuroleukemia. Bone marrow remained in cytogenetic remission. FISH analysis of the tumor revealed 2–3 copies of BCR-ABL as previously. A highly sensitive, quantitative, mutation-specific PCR (Gruber F, ASH 2004) showed the presence of the T315I mutation, which was confirmed by sequencing. A very low level of T315I transcript was also detected in the blood. Dasatinib dose was escalated to 100 mg BID, and low-dose hydroxyurea 500 mg BID was initiated to putatively enhance the access of dasatinib in the CSF sanctuary. He also received two doses of i.t. therapy (methotrexate, cytarabine). Patient’s symptoms (confusion, headache) related to neuroleukemia resolved rapidly, skin lesions disappeared and axillary tumor decreased in size. He is currently symptom-free and has no signs of active ALL. The favorable response to dasatinib dose escalation and low-dose hydroxyurea was unexpected. Preclinical data on T315I mutant cell lines would argue against a significant concentration dependence in kinase inhibition by dasatinib. Putatively, targets other than BCR-ABL may be of importance in particular in Ph+ ALL (e.g. Src, Lyn), and this effect may account for the response. Similar off-target activity of hydroxyurea is utilized in clinical trials to overcome resistance to multidrug HIV therapy - a setting resembling current treatment of Ph+ malignancies with kinase inhibitors.
Assembling the Players for Evaluation of Anti-Leukemic CTL Activity in NOD-SCID Mice.
Authors: Hsu Andy K.W. , Kerr Beverley M. , Lock Richard B. , Hart Derek N.J. , Rice Alison M. 
Published: October 2019

Abstract
Acute Lymphocytic Leukemia (ALL) patients, who relapse after hematopoietic stem cell transplantation, have a poor prognosis with few therapeutic options. An immunotherapeutic approach that enhances the graft versus leukemia effect post transplant may improve the survival of relapsed patients. We postulate that dendritic cells (DC) derived from cord blood CD34+ stem cells will be ideal for this. Further we propose the use of RNA as a source of antigen to induce T cell responses to poorly immunogenic tumours, such as ALL. We have shown that CD34+ cells can expand and differentiate into DC and are functional antigen presenting cells. In addition, we regularly achieve >90% transfection efficiency with >90% cell viability when CD34+-DC are electroporated with eGFP mRNA. Electroporation of CD34+-DC with flu mRNA results in processing, translation and presentation of epitopes by the DC, which are recognised by flu-specific cytotoxic T lymphocytes (CTL). We have induced anti-leukaemic CTL with leukaemic total RNA from the HLA-A2+ NALM-6 cell line. We have established a NOD-SCID mouse model of primary human ALL to test the efficacy of the anti-leukaemic CTL in vivo. Mice engraft within 4–6 weeks of transplantation. Mice transplanted with ALL3 had 93.9±0.8% (BM) and 84.3±4.7% (spleen) CD45+cells at sacrifice. Mice transplanted with ALL7 had 79.1±5.5% and 89.9±1.2% CD45+ cells in the BM and spleen respectively. Cells from the BM and spleen have been cryopreserved and total RNA extracted for later CTL generation. Experiments aimed at replicating the minimal leukaemia burden post transplant, show that the kinetics of appearance of human cells in the blood and the time of palpable splenic engraftment relates to the cell dose. This suggests that while the leukaemic burden is low, the kinetics of growth are identical and thus, by varying the inocula we model emerging relapse. Thus, we have “assembled the players” and are ready to test the efficacy of anti-leukaemic CTL generated by stimulation with RNA loaded CD34+-DC to control in vivo leukaemic growth.
Granulocytic Sarcoma (GS) as First Manifestation of AML.
Authors: Khalil Maged , Malik Tamer , Mousa Albeir , Kalavar Madhumati , Fogler Richard , Stephen Lichter 
Published: October 2019

