bluuebunny/crossref_metadata_2025_split huggingface dataset:
Nilotinib in Patients (pts) with Relapsed/Refractory Philadelphia Chromosome-Positive Acute Lymphoblastic Leukemia (Ph+ ALL) Who Are Resistant or Intolerant to Imatinib.
Authors: Ottmann Oliver G. , Larson Richard A. , Kantarjian Hagop M. , le Coutre Philipp , Baccarani Michele , Haque Ariful , Gallagher Neil , Giles Francis 
Published: October 2019

Abstract
Background: Ph+ ALL occurs in about 15% of adults with ALL and is characterized by a poor prognosis. Imatinib in combination with systemic chemotherapy has become the standard therapy for adults with Ph+ ALL. Nilotinib is a highly specific BCR-ABL inhibitor, which is 30-fold more potent than imatinib and active in vitro against 32 of a panel of 33 BCR-ABL mutations. Nilotinib was demonstrated in a phase I study to be active against a small subset of imatinib-resistant Ph+ ALL adult pts. Based on this preliminary data, a phase II, open-label study was designed to further evaluate the safety and efficacy of nilotinib in pts with relapsed/refractory Ph+ ALL.
Methods: The initial dose of nilotinib was 400 mg twice daily (BID) with escalation to 600 mg BID, when there was an inadequate response and no safety concerns.
Results: The safety and efficacy data were reported for 41 Ph+ ALL pts in which 38 had relapsed and 3 were refractory [(37 had active disease; 4 had minimal residual disease (MRD)]. The median age at study entry was 46 (18–75) years and 54% were men. At study entry 31% of pts had >35% Ph+ metaphases; chromosomal abnormalities other than Ph+ were noted in 32% (13/41) pts, and extramedullary involvement was present in 3 pts. The median time since initial diagnosis of Ph+ ALL was 15 months. Treatment with nilotinib is ongoing for 2 pts (5%). Most discontinuations were due to disease progression (68%). The median treatment duration was 53 (1–563) days and the median dose intensity was 800 mg/day. Thirty-one percent of pts had >35% of Ph+ metaphases, chromosomal abnormalities other than Ph+ were noted in 32% of the pts, and extramedullary involvement was present in 7% of pts. Complete response (CR) was reported in 10 (24%) pts including 1 patient with MRD. Hematological improvement was observed in 1 (3%) pt, stable disease was observed in 9 pts, 14 pts had progressive disease. The most common Grade 3/4 laboratory abnormalities were thrombocytopenia (60%), neutropenia (43%), anemia (21%), and hypophosphatemia (22%).
Conclusions: Nilotinib as a monotherapy appears to have promising activity and a favorable safety profile in relapsed/refractory Ph+ ALL pts. The use of nilotinib in combination with chemotherapy for Ph+ ALL merits further investigation.
PR1 Peptide Vaccine-Induced Immune Response Is Associated with Better Event-Free Survival in Patients with Myeloid Leukemia.
Authors: Qazilbash Muzaffar H. , Wieder Eric D. , Thall Peter F. , Wang Xuemei , Rios Rosa L. , Lu Sijie , Kant Shreya , Giralt Sergio , Estey Elihu H. , Cortes Jorge , Komanduri Krishna , Champlin Richard E. , Molldrem Jeffrey J. 
Published: October 2019

Abstract
Background: PR1 is a nonomeric HLA-A2-restricted peptide derived from the myeloid leukemia-associated antigens, proteinase 3 and neutrophil elastase. PR1-specific cytotoxic T lymphocytes (PR1-CTL) selectively kill MDS, AML and CML and contribute to complete cytogenetic remission. We conducted a phase I/randomized phase II trial to evaluate the safety and efficacy of a PR1 peptide vaccine to elicit PR1-CTL in leukemia patients.
Methods: Sixty-six HLA-A2+ patients with acute myeloid leukemia (42), chronic myeloid leukemia (13) or myelodysplastic syndrome (11) were treated with PR1 peptide vaccine. The first 54 patient received three vaccinations, and the last 12 patients received 6 vaccinations. PR1 was injected with incomplete Freud’s adjuvant (Montanide ISA) subcutaneously, at 3 week intervals at one of three dose levels: 0.25, 0.5 or 1.0 mg per vaccination. GM-CSF at a dose of 75 mg was injected subcutaneously into the same site. Immune response to the vaccine was defined as a ≥ 2-fold increase in peripheral blood PR1-CTL. Fifty-three patients had measurable disease and 13 were in complete remission at enrollment.
