bluuebunny/crossref_metadata_2025_split huggingface dataset:
Subcutaneous (SC) Homoharringtonine (HHT) for Patients (pts) with Chronic Myelogenous Leukemia (CML) in Chronic Phase (CP) after Imatinib Mesylate Failure.
Authors: Quintas-Cardama Alfonso , Cortes Jorge , Verstovsek Srdan , Laddie Nakia , Estrov Zeev , Kantarjian Hagop 
Published: April 2020

Abstract
HHT is a cephalotaxus alkaloid obtained from an evergreen tree that inhibits the synthesis of proteins leading to apoptosis. HHT by intravenous (IV) administration has demonstrated significant activity in pts with CML after failure to interferon (IFN) therapy, with cytogenetic (CG) responses in 30% of cases. A phase I study of SC HHT previously reported in pts in accelerated or blast phase (before imatinib was available), demonstrated efficacy (5 of 10 responses) and adequate tolerance at the same doses used IV. We thus started a phase II study to determine the activity of SC HHT in pts with CML in late CP after imatinib failure. Therapy with HHT consisted of an initial IV loading dose of 2.5 mg/m2 over 24 h, followed by 1.25 mg/m2 SC twice daily for 14 days every 28 days. Six pts have been treated and 5 are evaluable (1 pt lost to follow-up after 1 cycle). Best response to prior imatinib therapy for a median of 64 weeks (range, 12 to 96) was: complete hematologic response (CHR) in 3 pts and complete CG response (CG CR) in 2, and primary resistance in 1 pt. All 5 evaluable pts had also failed IFN, and other therapies: Ara-C (n=2), farnesyl transferase inhibitors (n=2). At the time HHT was started, all had lost CHR. Median age was 52.5 years (range, 36 to 66), time from diagnosis to treatment 58 months (18 to 164), WBC 24.35 x 109/L (6/4 to 43), platelets 308 x 109/L (147 to 536), and peripheral basophils 4/5% (3% to 17%). Mutations of the BCR-ABL kinase domain were identified in 2 pts (2 mutations each: G250E and Y253H in one, D276G and F359I the other). Pts received a median of 4.5 courses of SC HHT (range, 1 to 5). CHR was achieved in all 5 evaluable pts. Of these, 1 achieved a CG CR and a minor CG response (lowest Ph 80% and 90%, respectively). The pt that achieved CG CR had D286G and F359I mutations before therapy with HHT. Interestingly, this pt developed extramedullary blast disease (bones) that required radiotherapy while remaining in CG CR in peripheral blood and bone marrow. All pts developed myelosuppression and 3 had their HHT dose reduced due to prolonged neutropenia. Grade 3–4 non-hematologic toxicity included neutropenic fever (n=1), and fatigue (n=1). We conclude that SC HHT is well tolerated and may have clinical activity in pts with CML after imatinib failure. This study was terminated because of drug availability from this source; a new trial will be conducted obtaining HHT from a different sponsor.
Imatinib Mesylate in the Treatment of Relapse of Chronic Myeloid Leukemia after Allogeneic Stem Sell Transplantation.
Authors: Zhu Kanger , Zhang Tao , Chen Jie , Zhong Juan 
Published: April 2020

Abstract
Objective: To determine whether imatinib mesylate is effective against chronic myeloid leukemia (CML) that relapses as CML in chronic phase following allogeneic stem cell transplantation (allo-HSCT).
Methods: We studied 5 patients treated with imatinib mesylate for recurrent CML after allo-HSCT. 2 patients relapsed as CML in chronic phase with hematological evidence of relapse, and one of whom was refractory to donor lymphocyte infusion (DLI). The remaining 3 patients relapsed as CML in chronic phase with cytogenetic evidence of relapse. The patients were followed for hematological and cytogenetic response.
Results: all of 5 patients achieved hematological and cytogenetic response within 5 months.The 2 patients with hematological evidence of relapse and minimal level of donor chimerism experienced severe pancytopenia, followed shortly by a hematological recovery, disappearance of BCR-ABL fusion gene positive cells, and conversion of complete donor chimerism. In 3 patients, a hematological and cytogenetic response was associated with chronic graft-versus-host disease. With a median follow-up of 36 (12~46) months, after cessation of imatinib mesylate, all patients are alive and remain in complete cytogenetic remission.
Conclusion: We have shown that patients who relapsed as CML in chronic phase after allo-HSCT showed very good therapeutic responses to imatinib mesylate, which were rapid, durable, with conversion to full donor chimerism and complete disappearance of BCR-ABL fusion gene positive cells, in spite of a prolonged relapse, an apparent loss of donor chimerism, and a failed prior response to DLI.
Pregnancy during Treatment with Imatinib: A Case Report.
Authors: Fogliatto Laura , Brum Caroline , Zago Alethea , Faltoe Thiago , Rodrigues Fabio , Falhauber Gustavo , Leugeur Denise , Silla Lucia 
Published: April 2020

