bluuebunny/crossref_metadata_2025_split huggingface dataset:
ERBB Expression in Philadelphia Chromosome-Positive ALL as a Potential Therapeutic Target.
Authors: Hughes Dennis P.M. , Tracy Jeannette L. , Lee Kenneth E. , Zhang Pingyu , Estrov Zeev , Chandra Joya 
Published: April 2020

Abstract
Philadelphia chromosome-positive ALL (Ph+ALL) strikes older children and adults, is difficult to treat and often has poor outcomes with conventional therapies. Tremendous advances have been made in other cancers through identification of essential signaling molecules that can be inhibited by small molecule medicines. ERBB proteins are such targets for several adult carcinomas, including breast and lung cancer. Expression of one member of the ERBB family, Her-2, is associated with chemotherapy resistance in one report of adult B-ALL. We examined the expression, activation status and contribution to growth and survival of ERBB receptors in Ph+ALL cell lines Z33, Z119 and Z181. Phosphorylated Her-2 was detected by western blot in all 3 lines, as was trace amounts of Her-3. Western-blot identified expression of the p80 form of Her-4 in Z119, which correlated with flow cytometry assessment of Her-4. Expression in Z33 of EGFR, detected by western blot, correlated with down-regulation of both EGFR and Her-2 from the cell surface, as assessed by flow cytometry. Internalization of EGFR homo- and hetero-dimers is associated with receptor phosphorylation and active signaling. To assess the physiologic importance of ERBB signaling in Ph+ALL, cells were cultured in the pan-ERBB inhibitor CI-1033 (Pfizer Global Research and Development), which is specific for ERBB family receptors in tissue culture up to 20 μM concentrations. All lines demonstrated reduced cell yield after CI-1033 exposure, with average IC50 of 0.783 for Z119, 1.178 for Z181 and 1.737 for Z33. The increased sensitivity of Z119 to CI-1033 correlated with an increased rate of apoptosis: 3 μM CI-1033 caused a 26% increase in the fraction of sub-diploid Z119 cells at 24 hours, compared to 13% for Z181 and 16% for Z33. Higher sensitivity to ERBB inhibition also correlated with growth factor resistance, since Z33 and Z181 are dependent upon autocrine GM-CSF for growth while Z119 grows independent of known autocrine secretion of hematopoietic growth factors. These data suggest that Ph+ALL cells may acquire GM-CSF independence by relying more on ERBB-derived signals, since these receptors are capable of activating similar second messenger pathways. Our data suggest that, surprisingly, the ERBB family of receptor tyrosine kinases are intact and functioning in Ph+ALL, and inhibition of these signals may provide benefit to Ph+ALL patients, either in combination with imatinib or in patients who develop imatinib resistance.
Anti-Leukemic Effect of Maintenance Chemotherapy Is Mediated by Induction of Differentiation.
Authors: Lin Tara L. , Matsui William , Vala Milada S. , Brennan Sarah , Smith B. Douglas , Jones Richard J. 
Published: April 2020

Abstract
The clinical benefit of maintenance therapy (prolonged post-remission low-dose therapy) has been limited to two diseases, acute lymphocytic leukemia (ALL) and acute promyelocytic leukemia (APL), despite extensive study in many malignancies. Moreover, the mechanisms responsible for the anti-leukemic effects of maintenance therapy in both ALL and APL are unclear. Maintenance therapy in ALL consists of the low-dose cytotoxic agents methotrexate (MTX) and 6-mercaptopurine (6MP), while maintenance therapy in APL has primarily been all-trans-retinoic acid (ATRA). Interestingly, the addition of low-dose MTX and 6MP to maintenance ATRA has recently been shown to improve disease-free survival in APL. These clinical results, combined with our recent data and that from others showing that low-dose cytotoxic agents are potent differentiating agents, suggest that these agents may induce the differentiation of leukemic progenitors responsible for disease relapse. Therefore, we examined the differentiating effects of ATRA and low-dose MTX and 6MP on human APL and ALL cells. The APL cell line NB4 was treated with ATRA (1 μM), MTX (0.01 μM) and 6MP (1 μM) for 48 hours and then analyzed for apoptosis, clonogenic growth and surface expression of the myeloid differentiation antigens CD11b and CD15 by flow cytometry. As expected, ATRA did not induce immediate apoptosis, but inhibited clonogenic growth associated with markedly increased expression of both myeloid antigens, consistent with induction of terminal differentiation. Both MTX and 6MP had similar effects on the NB4 cells, and, thus, similarly appeared to induce terminal differentiation rather than cytoxicity. We then examined the effects of these agents on two ALL cell lines: REH, which is derived from pediatric ALL and contains the t(12;21) chromosomal translocation producing the TEL-AML1 fusion protein, and RS4;11, which is derived from adult ALL and contains the t(4;11) chromosomal translocation producing the MLL-AF4 fusion gene. ATRA, MTX and 6MP induced upregulation of CD19 and CD38 surface antigen expression. Similar to their effects on the NB4 APL line, the agents also inhibited clonogenic growth of the ALL cells without induction of immediate apoptosis. ATRA, MTX, and 6MP produce similar effects on APL and ALL cells in vitro. These results suggest that low-dose MTX and 6MP used as maintenance therapy improve clinical outcomes in ALL and APL by inducing the terminal differentiation of leukemic progenitors responsible for disease relapse. As the addition of low-dose MTX and 6MP has improved the results of maintenance ATRA in APL, the addition of pharmacologic differentiating agents such as ATRA to MTX and 6MP may improve ALL therapy, particularly for adults.