Abstract
Granulocytic sarcoma (GS), or chloroma is an extramedullary tumor of immature myeloid cells which occurs throughout the body, often associated with acute myeloid leukemia (AML) or in the accelerated phase of chronic myelogenous leukemia, but rarely as the first manifestation of AML, preceding the onset in marrow and blood by months or years[1, 2] Herein, we report GS of lymph nodes presenting as first manifestation of AML
Case Report
A 53 years old male presented with recurrent episodes of epigastric abdominal pain without history of trauma or infections, Physical examination was normal. Laboratory examination showed WBC 5.2, ANC 4.4, Hemoglobin 13.6 gm/dl, PLT.306, 000 and Retic 1.8. Computerized Tomography (CT) of abdomen and pelvis showed extensive abdominal and pelvic lymphadenopathy, gastric wall thickening and prominence of the pancreatic head versus peripancreatic lymphadenopathy. Subsequently Esophagogastroduodenscopy and colonoscopy were both negative for malignancy. Peripheral smear showed normal RBC, and no myeloblasts. Laparoscopic retroperitoneal lymph node biopsy revealed granulocytic sarcoma, with immunohistochemistry positive for CD43, CD117, CD68 and MPO
Bone marrow biopsy and aspirate were performed, showing increased M: E ratio, increased blasts (29%), with flow cytometry reporting positivity for CD13, CD33, CD34, CD117, and HLA-DR supporting the diagnosis of AML. Chromosomal analysis including Fluorescence in situ hybridization studies (FISH) showed no evidence of chromosomal abnormalities. Patient continued to have epigastric pain radiating to the back without fever, night sweats or weight loss.
He was treated with standard induction chemotherapy with Ara-c (7 days) and Idarubicin (3days), resulting in complete remission with resolution of the abdominal and pelvic lymphadenopathy.
Patient is currently receiving consolidation therapy with high dose Ara-c
Conclusion
Granulocytic sarcoma is a rare disease. The overall prognosis is poor. However, AML-type chemotherapy appears to improve survival.
Novel Therapeutic Approach Yields Excellent Results in Minimally Differentiated Acute Myeloid Leukemia (AML-M0): Time To Think out of the Box.
Authors: Banavali Shripad , Goyal Lovenish , Padhye Bhavana , Arora Brijesh , Bhagwat Roshni , Gujral Sumit , Nair Chandrika , Parikh Purvish 
Published: October 2019

Abstract
Background: AML M0 has dismal complete remission (CR) rates (<50% in most series) and poor long term survival with conventional combination chemotherapy (CT). Thus it is considered a candidate for allogenic bone marrow transplantation (BMT) in first remission and also for other novel therapeutic approaches. There is increasing recognition of angiogenesis as a pathogenic and prognostic factor in AML. The objective of our study was to evaluate the efficacy of low-dose oral metronomic CT in patients with AML-M0.
Materials and methods: Eleven patients fulfilling the diagnostic criteria for AML-M0 and ineligible for standard CT and/or BMT were accrued in this pilot protocol between June 1998 and Feb 2005. The treatment consisted of Prednisolone 40 mg/m2/d, Etoposide 50 mg/m2/d and 6-TG 40 mg/m2/d (PET), given orally on out-patient basis continuously for 21 days every month. Post-induction high dose Ara-C (HD-Ara-C) was given whenever possible.
Results: The median age was 17 yrs (range 1.5 to 52); 9 were males and 2 females. The median leukocyte count at presentation was 15.4 x 109/L (range 0.9 to 142) and platelet count was 62 x 109/L (range 21 to 442). CD56 and CD7 were positive in 3/5 and 8/11 of those evaluated. Cytogenetic studies were done in 7 patients. Ten of the eleven patients received at least 1 cycle of PET CT of which 9 (90%) achieved CR. The eleventh patient received only 1 week of CT before being lost to follow up, however by then she had already cleared all blasts (57%) in the peripheral blood. Importantly the whole induction was given on out patient basis with only 2 patients requiring admission. There was minimal to nil blood, platelet and antibiotic support required during the entire Induction therapy. Four of them received HD-Ara-C after achieving CR; two of them died in remission at 6 and 11 months. The other two are alive in CR at 36 months and 14 months. Others who could not get HD-Ara-C because of socio-economic reasons were continued on PET or ET chemotherapy for up to maximum of 12 cycles. The median overall survival was 20 months for those who continued treatment. So far no relapses are noted in those who received PET x 2 followed by HD-Ara-C.
Conclusions: The dramatic remission rates, excellent tolerability, minimal cost and morbidity with this protocol provide proof of principle that metronomic approach may be a superior alternative to conventional induction chemotherapy in the treatment of AML-M0. Additionally, incorporation of HD-Ara-C consolidation and metronomic maintenance may improve the long term outcome of this disease with dismal prognosis.
Prognostic Significance of Early Peripheral Blood Blasts Clearance Following Induction Chemotherapy for Adult Acute Myeloid Leukemia.
Authors: Pakkala Suchita , Winton Elliott , Langston Amelia , Heffner Leonard T. , Khoury Hanna J. 
Published: October 2019