Abstract
CFSA, an 18-year-old woman with a history of weight loss and abdominal discomfort was diagnosed with chronic myelogenous leukemia (CML) in December 2002. The WBC were 440 x 109 /L with 25% neutrophils, 20% bands, 9% metamyelocytes, 9% myelocytes, 8% promyelocytes, 10% basophils, 9% eosinophils, 1% lymphocytes and 8% blasts. The hemoglobin was 9,8 g/dL and platelet count 416 x 109/ L. A bone marrow examination demonstrated granulocytic hyperplasia and the presence of Philadelphia chromosome in 100% of the metaphasis. A diagnosis of CML was made and she was started on hydroxyurea and imatinib 600mg daily. No matched HLA donor was found. There was a partial hematological response. In February 2005 on imatinib (600 mg) she was pregnant and an ultrasound scan showed a viable fetus of 17 weeks. The WBC were 22 x 109 /L with 50% neutrophils, 23% bands, 8% metamyelocytes, 12% myelocytes, 1% promyelocytes, 5% lymphocytes, hemoglobin 11,4 g/dl and platelet count 290 x 109. Imatinib was stopped and she remained off treatment during pregnancy. Cesarean section was performed at 38th week because of preeclampsia (hypertension, headache and scotomas). A healthy girl weighing 2980 g, 46,5 cm in length with Apgar score of 9 was delivered. The infant’s physical examination, WBC, hemoglobin, platelet count and cranial ultrasonography were normal. The baby is presently healthy with no developmental abnormalities. There are few reports on the use of 600 mg a day of imatinib and pregnancy. It is of notice, although probably unrelated, the event of preeclampsia. The effects of imatinib on fetus are unkown and should be considered teratogenic until more studies or cases are reported.
STI 571 Combined with Hematopoetic Stem Cells Transplantation for Chronic Myeloid Leukemia.
Authors: Meng Fan Yi , Sun Jing , Liu Qifa , Xu Dan , Wei Yongqiang , Zhang Yu , Jiang Qianli 
Published: April 2020

Abstract
Objective: to study the efficacy of STI 571 combined with allogenic hematopoietic stem cell transplantation (Allo-HSCT) or autologous peripheral blood stem cell transplantation (APBSCT) in chronic myeloid leukaemia (CML).
Methods: 18 CML patients were divided into 2 groups: group A (14) and group B (4). Patients in group A including 10 in CML accelerating phase or blast crisis phase, 4 in chronic phase. They all underwent Allo-HSCT and the median duration of STI 571 treatment before Allo-HSCT was 25 days (7–60d). 9 had related complete HLA-matched donors and 5 had unrelated complete matched donors, the preparation regimen was TBI+CTX +VP16 or BU/CY ±ATG, routine protocol was used to prevent graft versus host disease (GVHD). Patients of group B were all in chronic phase, the median duration of STI 571 treatment before APBSCT was 5.5 months (4–26d), and bcr/abl detected by FISH was continuously negative. Mobilization protocol was CAE + G-CSF, 3 of 4 underwent TBI+ CY+ VP16 followed by APBSCT.
Results: in group B, PBSC were separated after 5 days of mobilization, and (3.9–9.6)×106/kg Cd34+ cells were obtained, however FISH- bcr/abl positive cells in separation products were higher than in bone marrow cells before separation (0.8% vs 2.8%). After a median follow up of 24 months (18–28 months), 2 cases relapsed, and one remains FISH-bcr/abl negative. In group A, 8 had GVHD, and after a median follow up of 8 months (4–20 months), 2 cases relapsed, 2 died of transplantation- related complications, 1 died of relapse, 9 remained disease free. Hematopoiesis was reconstituted in 8–21 days in patients of group A.
Conclusions: no obvious side effect was observed in STI 571 combined hematopoietic stem cell transplantation in CML patients.
Prognostic Factors for Allotransplantation in CML.
Authors: Copelan Edward C. , Elder Patrick 
Published: April 2020