The Effect of Early High Dose Ara-C in Children with High-Risk Acute Lymphoblastic Leukemia (ALL): Tokyo Children’s Cancer Study Group (TCCSG) Study L99-15.
Authors: Manabe Atsushi , Ohara Akira , Ikuta Kouichiro , Hanada Ryouji , Yabe Hiromasa , Kinoshita Akitoshi , Koike Kenichi , Okimoto Yuri , Noguchi Yasushi , Kajiwara Michiko , Takahashi Hiroyuki , Sugita Kanji , Fukushima Takashi , Isoyama Keiichi , Saito Masahiro , Kikuchi Akira , Ota Setsuo , Kumagai Masaaki , Hayashi Yasuhide , Saito Tomohiro , Tsuchida Masahiro 
Published: April 2020

Abstract
High dose Ara-C is employed in the treatment of acute myeloid leukemia; however, its effect on ALL has not been evaluated systematically. We tested high dose Ara-C incorporated in an early phase with a randomized fashion in children with high-risk ALL. Patients diagnosed as ALL between 1999 and 2003 were consecutively enrolled on TCCSG L99-15 study. Risk stratification was based on the age, initial white blood cell count, immunophenotype, cytogenetics, and the response to prednisolone monotherapy. Totally, 317 out of 770 children (41%) were categorized in a high-risk group. A standard-risk group constituted 35% and a very high-risk group constituted 24% of all the patients. Induction treatment consisted of a standard 4-drug regimen plus cyclophosphamide. Remission was obtained in 310 patients (98%). After remission was obtained, patients were randomized to receive either early intensification regimen A or B: regimen A consisted of high-dose cytarabine (2g/m2 x 8 times with L-asparaginase); regimen B consisted of a combination of cyclophosphamide, cytarabine (75mg/m2 x 15 times), and 6-mercaptopurine. Then all the patients were given an identical treatment including high-dose methotrexate (3g/m2 x 3 times), reinduction therapy, late intensifications, and maintenance therapy. The treatment was completed 24 months after diagnosis. The number of patients randomized in each arm was 155 cases for each arm. Clinical features including immunophenotype, specific karyotype, and the response to prednisolone monotherapy were not different in patients allocated in each arm. The median follow-up for patients who survived at the time of the analysis was 3.2 years. Event-free survival (EFS) (SE) and overall survival (OS) (SE) at 4 years for the 310 patients were 78.4% (2.9%) and 88.9% (2.3%), respectively. EFS (SE) at 4 years for patients in regimen A and B were 77.0% (4.1%) and 79.7% (4.0%) while OS (SE) at 4 years in regimen A and B were 88.3% (3.2%) and 89.7% (3.2%). The site of relapse was not different in two arms. In 23 cases with T-cell phenotype, patients treated with regimen A did not have better EFS than the others. Similarly, in 25 cases with E2A-PBX1 rearrangement, patients treated with regimen A did not have better EFS than the others. Although no patients in either regimen died of infections, more patients in regimen A experienced bacterial sepsis: 13 cases in regimen A vs. 8 cases in regimen B. In conclusion, we did not find any benefit of employing early high-dose Ara-C in children with high-risk ALL.
Important Role of Routine Cerebrospinal Fluid Examination in Diagnosing Central Nervous System Relapse during Maintenance Therapy in Pediatric Acute Lymphoblastic Leukemia.