Abstract
Early bone marrow blast clearance, defined by a remission marrow obtained on day 14 post-induction, is an independent prognostic indicator of CR, OS, EFS and RFS in adult AML. The prognostic significance of early peripheral blood blast clearance is unknown. We sought to evaluate the relationship between time to peripheral blood blast clearance post-induction and results of the day+14 bone marrow in a cohort of 100 adult AML patients homogeneously-treated at Emory University, between 1997 and 2004. Patients with acute promyelocytic leukemia were excluded from this analysis. In this cohort, median time to peripheral blood blast clearance was 5 days (range, 1–18). Patients were divided into 2 groups: early blast clearance (< 5 days; n=43; EBC) and delayed blasts clearance (≥ 5 days; n=57; DBC). Patient characteristics are summarized in the Table. EBC patients presented with a lower WBC (8.4 vs. 32.4) and LDH (99 vs. 389), but had comparable cytogenetic risks. Remission day+14 marrow, defined as a hypocellular marrow (<20%) with <5% blasts morphologically, was attained in 74% and 79% in the EBC and DBC groups, respectively. However, a trend for improved relapse-free and overall survival was observed in the EBC group. In conclusion, our analysis shows that early peripheral blood blasts clearance post-induction chemotherapy does not correlate with a remission day 14 marrow but may predict improved outcomes.
Patient Characteristics EBC DBC Number of patients 43 57 Gender, M/F 20/23 34/23 Median age (range), yrs 49 (23–86) 56 (18–79) Median WBC (range), μLx103 8.4 (0.4–278) 32.4 (0.4–763) Median LDH (range), U/L 99 (84–2700) 389 (59–2042) Cytogenetic Risk Groups Favorable 12% 18% Intermediate 59% 51% Unfavorable 26% 28% Unknown 5% 3% Remission day 14 Bone marrow 74% 79% Median DFS, months 22 18 Median OS, months 23 19
SNS-595, a Novel S-Phase Active Cytotoxic, Demonstrates Pharmacologic Properties Appropriate for the Treatment of Advanced Hematologic Malignancies.
Authors: Lawrence Chris E. , Arbitrario Jen P. , Kumer Jeff L. 
Published: October 2019

Abstract
Despite advances in the treatment of leukemia patients, response rates with intensive chemotherapy regimens remain less than 30% for relapsed or refractory acute leukemias and advanced chronic myelogenous leukemias. SNS-595, is a novel naphthyridine analog small molecule, a class of drugs not previously used in cancer treatment. SNS-595 acts specifically during the S-phase of the cell cycle to induce rapid apoptosis of cells that are actively synthesizing DNA, and a subsequent cell cycle arrest in the G2 phase of the cell cycle. Sunesis Pharmaceuticals, Inc., is developing SNS-595 for the treatment of both solid and hematologic malignancies. SNS-595 was previously evaluated in two models of hematologic cancer in nu/nu mice, causing a dose-dependent tumor growth inhibition (97% to 99%, n=6 mice per treatment group) in a LM-3 Jck (human acute lymphoma) hematologic xenograft. All 6 mice treated at 30 mg/kg had a major reduction in tumor volume, with 2 mice showing a complete response. SNS-595 also significantly inhibited tumor growth in mice bearing CCRF-CEM (human acute lymphoblastic leukemia) xenograft tumors. In phase I clinical trials in solid tumors the dose-limiting toxicity was neutropenia, and the incidence of gastrointestinal effects, nausea, and vomiting was low. No mucositis or peripheral neuropathies were observed. In the present study, CD1 mice (n=4 per treatment group) were administered either SNS-595 15 mg/kg or 20 mg/kg, by IV bolus on days 0 and 4, or the S-phase acting drug, cytarabine (Ara-C) 150 mg/kg, BID, by IP injection on days 0 and 4. SNS-595 was well tolerated, with no body weight loss observed through to day 16. Bone marrow isolated from the femurs showed a dose-dependent reduction in cellularity on day 6, 48hr after the second of the two SNS-595 administrations; at 15 and 20 mg/kg, cellularity was reduced to 15% (±2.9, n=4) and 7.5% (±1.4, n=4) respectively. SNS-595, 20 mg/kg, reduced absolute neutrophils to a nadir of 51 ±24 cells/μL blood (n=4) on day 8, from 1244 ±55 cells/μL at day 0 (n=4), but subsequently rebounded to normal levels by day 16. Total WBCs also reached a nadir on day 8, returning to normal by day 16. In the same timeframe cytarabine caused bone marrow ablation, with absolute neutrophil counts substantially reduced at day 8 and returning to normal by day 16. In conclusion SNS-595 has significant anti-tumor activity in hematologic xenografts, as well as significant ability to reversibly ablate murine bone marrow cells. These properties, combined with the good clinical safety profile observed in phase I patients, suggest that SNS-595 has the potential to demonstrate anti-tumor activity in patients with hematologic malignancies.
Relapse Free Survival of Elderly AML Patients Is Comparable to That of Younger Adults When Treated with a Modified Dose Intensive Cytarabine Regimen.
Authors: Langston Amelia A. , Heffner Leonard T. , Hutcherson Donald , Neely Jessica , Flowers Christopher , Waller Edmund K. , Lonial Sagar , Khoury Hanna J. , Winton Elliot 
Published: October 2019