Abstract
The role of hematopoietic cell transplantation in the treatment of chronic myelogenous leukemia (CML) has changed dramatically as the effectiveness of Gleevec has become clearer. The use of transplantation as first-line therapy and the timing of transplantation in those who do not achieve cytogenetic remission varies between centers. In order to better understand the likelihood of success following transplantation, we have analyzed prognostic factors in 126 patients with chronic phase CML who underwent allogeneic transplantation between 1984 and 2004. Median age was 37 (range 14–66). There were 69 males and 57 females. The interval between diagnosis and transplantation was most closely associated with survival in multivariate Cox analysis (P&lt;.001). Interval was significant when analyzed as a continuous variable; also patients transplanted within 3 months experienced significantly longer survival than those &gt; 3 months and patients less than 1 year from diagnosis had better survival than those more than 1 year from diagnosis. (P&lt;.001). Patients with fully matched sibling donors experienced significantly better survival that those with other donors (P=.01). Treatment with Interferon or Gleevec, age, use of peripheral blood cells vs marrow, and year of transplant were not significant prognostic factors. There is no evidence that age, which is often heavily considered in determining timing of transplantation, is a significant prognostic factor in patients with CML undergoing allogeneic transplantation after busulfan and cyclophosphamide.
Because interval between diagnosis and transplantation significantly affects outcome, allogeneic transplantation should be considered early in patients receiving Gleevec when an adequate cytogenetic response is not achieved or at the first sign of relapse. Earlier identification of failure, e.g. using quantitative PCR for Bcr-Abl, might improve outcome and should be studied.
Treatment of Anemia in Myelodysplastic Syndrome (MDS) with Darbepoetin-Alpha (DPO) and Granulocyte Colony Stimulating Factor (G-CSF).
Authors: Rose Shelonitda S. , Ali Yaqoob , Maffei Barbara , Saidi Parvin 
Published: April 2020

Abstract
MDS is a clonal stem cell disorder characterized by ineffective hematopoiesis and peripheral cytopenias. Anemia is often severe, transfusion dependent and associated with impaired quality of life. Evidence shows that treatment with erythropoietin (EPO) has an overall response rate of 20% and with G-CSF becomes more effective with an erythroid response rate of around 40%. Studies have independently demonstrated a synergistic effect between EPO and G-CSF on the anemia of MDS. DPO, a modified form of EPO with a longer half life has been shown to be effective in correcting anemia in a significant proportion of MDS patients. Synergy between DPO and G-CSF has not been studied. We report the clinical course and changes in the blood counts in a 77 year old male diagnosed with MDS, Refractory Anemia with Excess Blasts Type I (RAEB-I) who received DPO and G-CSF combination treatment. His baseline CBC showed WBC-2.4 ×103/μL, Hb-9.7g/dL, and Plt-106×103/μL. EPO level was 64.4 mU/mL. He was initiated on EPO 20,000 units weekly (QW) which was titrated to 40,000 units QW after one month. His Hb increased to 12 g/dl. For convenience, he was switched from QW EPO injections to DPO 100 μg every two weeks (QOW). This was followed by an initial drop in the Hb to 11g/dL requiring an increase in DPO dose to 200 μg QOW which was followed by stabilization and maintenance of Hb between 10–11 g/dL. After 7 months, Hb dropped to 9 g/dL requiring an increase in DPO to 300 μg QOW. Hb increased to 10 g/dl and remained between 10–10.5 g/dL for 7 months. Hb dropped again to 8.3g/dL. The DPO dose was increased to 300 μg QW, and he was given a course of IV iron for a total of 1 gm. Following transient Hb increase to 9–10g/dL, for few months Hb dropped to 8g/dL and he became transfusion dependent. In addition, he became progressively neutropenic with ANC &lt;500/μL and thrombocytopenic with Plt &lt;50×103/μL. At this point he was initiated on G-CSF 480 μg TIW along with DPO 300 μg QW. One month after the initiation of DPO plus G-CSF his CBC showed WBC 4.0×103/μL, Hb-11.2 g/dL and Plt-92×103/μL. The Plt response was transient and eventually remained stable between 50–60 ×103/μL. He continues to remain transfusion independent after 8 months of combination treatment maintaining Hb between 10–11 g/dL. In addition to having a major erythrocyte and neutrophil response following the initiation of combination treatment of DPO and G-CSF, this patient also had transient Plt response. The course of this patient suggests that the addition of G-CSF to DPO may improve anemia and neutropenia in patients with MDS who do not have a sustained response to DPO alone. In addition it also suggests that in-vivo synergy may exist between DPO and G-CSF for the production of red cells in MDS.
Oral Prednisolone Produces a Durable Response in Pediatric Myelodysplastic Syndromes (MDS).
Authors: Chandy Mammen , George Biju , Mathews Vikram , Viswabandya Auro , Bajel Ashish , Srivastava Alok 
Published: April 2020

