bluuebunny/crossref_metadata_2025_split huggingface dataset:
Feasibility Study of Temozolomide Maintenance Therapy in Elderly Patients with AML Following Induction Therapy with High Dose Mitoxantrone and High Dose Ara-C.
Authors: Katragadda Sreedhar , Arshad Muhammad , Liu Delong , Ahmed Nasir , Shi Quihu , Ahmed Tauseef , Seiter Karen 
Published: April 2020

Abstract
With intensive chemotherapy, approximately 50% of elderly patients with AML achieve a complete remission, however essentially all will relapse within 2 years. To date, there is no standard effective postremission therapy for these patients, and most elderly patients tolerate multiple courses of intensive chemotherapy poorly. We previously demonstrated that temozolomide has significant antileukemic activity in patients with relapsed/refractory acute leukemia (Seiter K, et al JCO 2002). In that study 9/20 patients treated had a significant reduction in bone marrow blasts, and 4 patients had a formal complete response. Currently we are evaluating the feasibility and efficacy of temozolomide maintenance therapy administered after one cycle of intensive induction chemotherapy in elderly patients with newly-diagnosed AML. Induction consists of ara-C, 3 gm/m2 daily for 5 days, and mitoxantrone, 80 mg/m2 times one on day 2. Patients achieving complete remission then receive temozolomide 200 mg/m2/d for 7 days every 5 weeks until progression. To date, 30 pts have been treated: median age 69 (range 60–84); M/F: 17/13; prior AHD: 23%; cytogenetics: good: 1, intermediate: 21, poor: 6, insufficient: 2. Response to high-dose ara-C/high-dose mitoxantrone induction: CR: 59%, progression: 24%, aplastic death: 17%. Two pts expired in remission unrelated to temozolomide: pneumonia, 1 pt, c. difficile: 1 pt. Of 17 patients in CR, 15 received temozolomide maintenance. The median number of temozolomide cycles was 2 (range 1–11). 3 pts stopped temozolomide after 1 cycle (1 refused further therapy, 1 had stem cell transplant, 1 died c. diff). Treatment was well tolerated and was administered in the outpatient setting. The median duration of remission is 5.5 months (95% CI: 3.0–9.8 months), and median survival is 7.6 months (95% CI: 5.7–13.3 months) for all patients and 10.2 months (95% CI: 5.6–15.2 months) for patients achieving CR. Temozolomide maintenance is feasible in patients with AML in CR. Further accrual is continuing to assess if remission duration and survival will be improved compared to historical controls.
Sweet’s Syndrome: A Frequently Unrecognized Complication Following Acute Myeloid Leukemia (Aml) Induction Chemotherapy: A Case Report.
Authors: Okura Toru , Aboulafia David M. , Picozzi Vincent 
Published: April 2020

Abstract
Sweet’s syndrome, also known as acute febrile neutrophilic dermatoses, is a distinct clinicopathologic entity of unknown etiology characterized by acute onset of fever, leukocytosis, and cutaneous plaques. It has been associated with a variety of disorders including infections, neoplasms, and autoimmune diseases. Paraneoplastic Sweet’s syndrome is most often associated with hematologic malignancies, including myelogenous leukemia and myelodysplastic syndrome (MDS), are most often associated. Although patients with neutrophilia are most likely to be diagnosed with Sweet’s syndrome, so, too, may patients who are neutropenic post-cytotoxic chemotherapy. Herein, we describe the clinical course of a 60-year-old Caucasian man with a history of high-risk MDS who, after progressing to AML and while neutropenic post-induction chemotherapy, was diagnosed with Sweet’s syndrome. The patient developed a warm, tender, indurated, erythematous lesion over his left anterior chest on day +6 of induction chemotherapy consisting of idarubicin and cytarabine. Despite broad spectrum antibiotics, the lesion darkened, formed blisters, and progressed rapidly to involve much of his left chest. On day +11, his WBC had fallen to 0.7×109cells/l and the wound was surgically debrided due to concern that he had developed necrotizing fasciitis. Surgical samples showed significant dermal infiltration of neutrophils and severe necrosis of skin and subcutaneous tissue, but no pathologic organisms or leukemic cells. Empiric antibiotic coverage was broadened to include amphotericin B, voriconazole, and valganciclovir, but the patient failed to improve. On day +18, he began taking 60mg Prednisone daily and his lesions quickly improved. Although Sweet’s syndrome most often occurs in conjunction with neutrophilia, it may also occur in neutropenic patients who have received systemic chemotherapy. This association with neutropenia is more frequent than is generally appreciated; as many as 20–50% of patients with hematologic malignancies may be diagnosed with Sweet’s syndrome while recovering from therapy-associated neutropenia. Cancer-associated Sweet’s syndrome may be more severe than that seen in patients without malignancy. Lesions may progress from plaques and nodules to vesicular, bullous, and even ulcerative skin lesions, as was seen in our patient. Our case report serves as a reminder that Sweet’s syndrome may occur in the setting of neutropenia and, if diagnosis and treatment are delayed, can lead to a life-threatening complication. Early skin biopsy and histopathologic assessment followed by corticosteroids is essential for recognition and management of this entity.