Results: The vaccine was well tolerated, with toxicity limited to grade I and II injection site reactions. PR1-specific immune response was observed in 25/53 (47%) patients with measurable disease. Clinical responses were observed in 9/25 (36%) immune responders versus 3/28 (10%) immune non-responders (p=0.03). The PR1 vaccine-induced immune response was associated with a longer event-free survival, 8.7 months vs. 2.4 months (p = 0.03), and a trend towards longer overall survival. Among the 13 patients treated in complete remission, 4 have remained in remission for a median of 30.5 months (range 11–59 months). This includes continued complete remissions in 3/10 who were IRV+, and 1/3 who were IRV-. PR1-specific immune response lasted for up to 4 years in some patients. In a multivariate model, low bone marrow blast count (<10%) emerged as a significant predictor of an immune response and a longer event-free survival (p=0.001).
Conclusion: PR1 peptide vaccine-induced immune response is associated with a clinical response and better event-free survival in patients with myeloid leukemia, who had measurable disease at vaccination. Patients with ≤10% bone marrow blasts are likely to obtain the maximum benefit.
Figure Figure
Whole Genome Association Study in Leukemia: Frequent Loss of Heterozygosity (LOH) and Single Nucleotide Polymorphism (SNP) in Acute Myeloid Leukemia with a Normal Karyotype.
Authors: Lee Young Y. , Park Joowon , Yoon Sung-Soo , Ahn Kwang-Sung , Choi Jung H. , Park Byoung B. , Kim Byoung K. 
Published: October 2019

Abstract
Acute myeloid leukemia (AML) is a heterogeneous disease with various chromosomal aberrations. The karyotype at diagnosis is generally recognized as the single most valuable prognostic factor. However, using conventional cytogenetic techniques, karyotype abnormalities are detected in only half of all AML cases and the other half are commonly described as normal-karyotype AML. Patients with normal-karyotype AML are classified as an intermediate risk group with a 5-year overall survival of between 35% and 45%, but clinical outcome may vary greatly. Also, classical cytogenetic methods are limited in resolution and dependent on highly skilled labor. Therefore, the appropriate choice of additional treatment in patients who attained first remission (chemotherapy versus autologous transplantation versus allogeneic transplantation) is unclear for these patients. Thus, additional markers with prognostic significance are needed to identify clinically relevant subgroups among AML patients with a normal karyotype. Recently, human genome-wide studies gain popularity to identify the genetic basis of complex disorders such as AML. Altered transcript levels in AML genomes are often related to copy number changes, and genome-wide detection of allelic imbalance in AML cells by polymorphic genetic markers has become an important technique to identify genetic events involved in the progression of AML. By using high density single-nucleotide polymorphism (SNP) microarrays designed to genotype more than 300K SNPs in the human genome DNA, the resolution of the whole genome scanning technique has increased considerably and allowed accurate and reproducible determination of copy number changes in whole genome of AML. It became possible to distinguish between LOH regions with underlying homozygous deletions and those with copy-neutral events. In the present study, we performed genetic changes in untreated AML with normal cytogenetics with infinium 300K SNP chip. SNP-based mapping array data and fluorescence in situ hybridization (FISH) copy number data correlated well. The most frequently identified alterations are located at 3p, 6q, 8p, 13q, 21q and 22p. LOH is found in these large regions and also in smaller regions throughout the genome with a median size of 1 Mb. Alterations was correlated with response to chemotherapy. Twenty six candidate genes showed significant evidence of linkage in the presence of disequilibrium, and ten of these were expressed in AML patients who failed to attain remission. Three other genes showing statistical evidence were not expressed. Many of the genes reported here have not been previously reported in relation to progression of AML. We show that this panel of markers adds important prognostic information for this largest subgroup in AML.
Favourable Treatment Outcome in Childhood AML Is Determined by Intact Apoptosis Signalling in Myeloid Leukaemia Cells.
Authors: Meyer Lüder H. , Dammé Manon , Eckhoff Sarah M. , Creutzig Ursula , Reinhardt Dirk , Karawajew Leonid , Ludwig Wolf D. , Stahnke Karsten , Debatin Klaus M. 