Abstract
Treatment options for children with MDS are limited except for allogeneic bone marrow transplantation. We present our experience with the use of long duration corticosteroids in children with MDS. Fifty five children (age&lt; 15 years) with pediatric MDS or myelofibrosis treated between 1991–2004 with corticosteroids were analyzed. All of these patients presented with cytopenia involving one or more lineages and a hypercellular marrow with dysplasia and increased reticulin. Prednisolone was started at 1 mg/kg daily or on alternate days for a period of 1–2 months. If there was no response, steroids were rapidly tapered and stopped. In children who showed a response, the steroids were slowly tapered to alternate day steroids and stopped over a period of 6–12 months. In patients who had relapse of symptoms on tapering, the dose of steroids was increased to previous levels and then tapered at a much slower rate. The median age was 3 years (range: 3 months – 14 years) with 36 males and 19 females. Forty six has pediatric MDS while 10 had pediatric myelofibrosis. The median duration of symptoms prior to starting steroids was 7 months (range: 1–24). Forty one patients (74.5%) showed a response with 31 (56.4%) showing a complete response while 10 patients (18.1%) showed a partial response with improvement in counts and transfusion independence. Fourteen patients (25.5%) showed no improvement and continued to be transfusion dependant. Fourteen of the 41 patients (34%) who responded to steroids relapsed on tapering of steroids but showed response to repeat courses of steroids. The median duration of steroid use in patients who have responded is 12 months (range: 1 – 96). None of the patients had any serious side effects including infections, hypertension or diabetes except one patient who developed disseminated tuberculosis 12 months after stopping steroids. Nine patients have shown progression of disease while 1 patient developed features of SLE 24 months after diagnosis of MDS. At a median follow up of 34 months (range: 4– 120), 32 patients (58%) are alive with 27 (49%) in complete remission [14 off treatment, 13 on treatment] and 5 in partial remission but transfusion independent. Prednisolone induces a durable response in children with MDS. The biological basis of this response needs to be evaluated.
Genes Important for Disease Progression of MDS-Leukemia Revealed by 40K cDNA Microarray.
Authors: Miwa Hiroshi , Teramoto Hidemi , Patel Vyomesh , Letwin Noah , Castellone Maria D. , Imai Norikazu , Shikami Masato , Imamura Akira , Gutkind Silvio , Nitta Masakazu , Lee Norman H. 
Published: April 2020

Abstract
[Background and Objectives] One of the causes of death in patients with myelodysplastic syndrome (MDS) is leukemic transformation. After the indolent phase, which can be treated with chemotherapy, leukemic MDS will progress to a phase of aggressive blast proliferation, which cannot be controlled by chemotherapy. In this study, we would like to know the molecular mechanisms of the disease progression.
[Materials and Methods] Bone Marrow samples were collected from both indolent (at initial diagnosis) and aggressive (after chemotherapies) phases from 4 MDS-leukemia patients. We extracted RNA from each sample and then amplified the RNA, reverse transcribed the amplified RNA to cDNA, and fluorescently labeled before hybridization for the microarray.
[Results and Discussion] Compared to the expression level at indolent phase, several genes including MEK kinase 5 (ASK1), Rho-associated protein kinase 1 (ROCK1), LIM domain kinase 2 (LIMK2) and GTP binding protein Rheb, were commonly up-regulated more than 2-fold at aggressive phase of 4 cases. These results were confirmed by real time RT-PCR. Since multidrug resistance protein was up-regulated at the ratio of around 1.5, more than 2-fold up-regulation in all 4 examined cases was considered to be significant. These molecules can be candidate markers to predict transition from indolent to aggressive phase of the disease, and also can be targets for novel therapy.
A Retrospective Review of Outcomes of Patients with Chronic Myelomoncytic Leukemia Treated with 5-Azacitidine.
Authors: Dhruva Anand , Damon Lloyd E. , Linker Charles , Martin Thomas G. , Navarro Willis H. 
Published: April 2020