Remission Induction Treatment for 6 Patients of Jehovah’s Witnesses with De Novo Acute Leukemia.
Authors: Fujita Hiroyuki , Iguchi Mai , Tachibana Takayoshi , Takemura Sachiya , Taguchi Jun , Tanaka Masatsugu , Maruta Atsuo , Ishigatsubo Yoshiaki 
Published: April 2020

Abstract
The treatment of acute leukemia with myelosuppressive chemotherapy usually requires the transfusions of blood and blood products. For religious reasons, Jehovah’s Witnesses (JW) do not consent to the transfusion of blood. We describe here six cases of JW with acute leukemia, who received induction chemotherapy without blood support.
From January 1996 to March 2006, six JW with newly diagnosed acute leukemia received remission induction chemotherapy at Shizuoka Red Cross Hospital or Kanagawa Cancer Center (acute myeloid leukemia (AML) n=5, acute lymphoblastic leukemia (ALL) n=1). All patients refused the consent for transfusions of packed red cells and platelet units and they were never forced accept them.
Remission induction therapy: One patient with M3 received all-trans retinoic acid alone. One ALL patient received prednisolone alone. Three AML patients received the following LVP regimen: L-asparaginase 5000U/sqm div from day 8 to day 21 + vincristine 1.4mg/sqm div day1, 6, 11, 16, 21, 26 + prednisolone 40mg/sqm div from day 1 to day 28, and one AML patient received a low dose of Ara-C regimen (20mg/sqm continuous div from day 1 to day 14).
Results (see Table): Four out of six patients achieved complete remission and two paitents died from cardiac arrest due to severe anemia before hematological recovery. No patients developed fatal bleeding complications, not even long lasting severe thrombocytopenia.
Conclusion: We have demonstrated the feasibility of remission induction therapy for JW with leukemia. This LVP regimen, or steroid based regimen, may be suitable for JW with acute leukemia because myelosuppression is relatively mild. While two patients experienced cardiac arrest due to severe anemia of under 3g/dL of hemoglobin, severe thrombocytopenia can be managed without prophylactic platelet transfusion.
Clinical characteristics of patients Pt#:Age/Sex/FAB/ Karyotype Induction therapy Epo use Nadir in Induction therapy (day) Out come Follow-up from Induction therapy WBC(×109/L) Hb(g/dL) PLT(×109/L) ATRA: All-trans retinoic acid, PSL: Prednisolone, , LDAC: Low dose of Ara-C regimen, Epo: Erythropoietin, CR: Complete Remisson, ED: Early Death, RLPs: Relapse 1: 28/F/M3/t(15;17) ATRA Yes 0.9 (day2) 3.6 (day3) 20 (day2) CR 10Y6M+, 2ndCR 2: 29/F/M1/normal PSL+LVP No 0.6 (day4) 2.4 (day19) 16 (day6) CR 2Y6M, dead in 2nd RLPs 3: 45/F/M2/normal LVP No 0.9 (day22) 3.0 (day30) 8 (day25) CR 2Y1M+, in 1st CR 4: 25/M/M2/t(8;21) LVP Yes 1.2 (day25) 1.5 (day31) 17 (day31) ED 31days 5: 15/F/L1/complex PSL Yes 1.3 (day5) 3.8 (day7) 1 (day4) CR 10M+, in 1st CR 6: 64/M/M2/complex LDAC Yes 0.6 (day6) 2.7 (day21) 1 (day21) ED 23days
The Intention To Treat Analysis of the Different Post Remission Therapy Modalities in AML Patients with the “Intermediate Risk Group (IPG)” Based on Cytogenetics.