Published: October 2019

Abstract
Defects in cell death signalling might be responsible for treatment failure and relapse in acute leukaemia. In a study on paediatric acute lymphoblastic leukaemia (ALL) we recently reported the importance of intact apoptosis signalling for favourable outcome. Here we addressed this issue in 45 paediatric acute myeloid leukaemia (AML) patient samples. Two key apoptogenic events: cytochrome c release and caspase-3 activation were analysed by flowcytometry in the leukaemia cells after induction of apoptosis by factor deprivation. Release of cytochrome c and consecutive apoptosome formation leads to activation of downstream effector caspases such as caspase-3. Both events were closely correlated to each other in good responding patients (less than 5% blasts in bone marrow or minimal residual disease negativity) and in patients achieving remission. No correlation was found in patients with poor treatment response or patients not reaching remission. Caspases other than caspase-3 acting upstream of mitochondria (e.g. caspase-8) are also involved in initiating or amplifying this complex. By incubation in presence or absence of the pan-caspase inhibitor zVADfmk cytochrome c release was observed to be dependent or independent on upstream caspases. Of note, only cytochrome c released in dependence on amplifying caspases was observed to correlate with activated caspase-3 in patients with good response to treatment or patients without relapse. This indicates that an intact apoptosome function and active amplifying caspases are elementary for favourable outcome in childhood AML. The functional integrity of this important apoptogenic checkpoint is subsumed by the parameter caspase dependent cytochrome c-related activation of caspase-3 (CRACdep). Division of our cohort according to this new paramenter resulted in two groups of 38 CRACdep -positive and 7 -negative patients, the distribution of the values being unrelated to features such as FAB subtype or risk groups. 30 of 32 patients sustaining complete remission for more than one year were CRACdep -positive (Fisher exact test, P= .015). Analysis of survival (N=45, log rank P= .014) and remission duration (N=40, log rank P= .001) revealed a superior outcome for CRACdep -positive patients. This was also observed when considering the high risk patients only. Notably, standard risk stratified patients merely displayed CRACdep -positivity. Thus, the propensity to undergo apoptosis as reflected by intact signalling in leukaemia cells is an important feature for favourable treatment outcome and may serve as additional stratification tool for paediatric AML patients.
TGF-β Receptor Kinase Inhibitor LY2109761 Reverses the Anti-Apoptotic Effects of TGF-β1 in Leukemic Cells Co-Cultured with Stromal Cells.
Authors: Tabe Yoko , Xu Yuanyuan , McQueen Teresa , Andreeff Michael , Konopleva Marina 
Published: October 2019

Abstract
Transforming growth factor β1 (TGF-β1) is an essential regulator of cell proliferation, survival, and apoptosis, depending on the cellular context. TGF-β1 is also known to affect cell-to-cell interactions between tumor and stromal cells through production of the extracellular matrix and stimulation of integrin receptors. We investigated the role of TGF-β1 in the survival of human leukemic cells growing in the context of bone marrow (BM) microenvironment, and the anti-leukemia effects of the novel TGF-β receptor inhibitor LY2109761. BM-derived mesenchymal stem cells (MSC) produced TGF-β in an autocrine fashion. Treatment with rhTGF-β1 (2ng/mL) inhibited the spontaneous and Ara-C-induced apoptosis in U937 cells (% AnnexinV(+), control 34.5±8.4; TGF-β1 18.4±4.5; Ara-C 88.6±3.0; Ara-C/TGF-β1 60.4±8.0, p=0.04). These effects were more prominent in U937 cells co-cultured with MSC (% AnnexinV(+), control 19.4±2.8; TGF-β1 3.5±1.0; Ara-C 69.0±3.6; Ara-C+TGF-β1 24.9±3.3; p=0.01). In U937 cells co-cultured with MSC, rhTGF-β1 conferred higher cell protective effects on leukemia cells attached to MSC than on floating cells. Conversely, the pro-survival effects of TGF-β1 were inhibited by 5mM LY2109761 (%AnnexinV(+); MSC(−), control 31.8±2.3, TGF-β1 19.5±3.0, LY 28.4±4.4, TGF-β1+LY 37.7±2.0; MSC(+), control 22.1±1.7, TGF-β1 7.8±0.9, LY16.1±2.6, TGF-β1+ LY 18.0±1.1, p<0.01). Similar results were obtained using TGF-β1 neutralizing antibody. TGF-β1 induced pro-survival phosphorylation of Akt in U937 cells cultured alone or co-cultured with MSC, which was abrogated by LY2109761. Further, rhTGF-β1 induced a moderate increase in C/EBPβ gene and LAP isoform (cell cycle arrest inducing) of C/EBPβ protein in U937 cells cultured without MSCs, while markedly upregulating C/EBPβ gene and protein, both LIP (cell proliferation inducing) and LAP isoforms, under MSCs co-culture condition, suggesting the novel role of C/EBPβ in TGF-β1-mediated U937 cell survival. In summary, these results indicate that TGF-β1-secreting BM stromal cells promote the survival of U937 leukemia cells via direct cell-to-cell interaction and promote chemoresistance of leukemia cells through the activation of Akt signaling and upregulation of C/EBPβ. The blockade of TGF-β signaling by LY2109761, which effectively inhibited the pro-survival signaling, may enhance the efficacy of chemotherapy against leukemia cells in the BM microenvironment.