Abstract
The chemotherapeutic agent 5-azacytidine (5-AZA) is an active agent in the treatment of myelodysplastic syndrome (MDS). Phase III data with 5-AZA for MDS of all types suggest a response rate (CR+PR) of 23% and hematologic improvement rate of 37% (Silverman, et al, 2002, JCO, 20:2429). We reviewed the outcomes of patients with the MDS subtype chronic myelomonocytic leukemia (CMML) in order to better characterize outcomes for patients with this specific subtype.
Methods: Retrospective analysis of outcomes in 13 patients (median age 67; range 50–82) with CMML, who were drawn from a group of 165 consecutive patients treated with 5-AZA between 1991 and 2004 at UCSF on an NCI Special Exception Program, was performed. All patients signed informed consent to participate in the Expanded Access Protocol and IRB approval at UCSF was obtained to retrospectively review this data. IPSS of patients were 2 LOW, 7 INT-1, 3 INT-2, and 1 HIGH. 11 patients had CMML-1 and 2 patients had CMML-2. Responses were determined using the MDS International Working Group (Cheson et al., 2000 Blood96:3671) criteria.
Results: Three patients (23%) had CR and 6 patients (46%) had HI at 4 months. 9/13 patients had a response at 4 months for an overall response rate of 69% (95% CI 38.6% to 90.0%). Cytogenetic responses were seen in 1 out of 4 evaluable patients. The median AML free survival was 11 months. The median overall survival was 14 months.
Figure Figure
Conclusions: For patients with CMML, 5-AZA provides an effective treatment option with significant improvements in peripheral blood counts, marrow blasts, and transfusion requirements. The overall response rate of 69% correlates well with larger studies in MDS.
Dysregulated Expression of Myeloid Nuclear Differentiation Antigen (MNDA) in MDS: Possible Role in TRAIL-Induced Apoptosis.
Authors: Briggs Robert C. , Shults Keith , Flye Leanne , McClintock-Treep Sara A. , Jagasia Madan H. , Goodman Stacey A. , Boulos Fouad I. , Jacobberger James W. , Stelzer Greg , Head David R. 
Published: April 2020

Abstract
A reduced level of MNDA expression has been reported with gene expression profiling in both sporadic and familial MDS. We undertook studies to evaluate MNDA protein expression in MDS, and its possible functional significance. Patients (n=7) clinical histories, lab data, cytogenetics, and morphology were reviewed blinded to study results to confirm diagnoses. Patients had Refractory Cytopenia with Multilineage Dysplasia (n=6) or Refractory Anemia with Excess Blasts-1 (n=1)(WHO). Patients lacking primary marrow disease (n=5) were used as controls. Samples were assessed with multiparametric flow cytometry (MPFC) for CD45 antigen density, log side scatter, CD34, CD71, and MNDA (using a specific rat monoclonal antibody) with an FC500 (Beckman-Coulter) flow cytometer, and analyzed with Winlist 5.0 and ModFitLT 3.0 (Verity Software) using published methods and ECFI-generated algorithms. Analyses were blinded to clinical results. Immunohistochemistry (IHC) for MNDA was performed using the same antibody and published methods. Both MPFC and IHC demonstrated MNDA expression in MDS predominantly in granulocyte-macrophage (G-M) progenitors, similar to controls. G-M progenitors in MDS demonstrated reduced MNDA protein expression compared to controls, with 3 patterns: uniform reduced MNDA protein, a mix of normal and absent MNDA protein, or a mix of reduced and absent MNDA protein. We interpret the normal expression in some cases as consistent with presence of a mixture of normal and MDS cells, while the mix of reduced and absent expression may represent clonal evolution of MDS. To evaluate possible functional significance of MNDA expression we used stable K562 clones that express ectopic MNDA protein via retroviral transduction. Parental K562 cells lack MNDA expression. Compared to parental K562, ectopic expression of MNDA failed to protect cells from intrinsic path apoptosis induced by genotoxic agents (mechlorethamine, etoposide, cisplatin) or H2O2. Apoptosis was evaluated by morphology, TUNEL assay, trypan blue exclusion, and phosphorylation of Histone H2B at serine 14 (a specific marker of apoptosis). In sharp contrast, ectopic MNDA expression provided marked protection of cells from extrinsic path apoptosis induced by TRAIL (TNF-related apoptosis inducing ligand) exposure. Disordered apoptosis is hypothesized to be a factor in MDS pathogenesis. Our results indicate MNDA promotes viability in myeloid progenitors, and its down-regulation in MDS might relate to the G-M progenitor sensitivity to TRAIL-induced apoptosis that has been reported in MDS.