Abstract
Introduction and Methods: Despite the development of new targeted therapies for treating AML, cytarabine (Ara-C) remains the most reliably effective agent, particularly when given in high dosage (HIDAC). The outcome of AML therapy in pts > 60 years of age remains dismal with slightly more than half of pts achieving remission, and < 15% becoming long term survivors. Elderly pts do not tolerate typical HIDAC regimens because of cerebellar and other toxicities, so we have employed a modified HIDAC regimen: Ara-C 2 gm/m2/day over 4 hours once daily on days 1–6, combined with daunorubicin 45 mg/m2 days 2,3,4 for induction. Consolidation consisted of one cycle of the same chemotherapy followed by two additional cycles of mHIDAC alone, unless the pt went on to autologous or allogeneic HPCT. We report a single institution experience with 59 consecutive pts ≥ 60 y/o (including 20 pts ≥ 70 y/o), and compare outcomes with 139 similarly treated pts < 60 y/o. Excluded were pts with antecedent MDS or chemotherapy-related AML, APL, and pts with major organ dysfunction.
Results and Discussion: The CR rate for pts age ≥ 60 was 66% vs 81% for those < 60 (p=0.02). The distribution of pts into cytogenetic risk categories was similar, except for an under-representation of good risk cytogenetics among older pts (3% vs 14%, p=0.025). Overall survival for older pts was worse than that for younger individuals primarily due to an excess of early deaths, however, disease free survival among complete responders was similar for the 2 age groups (see below). There were 11 (16%) early deaths within 60 days among older pts, 4 with residual leukemia and 7 during aplasia. Early death occurred in 7 (5%) of the younger pts, 2 with residual leukemia and 5 during aplasia. There were 4 deaths (3 infectious and 1 stroke) during consolidation, 3 in the older and 1 in the younger group. There were also 2 late deaths in remission (both older pts) which were unrelated to AML or therapy. Clinically significant cerebellar toxicity was observed in 4 (6.8%) of the older pts and 3 (2%) of the younger pts, for a total of 7 episodes associated with 535 courses of Ara-C delivered (1.3%). 60% of older pts were able to complete 2 or 3 courses of consolidation therapy. Our data confirm the challenges of treating older pts with AML, but suggest that a significant subgroup can tolerate and benefit from aggressive therapy which includes dose intensification of Ara-C. This mHIDAC regimen is effective and well tolerated, and repeated administration to older pts is feasible.
Overall Survival Overall Survival Relapse-Free Survival Relapse-Free Survival
Improved Survival of Lymphoma Patients after Introduction of Rituximab.
Authors: Dillman Robert O. , Chico Sherri 
Published: October 2019

Abstract
In a previous intramural study using tumor registry data, we found no difference in survival for all 222 patients diagnosed with low-grade (LG) or intermediate-grade (IG) non-Hodgkin’s lymphoma (NHL) during 1980–1989 compared to all 404 such patients who were diagnosed during 1990–1999 (ASH 2002). However, the anti CD20 monoclonal antibody rituximab, which was introduced in 1998, has been associated with improved survival in randomized trials of patients with intermediate grade B cell lymphomas. In this study we carried out two analyses. The first compared relative survival for 368 Hoag lymphoma patients diagnosed during 1995–2000 (median age 65 years) to national data from the Surveillance Epidemiologic and End Result (SEER) program. The 5-year relative survival rate for Hoag patients compared to SEER was 72% vs. 59% for 1995–2000, in sharp contrast to the relative 5-year survival rates observed during 1989–1994 which were only 46% for Hoag lymphoma patients vs. 51% for SEER. The second comparison was for observed survival for all 362 Hoag patients with LG or intermediate-grade IG B cell NHL, who were diagnosed during 1998–2003 (median age 65, 105 deaths), compared to 352 Hoag patients with LG or IG B-cell NHL, who were diagnosed during 1990–1997 (median age 63, 175 deaths). The respective 5-year survival rates were 58% vs. 51% (p=.032, 2-tailed log-rank test). We conclude that survival has improved for Hoag patients with lymphoma both by intramural historical comparisons and extramural contemporary comparisons. Improvement took place during the time that rituximab was adopted as standard therapy at Hoag, and suggests that the survival benefits that have been observed in randomized trials are also taking place in the general population of B cell lymphoma patients.