Authors: Mun Yeung-Chul , Lee S.M. , Park S.H. , Cho E.K. , Lee J.H. , Jo D.Y. , Kim I.H. , Yoon S.S. , Park S.Y. , Bang S.M. , Min Y.J. , Seo J.J. , Lee M.H. , Kim C.S. , Joo Y.D. , Chung S.Y. , Oh D.Y. , Zang D.Y. , Lee K.H. , Hyun M.S. , Song H.S. , Kim H.S. , Kwon H.C. , Kim H.J. , Park Y.H. , Ahn M.J. , Ahn J.S. , Park K.T. , Bae S.H. , Ryoo H.M. , Yoon H.J. , Kim B.S. , Ghim Thad , Seong Chu-Myong 
Published: April 2020

Abstract
The results of cytogenetics are one of the most important prognostic factors in the prognosis of AML. Three different post remission therapies were given with the IPG based on the MRC definitions using the cytogenetics results. The inclusion criteria included age&lt;65, PS&lt;3 with reasonable organ functions, cardiac ejection fraction&gt;50%, bilirubin&lt;2.0mg/dl, creatinine&lt;2mg/dl in de novo AML and secondary AML. The aims of this prospective intention to treat analysis were to compare the CR, recovery kinetics, DFS and OS in IPG based on cytogenetics with 3 different consolidation treatment modalities described as follows. Three plus seven(Idarubicin 12mg/m2, D1-D3; Ara-C 100mg/m2, D1–D7) were given to de novo AML and secondary AML. HDAC followed by three times of post remission therapy or auto PBPCT followed by two times of post remission therapy was given to IPG. If an HLA-identical sibling were available, then allo BMT was tried after 1st post-remission therapy. The median age of the cohort(Total 194) is 42.5(±17.6) (HDAC(n:89) : 47.6, auto PBPCT(n:51) : 46.6, and allo BMT(n:54) : 30.5). The median days for ANC &gt;500/μl and platelet&gt;20k/μl during induction were 22 days and 21 days respectively. Grade 3~4 toxicities were found in 34.1%, 27.7% and 47.2% during HDAC, auto PBPCT and allo BMT, respetively(p&lt;0.05). The relapse rate and the toxic death rate were 25.8%, 27.5% and 29.6%(p=0.24) and 9.1%, 5.5% and 16.6%(p&lt;0.05) in HDAC, auto PBPCT and allo BMT, respectively. So far, this trial seems to be tolerable in terms of toxicities, during induction and post remission therapies. Among IPG, the auto PBPCT arm had a tendency of superior median survival over the HDAC or allo BMT in terms of OS and LFS without statistical differences(HDAC:17m and 8m, auto-PBPCT:18m and 12m, allograft:15m and 8m). This intention to treat trial, which started in Jan, 2000, has proceeded until now in order to have better statistical power for the subset analysis.
Limited Phase I Trial of Sequential High Dose Cytarabine and Clofarabine (HiDAC→CLOF) in Relapsed or Refractory Acute Myeloid Leukemia.
