bluuebunny/crossref_metadata_2025_split huggingface dataset:
Changes in the Immune Functions during ALL Induction Therapy - Prospective Immune Monitoring in 23 Children.
Authors: Wiegering Verena A. , Eyrich Matthias , Schlegel Paul G. , Winkler Beate 
Published: April 2020

Abstract
Introduction: Inadequate lymphocyte functions are an important clinical problem complicating chemotherapy by severe bacterial and fungal infections. During an ongoing immune response, cytokines produced by T-cells are critical to the effectiveness of that response. To understand what happens with the immune system in the beginning of therapy, we investigated lymphocyte subpopulations and functioning (cytokines, immunoglobulins).
Patients: 23 children (median age 5y;range 2m-14y;15 female, 8 male) with B precursor ALL were treated according to the ALL-BFM 2000 protocol. Blood samples were drawn at diagnosis and on days 8, 15, 33 and 64 and before beginning of protocol M, protocol 2 and during maintenance therapy.
Methods: We analyzed lymphocyte subpopulations using flow cytometry. Intracellular cytokines (IFNg, IL2, TNFa, IL4, IL5, and IL10) were determined by FACS after in vitro stimulation with PMA, ionomycin and brefeldin for 24h. Additionally, we measured various cytokines in unstimulated sera by ELISA. Furthermore, we studied TRECs and Spectratype values and immunoglobulins.
Results: As to lymphocyte subpopulations, B-cells decreased rapidly from a median value of 301+120/mm_ before chemotherapy to 85+138/mm_ during chemotherapy (“day 33”) and did not reappear until the end of therapy.
T cells decreased at the beginning of chemotherapy, but there was a partial recovery proportional to the intensity of chemotherapy. Also we found a shift towards CD8+ cells. NK cells did not show significant changes.
As to cytokines in CD3+ T-cells, we detected an increase of IFNg (diagnosis:11+9%, day 33: 22+7%). We could detect a correlation between gd-TCR and IFNg production (FACS) as well as IFNg values (ELISA) and high memory cell count. Also CD45RA+cells correlate with CD4IL2+cells. Finally TGFb in unstimulated sera correlated strongly (p&lt;0,01) with CD19+cells. TGFb was also produced by blasts. We detected difference in cytokine profile between conditioning with dexamethasone vs. prednisone, especially the IFNg secretion was much higher in the prednisone branch (p&lt;0,01). TREC values were higher in the dexamethason branch, but this might be due to the age, because younger children had significantly higher TREC values. Analyses of TCR repertoire show a slightly higher complexity in the prednisone branch. Until d15 the repertoire complexities were reduced and increase slowly continuingly during therapy. We could detect Vb gene families with high complexity during the whole therapy (for example BV22, BV23) and with low complexity (BV13b, BV6a). The complexity correlated positively with the number of naïve T-cells and with the age (p&lt;0,01).
Summary: We detected a shift towards Th1-cytokines during ALL-induction-therapy. B cells were erased during chemotherapy. This might be of clinical importance of the possible necessity of prophylactic immunoglobulins to prevent serious infection because of the lack of B-cells.
Multi-Agent Phase I Trials in Childhood Acute Lymphoblastic Leukemia (ALL).
Authors: Sposto Richard , Raetz Elizabeth A. , Reynolds Charles P. , Gaynon Paul S. 
Published: April 2020

Abstract
Background: Single agent phase I trials with conventional methodology may not be suitable for children with relapsed leukemia. Accrual of children with ALL in relapse to single-agent phase I trials is poor due to clinical urgency and a &gt; 30% likelihood of complete response (CR) with a variety conventional agents combinations (Br J Haematol.2005; 131(5): 579) with the option of hematopoietic stem cell transplant in remission. As most drugs are ultimately used in combination, a Phase I trial testing a new agent in combination with conventional agents would seem most useful and might increase accrual. However, with conventional phase I methodologies determination of a maximum tolerated dose is complicated by the toxicities of the accompanying conventional agents and by the background morbidity of relapsed leukemia.