Membrane Type-Matrix Metalloproteinases (MT-MMPs) Are Expressed in Acute Myeloid Leukemia Cells and Are Upregulated by TNF-α.
Authors: Shirvaikar Neeta , Jalili Ali , Ilnitsky Sara , Larratt Loree , Mirza Imran , Janowska-Wieczorek Anna 
Published: October 2019

Abstract
Membrane type-matrix metalloproteinases (MT-MMPs) play a key role in tumor cell progression and metastasis but their role in hematological malignancy and leukemic cell dissemination is still unclear. To date, six MT-MMPs have been identified, of which four (MT1-, MT2-, MT3- and MT5-MMP) possess a trans-membrane domain that tethers the enzyme to the plasma membrane and two (MT4- and MT6-MMP) are anchored to the cell surface via a glycophosphatidyl inositol domain. MT-MMPs are known to activate pro-forms of MMPs. We examined the expression of all six MT-MMPs in 13 myeloid and lymphoid cell lines using RT-PCR, Western blotting and FACS. We found that
MT1-MMP was expressed on most of the cell lines tested, MT2-MMP was expressed in myeloid cell lines such as THP-1, HEL, K562 and U937, and in T cell lines such as Jurkat and CEM, but not in any of the tested B cell lines, MT3-MMP was not expressed in any of the cell lines except for THP-1, MT4-MMP was strongly expressed in all myeloid but not lymphoid cell lines and MT5-MMP and MT6-MMP were expressed in most of the myeloid cell lines.
Next, we examined the expression of all six MT-MMPs in primary AML samples and found that MT1-MMP is expressed in 20 out of 24 AML patient samples as detected by RT-PCR and Western blotting, MT2-MMP and MT4-MMP were expressed in 21 and 22 out of 24 samples, respectively, and MT6-MMP was expressed in 17 out of the 17 samples tested. In contrast, MT3- and MT5-MMPs were not found in the primary AML samples. Zymographic analysis showed that the pro form of MMP-2 was secreted in media conditioned by AML blasts and became activated only when these AML blasts were co-cultured with BM stromal cells. Since TNF-α is endogenously secreted by AML blasts we next stimulated these cells with human recombinant TNF-α and found strong upregulation of MT1-MMP and MT6-MMP. Moreover, zymography demonstrated that TNF-α-stimulated AML blasts are more potent in activation of pro-MMP-2 than unstimulated cells, indicating that activation may occur via upregulation of MT-MMPs. Furthermore, we found that TNF-α stimulation led to stronger upregulation/induction of MT1- and MT2-MMPs in CD34+ cells than in CD34- cells isolated from AML patients. In conclusion, we report here for the first time that MT1-, 2-, 4- and 6-MMPs are expressed in AML blasts and suggest that these MT-MMPs may contribute to the invasive phenotype of this malignancy.
Maintenance Chemotherapy (MC) after Autotransplantation in First-Remission Acute Lymphoblastic Leukemia (ALL): Single-Center Experience of 100 Patients.
Authors: Sirohi Bhawna , Powles Ray , Treleaven Jennifer , Kulkarni Samar , Saso Radovan , Potter Mike , Ethell Mark , Morgan Gareth , Singhal Seema , Mehta Jayesh 
Published: October 2019

Abstract
Results of autotransplantation in adult ALL are poor. MC, a component of standard ALL therapy, is usually not employed after autografting. 100 adults with ALL in CR1 received melphalan 110 mg/m2 with TBI followed by marrow (n=35) or melphalan 200 mg/m2 followed by blood stem cells (n=65) between 7/1984 and 2/2003. Daily 6-MP 25 mg was started when WBC and platelets reached 3 and 100 × 109/L respectively, and its dose increased gradually. Weekly methotrexate (MTX) 5 mg was added when the 6-MP dose reached 75 mg. Until 1995, monthly vincristine (1.4 mg/m2) and prednisolone (40 mg/m2 daily for a week) (VP) were given if 6-MP and MTX were not tolerated. After 1995, VP was given routinely. Starting MC was delayed only by inadequate counts, relapse, or medical problems that could get exacerbated. 6-MP and MTX doses were adjusted to maintain ANC >1 × 109/L. MC was stopped 2 y after starting 6-MP. 6 patients, all TBI and marrow recipients, died of toxicity (P=0.001). The 7-y cumulative incidence (CI) of relapse was 45%. The 7-y DFS and OS probabilities were 45% and 48%.