Authors: Powell Bayard L. , Lovato James , Kimbrough Claire , Lyerly Susan , Galloway-Daniels Sonya , Motley Cathy , Harrelson Robin , Keung Yi Kong , Thakuri Mohan C. , Molnar Istvan , Levitan Denise , Hurd David Duane 
Published: April 2020

Abstract
High dose cytarabine (HiDAC) is the most effective single agent for the treatment of acute myeloid leukemia (AML); clofarabine (CLOF) is also an active agent in AML. Preclinical data suggest synergy between cytarabine and clofarabine. We conducted a two step limited phase I trial of sequential HiDAC (2g/m2 over 3 hours) followed by CLOF (30 or 40 mg/m2 infused over 2 hours), each given daily for 5 days, in adults with AML in first or second relapse or refractory to initial induction chemotherapy. Patients with persistent leukemia on day 12–14 received a second course of HiDAC→CLOF; phase I toxicity evaluation was based on cycle 1 data only. Nine patients (6 men and 3 women) were treated. The median age was 55.5 years (range 29.2 – 68.1). All had relapsed AML; two had prior autologous stem cell transplant. The initial cohort of 3 patients received clofarabine 30 mg/m2 with one dose limiting toxicity (DLT); an additional 3 patients were treated in cohort 1. The second cohort was treated with CLOF 40 mg/m2, the target dose for a planned phase II trial of HiDAC→CLOF. Hematologic toxicities and infections were not considered DLT. In the first cohort (30 mg/m2; n = 6) there was 1 DLT - grade 4 skin rash in a patient who subsequently died on day 17 with sepsis-related multi-organ failure; 3 patients had reversible grade 3 elevations in AST/ALT, 1 had grade 3 skin toxicity. In cohort 2 (40 mg/m2 ; n = 3) there was no DLT; 1 patient had grade 3 AST/ALT; 2 had grade 3 skin. Three of nine patients received a second course of induction HiDACCLOF. Two of six patients in cohort 1 achieved complete remission (CR), 1/3 patients in cohort 2 achieved CRi(CRp). Two of three CR/CRi patients received one course and one received two courses of HiDAC→CLOF induction. Conclusion: HiDAC→CLOF was associated with transient elevation in AST/ALT (4/9) and skin rash (3/9; primarily extensive palmar/plantar); skin toxicity appeared especially prominent in patients with palmar/plantar toxicity during prior therapy with HiDAC. Toxicities (other than skin) were comparable to other salvage regimens for relapsed and refractory AML. This combination is active in relapsed AML with 3/9 CR/CRp. A phase II trial of HiDAC→CLOF is underway; prophylactic intravenous hydrocortisone has been incorporated in an attempt to decrease skin toxicity.
Updated Results of a Phase I Study of Flavopiridol in Acute Leukemias Using a Novel, Pharmacokinetically Derived Schedule: Clinical Activity Including Hyperacute Tumor Lysis Syndrome (TLS), Pharmacokinetics (PK), and Pharmacodynamics (PD).
Authors: Blum William , Klisovic Rebecca B. , Kefauver Cheryl , Johnson Amy , Phelps Mitch , Dalton James T. , Lucas David , Huynh LeNguyen , Liu Shujun , Grever Michael R. , Colevas A.D. , Marcucci Guido , Byrd John C. 
Published: April 2020

Abstract
Flavopiridol is a cyclin-dependent kinase inhibitor that induces apoptosis in acute leukemia cell lines. In earlier studies with flavopiridol in several malignancies, plasma concentrations of flavopiridol were not reached or maintained at sufficient levels to induce apoptosis due to unexpectedly high levels of bound drug in human serum relative to fetal calf serum used in preclinical studies. PK modeling in chronic lymphocytic leukemia (CLL) cells cultured in human plasma in vitro indicated that administering flavopiridol by 30 minute intravenous (IV) bolus followed by 4 hour continuous IV infusion (CIVI) would achieve sustained in vivo plasma drug concentration and time exposure similar to that necessary to induce apoptosis. We designed a phase I dose escalation trial in acute leukemias of single agent flavopiridol given as a 30 minute bolus followed by a 4 hour CIVI on days 1–3 with the ability to repeat cycles every 21 days; 16 patients (pts) have been enrolled to date. Dose escalation was as follows (bolus dose/4 hr CIVI dose in mg/m2): 20/30 (n=3), 30/35 (n=7), 30/50 (n=3), and 40/60 (n=3). Based