Methods: The Children’s Oncology Group (COG) study, AALL01P2, employed vincristine, prednisone, doxorubicin, and pegylated asparaginase for children with ALL in first marrow relapse. We determined the incidence of conventional non-hematologic dose limiting toxicities (DLT’s) and modeled the impact on a hypothetical phase I trial of a candidate agent with no additional toxicity.
Results: Among 111 patients on AALL01P2, 19% had conventional non-hematologic DLT’s. Induction therapy was judged clinically acceptable. With a traditional Phase I escalation scheme that accepts 0/3 and 1/6 DLT’s at a dose-level and rejects 2/3 and 2/6 DLT’s, an agent that adds no morbidity would be rejected as too toxic at any dose 30% of the time.
Conclusion: Background morbidity confounds identification of an acceptable dose of a non-toxic new agent tested in combination with conventional drugs for recurrent ALL. We propose a modification to the traditional Phase I design that increases the DLT thresholds to 1/3 and 2/6, which effectively compensates for background toxicity and reduces the chance of falsely rejecting an acceptable agent.
A Phase I Study of Oral 6-Thioguanine, Followed by Continuous Infusion Cytarabine, Followed by Intramuscular PEG-Asparaginase (“TGAP”) in Children with Relapsed or Refractory Acute Leukemia or Non-Hodgkin’s Lymphoma.
Authors: Fu Cecilia H. , Franklin Janet L. , Gaynon Paul , McCarthy Colleen , Panosyan Edward , Siegel Stuart E. , Avramis Vassilios I. 
Published: April 2020

Abstract
Background: We found enhanced cytotoxicity against human leukemia cell lines resistant to cytarabine with the sequence specific three-drug combination, 6-thioguanine (6TG) + cytarabine + PEG-asparaginase (“TGAP”) [Fu et al, Cancer Chemother Pharmacol 48:123–133, 2001] and developed a Phase I study to evaluate TGAP’s feasibility in children with relapsed/refractory leukemia or non-Hodgkin’s lymphoma with marrow involvement.
Patients and Methods: Three days of twice daily 6TG was followed by cytarabine @ 487 mg/m2 loading dose and 126 mg/m2/hr by 72-hour continuous infusion. Cytarabine was followed by pegylated asparaginase @ 2,500 units/m2. Complete response (CR) required fewer than 5% marrow blasts with recovery of neutrophils and platelets. Partial response required marrow blasts between 5% and 25% with no peripheral blasts.
Results: Between April 1999-January 2006, 11 patients, age 1 to 18 years, were enrolled after local IRB approval and individual or parental informed consent. Six patients had relapsed/refractory ALL, 4 patients had relapsed ANLL (2/4 had Down syndrome) and 1 patient had relapsed Burkitt’s lymphoma/leukemia. Six patients were enrolled at dose level #1 (6TG @ 100mg/m2/dose) and 5 patients were enrolled at dose level #2 (6-TG @ 150mg/m2/dose). The last patient enrolled was later found ineligible, but was included for toxicity. Chemotherapy was well tolerated in 9 patients. All patients developed grade 3–4 neutropenic fevers or bacteremia. Other grade 3–4 toxicities included transient elevations in transaminases. Asparaginase related pancreatitis occurred in two patients, in one with symptoms. Dose limiting acute vascular leak syndrome occurred in two patients at dose level #2 during the cytarabine infusion and just after the completion of therapy. Both required mechanical ventilation but recovered fully. Complete responses (CR) occurred in 2 of 10 evaluable patients and partial response (PR) occurred in 2 for total response rate (CR + PR) of 40%. All four responders tolerated a second course of TGAP. Both CR patients subsequently underwent matched unrelated BMT with no veno-occlusive disease or other excessive toxicity. In one CR patient, ara-CTP incorporation in the patients leukemic blasts ex vivo studied at baseline, pre chemotherapy, and repeated after 6TG and a 24-hour infusion of cytarabine showed a four-fold increase in intracellular ara-CTP, confirming our previous work in cell lines.