Age ≥30 y (49 patients), >4 wks to attain CR (20 patients), and karyotypes t(4;11) and t(9;22) (14 patients) were associated with higher relapse and lower DFS/OS. Patients with 0 (standard-risk; 42 patients), 1 (intermediate-risk; 36 patients), and 2–3 (high-risk; 22 patients) adverse features had 7-y CI of relapse of 19%, 53%, and 82% (P<0.0001), and 7-y DFS probabilities of 73%, 36%, and 7% (P<0.0001). 70 patients received 6-MP, 53 received MTX and 40 received VP. 22 patients received no MC at all, 14 received 1 agent, 43 received 2 agents, and 21 received 3 agents. MC did not result is any life-threatening toxicity. Amongst the 86 patients alive in CR at 4 months, the 7-year CI of relapse was 58%, 64%, 41%, and 23% for those receiving 0, 1, 2, and 3 MC agents (P=0.015). The corresponding 7-y DFS was 15%, 29%, 58%, and 61% (P=0.014). Patients getting MC had better outcome than those getting none. Patients getting 2/3 agents had better outcome than those getting 0/1 agents. MC intensity was an independent determinant of outcome in Cox analysis. The curves below show the effect of MC intensity.
When analyzed by disease risk, the benefit of MC was confined to patients with low- or intermediate-risk disease. While we cannot rule out the possibility that the ability to tolerate MC may have been a surrogate marker for a better-quality remission, the safety of post-transplant MC and its results are encouraging. We conclude that MC reduces relapse and improves DFS in non-high-risk ALL after autotransplantation, and this strategy should be incorporated as standard practice if an autograft is performed in ALL.
Figure Figure Figure Figure
Autologous Peripheral Blood Stem Cell Transplantation (PBSCT) Combined with Haploidentical Lymphocytes Infusion Increases the Long Term Survival of Adult Acute Myeloid Leukemia with Standard Risk.
Authors: Wu Bingyi , Kunyuan Guo , Hu Haiyan , Yang Yuliang , Deng Lan , Wu Jing 
Published: October 2019

Abstract
OBJECTIVES: The long term survival of adult patients with acute myeloid leukemia with standard risk factor which treated by autologous peripheral blood stem cell transplantation is about 30–50%. We designed a new therapy to improve the long term survival of adult patients with acute myeloid leukemia with standard risk factor. After completely remission, patients underwent 2–3 courses of consolidation chemotherapy. Autologous peripheral blood stem cell transplantation (PBSCT) was performed. After hematology recovery, haploidentical lymphocytes irradiated with 7.5 Gy were infused into patients. Here we evaluate the outcome of this approach in adult patients with acute myeloid leukemia with standard risk.
METHODS: From July 1998 to July 2007, twenty-four patients including 17 males and 7 females, median age 36 year old (range 14–58) with acute myeloid leukemia with morphology M2 subtype and normal karotype received this approach therapy. Autologous peripheral blood stem cells were collected by aphereses and froze in −198° and storied after 2–3 courses of median dose cytarabine consolidation chemotherapy The autologous stem cells were grafted to patients following the conditioning with the BuCy regimen (Bu16mg/kg and CTX 120mg/kg). Haploidentical lymphocytes obtained by leukapheresis from sibling donors or other relatives were irradiated with 7.5 Gy and were infused into patients after hematopoietic reconstitution.
RESULTS: A median dose of 2.5×108/kg, nucleated cells/kg (range, 2.97×107/kg-6.0×108/kg)containing 5 × 106 CD34+ cells/kg (range,1.5– 4.8) were autografted. All patients were got hematopoietic reconstitution. The median time for granulocyte recovery >0.5 × 109 /L was 11 days and for platelets >20 × 109/L was 14 days following transplantation. All patients were administrated a median dose of 2.0×108/kg haploidentical lymphocytes irradiated with 7.5 Gy. Severe acute GVHD occurred in two patients. One died with severe acute GVHD. Hematopoietic reconstitution delayed in four patients. No other side effects were observed. For the whole group of 24 patients, the median overall survival rate (OSR) was 83.7%. The median disease-free survival (DFS) time was 28.3 moths (range 2–120 m) and the 5-year DFS rate was 50%. The 2-year OS rate was 71%. After a median follow-up of 5.0 years from transplantation, the median DFS and OS were 28.3 years respectively, and the 3-year rates were 50%. Nineteen patients were still in continuous complete remission, 4 patients had relapsed and 3 had died.
CONCLUSIONS: Autologous peripheral blood stem cell transplantation (PBSCT) combined with haploidentical lymphocytes infusion may prolong the long term survival of adult acute myeloid leukemia with standard risk.