Authors: Lieberman Lani , Grant Ronald , Hitzler Johann K. , Gassas Adam 
Published: April 2020

Abstract
Despite the success of central nervous system (CNS) preventive therapy in reducing the incidence of CNS recurrence in pediatric acute lymphoblastic leukemia (ALL) on therapy, CNS relapse continues to be a significant cause of treatment failure and is observed in 5–10% of patients. While most pediatric ALL treatment protocols mandate periodic lumbar puncture (LP) surveillance for the length of therapy, some centers have stopped collecting routine CSF samples unless there are suggestive signs or symptoms of CNS involvement. Our objective herein was to assess the value of routine cerebrospinal fluid (CSF) obtained while performing routine LPs for administration of intrathecal chemotherapy in diagnosing CNS relapse in children with ALL in the maintenance phase.
Patients and Methods: All children (0–18 years) with ALL, diagnosed and treated at the Hospital for Sick Children, Toronto, Canada between 1994–2004 were subjected to a retrospective analysis. Original reports for CNS relapse during maintenance therapy were examined to determine whether CNS relapse was diagnosed based on routine CSF sample obtained while administering intrathecal chemotherpy or a CSF sample obtained based on signs and symptoms or after a diagnosis of a bone marrow relapse.
Results: Four hundred and ninety four children were diagnosed and treated in our institution during the study period. Children were treated based on the children oncology group (COG), pediatric oncology group (POG) and local protocols where applicable. Thirty-one children (6.3%) suffered CNS relapse while on maintenance therapy. Twenty-one had an isolated CNS relapse and ten had a combined bone marrow and CNS relapse. Seventy-six percent (16/21) isolated CNS relapses were diagnosed base on routine CSF samples obtained from asymptomatic children while administering intratheacal chemotherapy. Conversely, all patients with combined bone marrow and CNS relapse presented with symptoms and signs that warranted CSF examination.
Conclusion: Routine CSF examinations are important in detecting CNS relapse in children with ALL during maintenance therapy. Furthermore, routine CSF sampling may detect isolated CNS relapse in asymptomatic children with ALL prior to extension into combined relapse where prognosis is less favorable.
A Report of the Event Free Survival (EFS) for Children with Newly Diagnosed Standard Risk Acute Lymphoblastic Leukemia (ALL) Treated on Pediatric Oncology Group (POG) Protocol 9605.
Authors: Bell Beverly A. , Abish Sharon B. , Chauvenet Allen , Kurtzberg Joanne , Pullen Jeanette , Devidas Meenakshi , Shuster Jonathan , Camitta Bruce M. 
Published: April 2020

Abstract
POG 9605 opened in 1996, as a randomized 2x2 factorial design for children with standard risk ALL to determine: 1) whether the addition of 6 months of delayed intensification with divided dose oral methotrexate (ddMTX) improves the event free survival (EFS) and 2) the effect on EFS of delivering oral 6-mercaptopurine (MP) on a divided (twice daily) vs. once daily schedule, during delayed intensification and continuation. A total of 1063 eligible patients were randomized to the post induction therapy. Following remission induction, consolidation was defined as weeks (wk) 5–24 from diagnosis, and all patient received MTX 1 g/m2 IV over 24 hours q3 wks x 6 courses, with leucovorin rescue 10 mg/m2 p.o./IV q6h for 5 doses beginning 42 hours after the start of MTX infusion, oral MP 50 mg/m2/day, prednisone/vincristine (VCR) pulses, (prednisone 40 mg/m2/day x 7 days, with VCR 1.5mg/m2/dose (max 2 mg) IV days 1 and 8, on wks 8.17 and 25. Late intensification was defined as wks 25–52. Patients were randomized to the following regimens: 1) MTX 20 mg/m2 IM q wk, MP 75 mg/m2 p.o. qhs, 2)ddMTX 25 mg/m2 p.o. q6h x 4 doses q2wks, leucovorin 5 mg/m2 p.o. q12h x 2 doses, (beginning 48 h after the start of ddMTX), MP 75 mg/m2 po qhs, 3)MTX 20 mg/m2 IM q wk, MP 37.5mg/m2 p.o. BID 4)ddMTX (as in regimen 2) MP 37.5 mg/m2 p.o. BID. All regimens received prednisone/VCR pulses wks 25, 41, 57, 73 89 and 105. Continuation therapy was defined as wks 53 to 130. All patients received MTX 20mg/m2 IM weekly. Reg 1&2: MP 75 mg/m2 qhs; Reg 3&4: MP 37.5 mg/m2/dose BID. CNS prophylaxis was age adjusted, initially with triple intrathecal chemotherapy (TIT), amended in 1999 to deliver IT MTX alone, and leucovorin rescue was subsequently added because of projected excessive neurotoxicity. The overall EFS for this study is 77%±1.6 %(s.e.) at 6 years. This study had a 2x2 factorial design to answer the two questions related to MTX and MP delivery, respectively. However, the results showed statistically significant interaction between the MTX and MP questions (P=0.0081). There were significant differences in EFS between the four arms (stdMTX-stdMP 70.7%±3.6%, ddMTX-stdMP 82.7%±2.9%, stdMTX-ddMP 80.7%±3.2%, ddMTX-ddMP 76.4%±3.2%), P=0.0141. Although ddMTX-stdMP and stdMTX-ddMP had significantly better EFS compared to the stdMTX-stdMP arm (P=0.005 and P=0.01, respectively), this was not designed as a four arm study and has insufficient power to determine which arm was superior.