on prior experience with flavopiridol at our institution in CLL, aggressive measures for the prevention and management of hyperacute tumor lysis syndrome (TLS) were employed. Pts had relapsed/refractory AML (N=12) and ALL (N=4), and were 25–78 yrs old (median age 64 yrs). Average plasma levels were 1.0–2.5 μM at the first three dose levels during the infusion (N=13) and declined with terminal half-lives comparable to previously reported 72 hr and more recent 4.5 hr infusions. Clinically significant TLS occurred in 2/16 pts with chemical evidence of lysis in 4 additional pts. A dose-limiting toxicity (renal failure) occurred at dose level 4 (40 mg/m2 bolus/60 mg/m2 CIVI), and the level is currently being expanded. Treatment was otherwise well tolerated. Downregulation of Mcl-1 protein by standard immunoblotting at 4 and/or 24 hrs was demonstrated in blood and/or bone marrow cells of 6/10 patients Anti-leukemic activity including transient reductions in WBCs/circulating blasts (n=7), bone marrow blasts (n=2), and platelet transfusion independence (n=1) was observed. Two received a second course of therapy, but no pt experienced an objective response by standard criteria. The current dose level exceeds that previously given in ongoing CLL studies; dose escalation to identify the maximum tolerated dose using this pharmacokinetically derived schedule in acute leukemia continues. Given the activity of this drug as a single agent, combination studies with conventional chemotherapy or other novel agents in acute leukemias should be considered.
Arsenic Trioxide-Induced Cell Death Occurs Partially Independent of the Pro-Apoptotic Bcl-2-Family Members Bax and Bak.
Authors: Scholz Christian , Richter Antje , Richter Anja , Dörken Bernd , Daniel Peter T. 
Published: April 2020

Abstract
Arsenic trioxide (As2O3, arsenite) efficiently kills cells from various hematologic malignancies and has successfully been employed for the treatment of acute promyelocytic leukaemia, myelodysplastic syndrome, and multiple myeloma. Investigating the mechanisms of arsenic trioxide-induced cell death, we recently demonstrated that arsenite-mediated cell demise has a partially necrotic phenotype, occurs independently of the extrinsic death receptor pathway of apoptosis, and is not hampered by the absence of functioning caspases. On the contrary, cell death proceeded entirely via an intrinsic, mitochondrial pathway and was efficiently blocked by the anti-apoptotic Bcl-2 family members Bcl-2 or Bcl-xL. Here, we address the role of the pro-apoptotic multi-domain Bcl-2 family members Bax and Bak. By employing different cell lines deficient for Bax and/or Bak, we demonstrate that Bax- or Bak-deficiency as well as the combined absence only partially blocks arsenite-induced cell death. While the detection of an additive effect of the combined Bax-/Bak-deficiency argues for a non redundant function of Bax and Bak, the persistence of a substantial percentage of arsenite-mediated cell demise in different double deficient cell lines nevertheless suggests a mode of arsenic trioxide-mediated cell death independent from these central inducers of apoptotic cell demise. The presented data add to the notion that arsenic trioxide kills tumor cells independent of the apoptotic machinery, and warrants further investigation on the efficacy of this compound in malignancies with deficiencies of the apoptotic cell death pathways.
Advanced Stage Hodgkin Lymphoma: The Predictive Value on Treatment Outcome of Early FDG-PET Scan Is Independent of and Superior to IPS Score.
Authors: Gallamini A. , Hutchings M. , Rigacci L. , Specht L. , Merli F. , D’Amore F. , Nassi L. , Hansen M. , Vitolo U. , Kamper P. , Trentin L. , Stelitano C. , Di Raimondo F. , Sancetta R. , Luminari S. , Viviani S. , Iannitto E. , Levis A. 
Published: April 2020

Abstract
Background: FDG-PET scan performed early during chemotherapy (CT) is a powerful prognostic tool in lymphoma management. This study aimed to compare the predictive value on treatment outcome of the International Prognostic Score (IPS) with that of FDG-PET scan performed after two courses of standard CT in untreated advanced stage (AS) HL patients.