Conclusions: TGAP is a feasible combination for patients with relapsed leukemias. A phase II study is currently under development using the maximum tolerated dose for 6TG of 100mg/m2/dose in combination with CI ara-C and IM PEG-asparaginase.
Hypersensitivity Reaction of Gemtuzumab Ozogamicin (Mylotarg™) Associated with Platelet Transfusion: Two Case Reports.
Authors: Hanbali Amr , Wollner Ira , Neme Klodiana , Ulreich Cynthia 
Published: April 2020

Abstract
Introduction
Gemtuzumab ozogamicin (Mylotarg™) is a monoclonal antibody developed for the treatment of myeloid leukemias. Mylotarg is composed of a recombinant humanized IgG4 kappa antibody conjugated with a cytotoxic antitumor antibiotic, calicheamicin. It binds specifically to the CD33 antigen, which is expressed on the surface of leukemic myeloblasts and immature normal cells of myelomonocytic lineage. It is approved for the treatment of CD33 positive AML in first relapse in patients &gt;= 60 years of age and are not considered candidates for cytotoxic chemotherapy. Hypersensitivity reactions, including anaphylactoid reactions, anaphylactic shock, dyspnea, and severe hypotension, have been reported during clinical use of gemtuzumab ozogamicin. Infrequently, hypersensitivity reactions have been fatal. It is unknown if the risk of hypersensitivity reaction increases with administration of blood products in the same day of Mylotarg infusion. We are reporting 2 cases of severe hypersensitivity reaction to Mylotarg on 2 patients who received platelete transfusion in the same day.
Case reports:
Case number 1: A 75 year old male diagosed with AML with normal cytogenetics in April 2005. Relapse was noted in March 2006. He was admitted for Mylotarg infusion at a dose of 9mg/m2 which was started at 11:00 a.m. after receiving the appropriate premedications and finished at 1:00 p.m. without any signs of distress or reaction. He received 6 units of platelets at 6:40 p.m. At 1:00 a.m. the next morning he went into severe respiratory distress and died shortly after that in the ICU.
Case number 2: A 68 y/o male with the history of NHL in 1991, received CHOP chemotherapy in 1991 and 1992, now has secondary AML (diagnosed in October 2005 and underwent chemo in November 2005, and relapsed after induction and consolidation. He was admitted for Mylotarg infusion. Initially he received 6 units of platelets at 8:30a.m. Mylotarg was started at 10:15a.m. and finished at 12:10p.m.No signs of distress or reaction post infusion. At 2:30 p.m. the patient started having chills, rigors with fever, tachycardia, hypertension and hypoxia (pO2 86%). The patient was treated with Solu-medrol, Benadryl, Tylenol and Demerol. The reaction ceased with no further adverse events
Conclusion:Mylotarg is known to cause hypersensitivity reaction, but it is unknown if the risk of this reaction increases with blood products transfusion around the time of Mylotarg transfusion. We are reporting these 2 cases to draw attention to this serious observation.
Treatment with Homoharringtonine and Cytarabine in Patients with High Risk Acute Myelogenous Leukemia (AML).
Authors: Chang Naibai , Wei Jianping , Zhao Shengming , Liu Hui , Fan Yun , Li Jiangtao , Xu Xiaodong , Gu Xichun 
Published: April 2020

Abstract
Objective: To evaluate response of homoharringtonine in patients with high risk AML or as a second-line therapy in patients with AML refractory to anthracycline based chemotherapy.