Therapy-Related Myelodysplastic Syndrome (sMDS) /Acute Myelogenous Leukemia (sAML) in Acute Promyelocytic Leukemia (APL) Patients with Long-Lasting Molecular Remission: The GIMEMA Experience.
Authors: Latagliata R. , Breccia M. , Fazi P. , Gubbiotti S. , Di Bona E. , Specchia G. , Chiarenza A. , Murru R. , Carella A.M. , Ferrara F. , Rossi G. , Melillo L. , Sica S. , Invernizzi R. , Cimino G. , Petti M.C. , Avvisati G. , Lo-Coco F. , Mandelli F. 
Published: April 2020

Abstract
The occurrence of a sMDS in patients potentially cured from a previous APL has been recently reported. To evaluate the real incidence and the clinical characteristics of sMDS/sAML post APL, the follow-up of 336 patients with newly diagnosed APL enrolled by 22 GIMEMA Centers in the LAP AIDA 0493 protocol has been revised. After the induction, 314 patients (93.4%) achieved complete remission (CR): of them, 225 (71.6%) are still alive in 1st CR, 12 (3.8%) died in CR and 71 (22.7%) relapsed. The remaining 6 patients (1.9%) developed a sMDS while in 1st morphological CR, after a median time from CR achievement of 42 months (range 27 - 75). Among the 71 relapsed patients, 15 had no further data and 41/56 (73.2%) achieved a 2nd CR after salvage treatments: 2 of them (4.8%) developed a sMDS while in 2nd morphological CR, after 48 and 27 months from 1st CR, respectively. Furthermore, another patient showed a sMDS while in 3rd CR. As to clinical and biological characteristics of these 9 sMDS patients, there were 3 male and 6 female with a median age at sMDS diagnosis of 57 years (range 31 – 71): cytogenetic analysis failed in 2 patients, was normal in 1 patient and revealed abnormalities of chromosomes 5 or 7 in the remaining 6 patients, with a complex karyotype in 4 of them. One patient underwent allogeneic BMT soon after sMDS and is still alive after 57 months, 2 patients are in stable myelodysplastic phase after 25 and 63 months respectively. An evolution in sAML occurred in the remaining 6 patients, after a median sMDS duration of 7.6 months (range 2 – 45): 5 sAML patients received only supportive care +/− palliative chemotherapy, 1 patient underwent intensive chemotherapy but was resistant. All sAML patients died after a median time from AML evolution of 4 months (range 0.8 – 5) In conclusion, the incidence of sMDS post APL seems low in 1st molecular CR, but increases in patients achieving 2nd or subsequent CR: clinical characteristics and prognosis are similar to those observed in other sMDS. A longer follow-up will help us to define the late occurrence (&gt; 5 years from CR) of this severe complication. In addition, the availability of prognostic score systems at initial diagnosis and residual disease monitoring by PCR might allow better tailoring of treatment intensity in APL, in an attempt to spare unnecessary toxicity and minimise the risk of sMDS/sAML development for patients who have low risk disease.
A 3-Year Follow-Up of All-Trans Retinoic Acid (ATRA) and Arsenic Trioxide (As2O3) as Front Line Therapy for Newly Diagnosed Acute Promyelocytic Leukemia (APL).
Authors: Hu Jiong , Liu Yuan-Fang , Zhu Yong-Mei , Shi Zhan-Zhong , Li Jun-Min , Wang Li , Chen Yu , Shen Zhi-Xiang 
Published: April 2020

Abstract
PURPOSE: To confirm the potential benefit of front-line use of all-trans retinoic acid (ATRA) combined with arsenic trioxide (As2O3) in patients with newly diagnosed acute promyelocytic leukemia (APL) with prolonged follow-up to median of 3-year and compared with historical control.