Patients: From December 2001, 202 new AS HL patients were consecutively admitted to 11 Italian and 3 Danish hematological centers, on behalf of Intergruppo Italiano Linfomi and Danish Lymphoma Cooperative Group. The mean age was 35.5 years (14–79), the male/female ratio 105/97; AS (IIB–IVB) was present in 153, and unfavorable stage IIA (&gt; 3 nodal sites involved or sub-diaphragmatic presentation or bulky disease or ESR &gt; 40) in 49. Bulky and extranodal disease was recorded in 71 and 58 patients, respectively. All patients had FDG-PET at baseline (PET-0) and after 2 courses of CT (PET-2). 192 patients were treated with ABVD, 8 with ABVD-like CT, 2 with BEACOPP. 102 patients received consolidation radiotherapy after CT. All patients were given the therapy programmed at baseline, except in case of overt progression.
Results: The mean time from the diagnosis to latest follow-up was 796 days (range 91–1716). 164 patients attained CR while 38 were chemoresistant: 34 showed disease progression during CT and 4 showed early relapse (within 6 months) after CR entry: (+28 – +178 days). 4 out of the 164 pts attaining CR relapsed later than 6 months. In univariate analyses, both PET-2 (p&lt;0.0001) and IPS (p&lt;0.001) were significantly associated with a higher probability of treatment failure. However, in a multivariate analysis only PET-2 was independently predictive of relapse/progression probability (51.0; 95 % C.I. 20.9 – 124.2). The sensitivity of PET-2 for treatment failure was 85%, the specificity 96% and the overall accuracy 94%. The 2-y FFS probability for PET-2 negative and for PET-2 positive patients were 96% and 14%, respectively (log Rank test, p&lt;0.0001; Fig. 1).
Conclusions: so far, FDG-PET after two cycles of CT is the most powerful tool available for predicting treatment outcome in AS HL.
Figure Figure
Identification of Combined Clinical and Biomarker Prognostic Factors in Follicular Lymphoma.
Authors: Foster Cheryl J. , Farmer Patricia L. , Baetz Tara , Brettschneider Julia , Feilotter Harriet E. , LeBrun David P. 
Published: April 2020

Abstract
Follicular lymphoma (FL) is generally an indolent disease, progressing slowly over a period of many years. However, some patients experience a rapid progression or histological transformation to an aggressive lymphoma requiring more aggressive treatment. Identification of these patients at the time of the initial diagnosis would allow more informed decisions to be made regarding clinical management. We investigated whether the expression of specific proteins in FL cells in combination with baseline clinical data could predict for relapse, transformation and survival of patients with follicular lymphoma. A tissue microarray (TMA) was generated of 67 cases of FL diagnosed between 1974 and 2003. Clinical baseline and follow-up data were obtained (median of 58 months). Forty-one patients experienced relapse within the follow-up period and thirty-one individuals transformed to aggressive lymphoma. Median overall survival was 13.6 years. Immunohistochemistry (IHC) staining was obtained for markers routinely used in lymphoma diagnosis, as well as oncogenesis-relevant proteins including p53, bcl-2, bcl-6, mum1, p16 and p65. Evaluations of the presence of benign T-cells, infiltrating macrophages, and the follicular dendritic cell network were also made. Univariate analysis was undertaken using the Kaplan-Meier method in order to assess the prognostic power of various clinical, histological and IHC variables with respect to overall survival, time to transformation and time to relapse. Variables that had prognostic significance (p&lt;0.05) in univariate analysis were included in multivariate models of these end-points. High tumour grade, expression in tumour cells of p16 and lack of bcl-2 predicted shorter transformation-free survival in multivariate analysis. Advanced tumour stage, presence of B symptoms, expression of p53 or p16 in tumour cells, presence of benign T-cells in the tumour environment and integrity of the benign follicular dendritic cell network had independent prognostic power for shorter relapse-free survival. Greater than 5 nodal sites of disease, presence of B symptoms at diagnosis and expression of p53 in lymphoma cells each emerged as significant and independent predictors of overall survival using a Cox regression model. These results indicate that protein-based expression profiling using TMAs in combination with clinical data is a potentially productive means of identifying a prognostic index that can be implemented in the clinical management of follicular lymphoma patients. Further study is required to compare these results to existing clinical prognostic scores.