Patients and methods: From Jan 1998-Jan 2006, there were 66 patients enrolled in this regimen. Male:female=40:26. Median age was 47 (17–69). There were 48 newly diagnosed AML, 5 relapsed AML and 13 secondary AML (secondary to MDS) in this group. Among these patients, there were 40 patients untreated previously — 20 patients had unfavourable chromasomal abmormalities, 10 patients had pgp positive, 10 patients had normal chromasome but high CD34 expression on leukemic cells. The remaining 26 patients were previously treated with daunorubincin or mitoxantrane combined with cytarabine at least two cycles and failed to achieve response. Homoharringtonine was given at dose of 4mg/m2/d(2.5mg/m2/d for age≥60 years) intraveniously for 7 days. Cytarabine was given at dose of 100mg/m2/d at same time. The therapy was repeated every 21 days.Post remission therapy was divided into two cohot —same regimen maintainance in 20 cases and cytarabine 1g/m2/d q12h for 4 days at least 4 cycles in 20 cases.
Results: 40/66 patients achieved complete remission. 3/66 achieved partial remission. In patients refactory to anthracycline based regimen, the CR rate was 57.7%(15/26). In previously untreated high risk AML patients,the CR rate was 62.5%(25/40). Median disease free survival were 4.25 months (2–30) in cohot 1 and 18 months (12–47) in cohot 2 (P&lt;0.05). CD95(APO-1/Fas) was tested by flow cytometry during treatment. APO-1/Fas (CD95) increased from (9.56±5.58)% to (25.64±0.70)% after induction chemotherapy. Main toxicities were marrow suppression and infection. There were 7 early deaths, 5 patients died of cerebral hemorrage and 2 cardiovascular events.
Conclusions: Homoharringtonine is effective in patients with high risk AML. It is also a choice of second line therapy in patients refractory to anthracycline based chemotherapy. Intensive post remission therapy is superior to conventional dose maintainance therapy in high risk AML. One of the ways for homoharringtonine to induce leukemic cell apoptosis is probably through Fas pathway.
Salvage Therapy with Flag/Idarubicin/Mylotarg (Flag-IM) Results in a Superior CR/CRp Rate and Low Toxicity When Compared to Mitoxantrone/Etoposide/Cytarabine (MEC) in Patients with Relapsed and Refractory AML.
Authors: Van Tine Brian A. , Augustin Kristan M. , Kuperman David I. , Nervi Bruno , Westervelt Peter , DiPersio John F. 
Published: April 2020

Abstract
Salvage therapy for relapsed AML has been historically unsatisfactory. Response to salvage therapy for AML was investigated using a retrospective chart review of patients at the Siteman Cancer Center who failed standard induction therapy. We identified and studied 42 patients with relapsed (N=24) or refractory (N=18) AML who received either (33/42 patients) Mitoxantrone 8mg/m2, Etoposide 100 mg/m2, Cytarabine 1000 mg/m2 (days 1–5) (MEC) or (9/42 patients) Mitoxantrone 10 mg/m2, Etoposide 100 mg/m2 (days 1–5) (MV) as salvage therapy. 40/42 patients were evaluable for response by formal restaging after day +30. 13/40 entered a CR and 7/40 entered a CRp. Only 7/20 (35%) CR/CRp remained progression free with a median follow up of 5.3 months (range = 2–10 months). 6/7 who remained in CR/CRp received an allogeneic stem cell transplant and/or donor lymphocyte infusion after treatment. Median follow up for transplanted patients is 38 months with a range of 10–80 months. A similar analysis was performed on 16 patients with relapsed (N= 12) or refractory (N= 4) AML that received Fludarabine 25mg/m2, Cytarabine 2000 mg/m2, Idarubicin 12mg/m2 (days 1–5), G-CSF 5mcg/kg (day 1+), and Gemtuzumab 9 mg/m2 (day 8) (Flag-IM) for CD33+ AML. Only 15/16 patients were evaluable for response by formal restaging after day +30. Flag-IM treatment resulted in 12/15 patients achieving CR/CRp (6 CR, 6CRp). This group included 3 patients that had previously failed MEC or MV salvage therapy. 10/12 CR/CRp patients received allogeneic transplants (4 sib, 6 unrelated) and 5 (50%) are alive and disease-free with a median survival of 13.4 months (range2–27) months. In spite of a short median duration of only two months (range 1–4) from Flag-IM to allogeneic transplant, no veno-occulsive disease (0/10) was observed, and only 4/10 patients developed mild hyperbilirubinemia (range 1.3–3.8) after myeloablative conditioning for allogeneic transplant.