PATIENTS AND METHODS: Two groups of newly diagnosed patients with APL were included in the analysis. The study group received combination therapy of ATRA and As2O3 includes 56 patients since April 2001. The historical control groups included 56 patients from May 1998 to March 2001. No statistically significant differences of clinical characteristics such as sex, age and hematological data were documented between two groups. For the study group groups, all patients received 25mg/m2 ATRA orally and 0.16mg/kg As2O3 intravenously per day till CR. Once CR achieved, they were given 3 courses of consolidation chemotherapy and then 5 cycles of sequential treatment of ATRA, As2O3 and 6-MP/MTX. For the historical group, the induction therapy was ATRA given at 25mg/m2 daily till CR and chemotherapy was added in case of leukocytosis. The post-remission therapy consists of chemotherapy with ATRA.
RESULT: In study group, 52 (92.9%) patients achieved CR and the time to CR was 26.4±4.5 days. At last follow-up at February 2005, only two patients underwent extramedullary relapse and one died from CNS leukemia while all other patients were alive and remained in hematological remission. With a median follow-up of 34 months (21 to 46 months), the 3-year OS and EFS were estimated as 97.4% and 93.5%. For the historical control groups, the median follow-up was 56 months (12 to 79 months). The 3-year estimated OS and EFS was 83.2% and 57.7% (P=0.069 and 0.00001 respectively). Of notice, in the last follow-up, all evaluable patients in clinical remission maintained a complete molecular response (undetectable PML-RARa via both regular and real-time RT-PCR).
CONCLUSION: Our 3-year follow-up data demonstrate a solid clinical benefit of front-line combination of ATRA and As2O3 in terms of EFS. There was also a trend toward improvement in OS which might translate into better chance of curing the disease.
Tolerability of Chemotherapy for AML or MDS in Children with Fanconi Anemia.
Authors: Mehta Parinda A. , Ileri Talia , Harris Richard E. , Williams David A. , Auerbach Arleen D. , Smith Franklin O. , Mo Jun , Smolarek Teresa , Kelly Patrick , Davies Stella M. 
Published: April 2020

Abstract
Fanconi anemia (FA) patients have a 33% cumulative incidence of AML by 40 years of age (Kutler et al, 2003). Chemotherapy treatment of FA patients with MDS or AML is challenging because of constitutional sensitivity to DNA-damaging agents. Severe toxicity and marrow aplasia without hematological recovery have been described, largely in case reports of children given chemotherapy prior to diagnosis of FA. The definitive treatment for hematological malignancy in FA is stem cell transplant (SCT). However, transplant in patients with overt AML has a poor prognosis and also a donor may not be immediately available. Relapse post-SCT is usually fatal. Between 2002 and 2005 we treated 6 children with FA and AML or hypercellular MDS with monosomy 7, referred to the Fanconi Anemia Comprehensive Care Clinic at Cincinnati Children’s Hospital, with a uniform chemotherapy protocol (“mini-FLAG”).
Figure Figure
Clinical characteristics of patients, toxicity and efficacy of mini-FLAG are shown below: 3 patients belonged to complementation group A and one each to group D1, J and F. Overall, mini-FLAG was well tolerated with no mucositis or organ toxicity. Two of the three patients with leukemia achieved clearance of blasts and cytoreduction was attained in those with MDS. In all cases, patients proceeded to SCT once cytoreduction was achieved so reconstitution of normal hematopoiesis and durability of response could not be assessed.
Table 1 Pt # Age / Gender Marrow cytogenetics Toxicity of mini-FLAG Marrow morphology pre-mini-FLAG Marrow morphology after mini-FLAG 1 16.3yrs/M 45,XY, t(2;3) No organ toxicity AML; 51% blasts No residual blasts; markedly hypocellular marrow 2 14.2yrs/F 47,XX, t(6;11) No organ toxicity AML; 80% blasts Hypoplastic; &lt;5% blasts 3 2yrs/M Complex karyotype including add(1)(q21),add No organ toxicity; reversible skin rash with Ara-C AML; 75% blasts Blasts reduced to 36%; marrow blasts cleared with daunomycin + Ara-C 4 13.7yrs/F 46,XX,del(7) No organ toxicity CMMoL; hypercellular Normocellular marrow; morphology still CMMoL 5 8.5yrs/M 46,XY,der(2)t(2;3)(q3?6;q?),der (7)del(7)(p11.2) No organ toxicity MDS; hypercellular; prominent abnormal monoblasts Hypocellular; minimal dysplasia 6 10.6yrs/F 45,XX,-7 No organ toxicity Mild dysplastic changes Hypocellular; Monosomy 7 in 13% of cells
Three children survive; one died of relapsed leukemia 4 months post-SCT and 2 of complications of SCT. These data show that mini-FLAG can be used with minimal toxicity and significant but heterogeneous responses in children with FA. A future prospective multi-center study is needed to optimize use of chemotherapy in FA and determine the effect of pre-transplant chemotherapy on outcomes of SCT.