In conclusion, in this limited retrospective analysis, Flag-IM results in a superior CR/CRp rates when compared to MEC/MV (80% versus 50%) (p = 0.045 by 2 sided t-test) in patients with relapsed/refractory AML. Thirty day treatment related mortality after MEC/MV (2/42) and Flag-IM (1/16) were similarly low, as was VOD in patients receiving myeloablative allotransplant after Flag-IM (0/10). DFS after allogeneic transplant in those patients achieving CR/CRp after MEC/MV (6/20) and Flag-IM (4/10) (p=0.34) were similar. No patient survived greater then 10 months without allogeneic transplant. Flag-IM is an effective salvage therapy associated with acceptable toxicity in patients with relapsed refractory AML.
Differential Effects of Bexarotene on Intrinsic and Extrinsic Pathways in TRAIL-Induced Apoptosis in Myeloid Leukemia Cell Lines.
Authors: Ying Shao Xu , Li Xiao , Seal Sudeshna Seal , Abbassi Nissa , Pagel John M. , Gopal Ajay K. , Deeg H. Joachim 
Published: April 2020

Abstract
Tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) is an attractive candidate for cancer therapy since it induces apoptosis preferentially in tumor cells. However, not all human cancer cells are sensitive to TRAIL. Here, we show that a synthetic RXR-selective retinoid, bexarotene, overcomes TRAIL-resistance in KG1a leukemia cells (P&lt;0.001) by down-regulating FLIPLong and activating caspase-8, thereby triggering the extrinsic apoptotic signaling pathways. Over-expression of FLIPLong all but abolished apoptosis induced by TRAIL plus bexarotene. Bexarotene and TRAIL also showed an enhanced apoptosis-inducing effect in ML1 leukemia cells (P&lt;0.01), in this case, however, involving the intrinsic pathway with downregulation of Bcl-xL and cleavage of caspase-9. Blockade of caspase-8 almost completely prevented enhancement of TRAIL-induced apoptosis by bexarotene, while the RXR-specific antagonist HX531 failed to block apoptosis induced by TRAIL plus bexarotene in both KG1a and ML1 cells. These data indicate that the positive interactions between bexarotene and TRAIL involved the death ligand-dependent extrinsic pathway and were able to overcome TRAIL resistance. We conclude that bexarotene overcame resistance or enhanced the effects of TRAIL in both type I (KG1a) and type II (ML1) leukemic cell lines, apparently via downregulation of multiple antiapoptotic molecules, including FLIPLong, and Bcl-xL.
MMRI-23: A Potential Role in AML Antibody-Mediated Therapy.
Authors: Modra Courtney J. , Jamriska Lubomira , Rao Min , Clark Georgina J. , Hart Derek N.J. 
Published: April 2020

Abstract
Novel targets expressed on early AML precursor cell populations, with restricted expression on normal tissues, provide attractive options for antibody based therapeutics. We identified the CD300 family as Ig superfamily members with the capacity, through signaling motifs, to induce triggering and inhibitory signals to the leukocytes on which they are expressed. Here we report on an inhibitory member of this family, 35-L5, as a potential target for antibody-mediated therapy in AML. To assess its potential, we analyzed 35-L5 transcript and cell surface expression on normal blood cells, cell lines, and AML cells using quantitative RT-PCR and a monoclonal antibody (MMRI-23) made against a recombinant 35-L5 Ig fusion protein. RT-PCR showed its expression in normal PBMC was restricted to CD14+ monocytes, CD11c+ dendritic cells (myeloid DCs), monocyte derived dendritic cells (MoDC), with limited expression by B cells. MMRI-23 bound CD14+ monocytes, myeloid DC and MoDC, but not CD19+ B, CD4+ T, CD56+ NK cells and CD11c− (plasmacytoid) DC. Interestingly, MMRI-23 binding varied between donors and 35-L5 expression was upregulated on mature MoDC, when compared to immature MoDC from the same donor (3 from 6 donors). However, MMRI-23 binding to PBMC remained stable when cultured with activation agents PMA and ionomycin, LPS, or PHA for 24 and 48 hours. 35-L5 transcript and surface protein expression was evident in the monocytic derived U937, leukemic derived HL60, erythroleukemic derived HEL, CML derived K562, and B lymphoblast derived Daudi cell lines, but was limited in the KMH2 and HDLM2 cell lines and absent in the Jurkat, Raji, L428 and Mann cell lines. Preliminary studies in AML using quantitative RT-PCR showed that 35-L5 transcript was increased compared to control normal CD14 cell expression (n=9). Furthermore, MMRI-23 bound to 6 of 8 AML samples of the FAB M1, M2 and M5 subtypes. MMRI-23 crosslinking induced neither cell apoptosis, nor cell differentiation and change of CD14, CD33, CD64, CD16, CD11b expression. Defining the role of 35-L5 on normal and AML progenitor cells is necessary to evaluate its potential as a possible target for antibody-mediated therapy. MMRI-23 may have potential for drug conjugated antibody-mediated therapy, but 35-L5’s inhibitory function may also be exploited to develop a novel mechanism for controlling myeloid leukemias.
“Fulminant” Acute Promyelocytic Leukemia: Clinical and Biological Features.
Authors: Di Bona Eros , Ferrara Felicetto , Specchia Giorgina , Leoni Franco , Melillo Lorella , Falanga Anna , Rossi Giuseppe , Fazi Paola , Coco Francesco Lo , Mandelli Franco 
Published: April 2020

Abstract
Acute promyelocytic leukemia (APL) is associated with severe hemorrhagic coagulopathy, which is the main cause of early death. The introduction of ATRA ameliorated the complete remission rate and improved the overall survival compared to treatment with chemotherapy alone. However, the pioneristic large randomized trials comparing ATRA alone versus chemotherapy alone in previously untreated patients failed to demonstrate a significant reduction of early hemorrhagic deaths, notwithstanding ATRA capability to quench the ongoing coagulopathy. Nevertheless, the incidence of such very early deaths remains unsettled, leading to a bias in the evaluation of real impact of ATRA in clinical outcome of APL. We have retrospectively collected and examined a total of 31 very early deaths from APL from the database of 7 Italian Centres. Very early death was defined as death occurring within 72 hours from the first clinical observation. The incidence was 9.7% (31 of 318 APL enrolled in the same period in GIMEMA APL trials). Median age was 53 years (21–88), M/F ratio 0.9, 13 were variant forms of APL, median peripheral blood cell count was: WBC 41.2 ×109/L (0.68–181), with 94% of blast cells, platelets 24 ×109/L (6–96); BCR type 1, 2, 3 were observed in 10, 2, and 7 cases, respectively; clinical features of disseminated intravascular coagulopathy (DIC) were present in all but two patients, while median WHO grade of hemorrhage was 3. Median time from symptoms onset to diagnosis and from diagnosis to death was respectively 72 and 44 hours. One third of the patient did not receive any therapy, the others received some doses of ATRA with or without chemotherapy. The majority of these patients was not enrolled in any clinical trial. These preliminary data suggest that a relevant percentage of APL patients died before starting any effective treatment. Every clinical trial should include this slice of patients to give realistic clinical outcome of APL therapies. Seventy-two percent of patients showed WBC≥10×109/L and variant form was more frequent (42%) than expected (usually 20–25% of APL). Based on the possible confused morphological features with monocytic leukaemia, diagnosis required rapidly confirmative molecular methods and heavy supportive and transfusional therapies. Moreover, underlying APL should be considered as a differential diagnosis when apparently spontaneous cerebral hemorrhage occurs; in some instance, a prompt supportive and differentiating therapy could be lifesaving.