Oncology Intelligence

Chronic Myeloid/Myelogenous Leukemia
Monday, September 19, 2016 3:08 PM|Dave Levitan|Chronic Myeloid Leukemia on Cancer Network|Labels: CML
A study found that the protein EZH2 is required for chronic myeloid leukemia initiating cells to survive. Inhibiting EZH2 could improve outcomes in TKI-resistant disease.
Wednesday, September 14, 2016 10:47 PM|Lin Li, Na Xu, Jin-fang Zhang, Lu-lu Xu, Xuan Zhou, Bin-tao Huang, Yu-ling Li, Xiao-li Liu|International Journal of Medical Sciences|Labels: Eph, CML, clinical trial

Introduction: The mechanism of EphB4/ephrinB2 in the resistance of chronic myelogenous leukemia to imatinib keeps unknown.

Methods: The imatinib resistant chronic myelogenous leukemia cell line-K562-R, was established. EphB4 receptor expression was detected in patients and resistant cells. Cell migration and drug sensitivity were tested in the EphB4 knockdown cells and mouse models.

Results: The EphB4 receptor was over-expressed in blast crisis patients compared to chronic phase patients. The level of EphB4 receptor expression was associated with a complete cytogenetic response within 12 months. Enhanced expression of the EphB4 receptor was detected in the K562-R cells. EphB4 knockdown inhibited cell migration ability and restored sensitivity to imatinib in vitro and in vivo. Restored sensitivity to imatinib was observed in K562-R cells, along with increased levels of phospho-EphB4 and decreased phosphorylation levels of RhoA, Rac1, and Cdc42.

Conclusion: Our study illustrates that aberrant activation of EphB4/ephrinB2 may mediate chronic myeloid leukemia resistance involved in cytoskeletal proteins.

Wednesday, September 14, 2016 4:21 PM|Fred Hutchinson Cancer Research Center/UW Medicine Cancer Consortium - Clinical Trials|Labels: CML, clinical trial
This phase II trial studies how well selective T cell depletion works in preventing graft-versus-host disease (GVHD) in patients with acute lymphocytic leukemia, acute myeloid leukemia, or chronic myelogenous leukemia undergoing donor peripheral blood stem cell transplant. Giving chemotherapy and total-body irradiation before a donor peripheral blood stem cell transplant helps stop the growth of cancer cells. It may also stop the patient's immune system from rejecting the donor's stem cells. When the healthy stem cells from a donor are infused into the patient they may help the patient's bone marrow make stem cells, red blood cells, white blood cells, and platelets. Sometimes the transplanted cells from a donor can make an immune response against the body's normal cells. Removing a subset of the T cells from the donor cells before transplant may stop this from happening.
Wednesday, September 14, 2016 4:21 PM|Fred Hutchinson Cancer Research Center/UW Medicine Cancer Consortium - Clinical Trials|Labels: CML, clinical trial
The purpose of this study is to fulfill the post-authorization commitment made by Pfizer to the European Medicines Agency in providing additional safety and efficacy data in approximately 150 Philadelphia Chromosome Positive Chronic Myeloid Leukemia patients with high unmet medical need, including 75 Chronic Phase, Accelerated Phase or Blast Phase patients in the fourth or later line treatment setting (i.e., after treatment with at least 3 other Tyrosine Kinase Inhibitors).
Monday, September 12, 2016 12:52 PM|Agerstam, H., Hansen, N., von Palffy, S., Sanden, C., Reckzeh, K., Karlsson, C., Lilljebjorn, H., Landberg, N., Askmyr, M., Hogberg, C., Rissler, M., Porkka, K., Wadenvik, H., Mustjoki, S., Richter, J., Jaras, M., Fioretos, T.|BLOOD First Edition Papers|Labels: NFKb, CML, clinical trial, IL

Chronic myeloid leukemia (CML) is currently treated with tyrosine kinase inhibitors but these do not effectively eliminate the CML stem cells. As a consequence, CML stem cells persist and cause relapse in most patients upon drug discontinuation. Furthermore, no effective therapy exists for the advanced stages of the disease. IL1RAP (IL1R3) is a co-receptor of IL1R1 and has been found upregulated on CML stem cells. Here we show that primitive (CD34+CD38-) CML cells, in contrast to corresponding normal cells, express a functional IL1 receptor complex and respond with NFKB activation and marked proliferation in response to IL1. IL1RAP antibodies that inhibit IL1 signaling could block these effects. In vivo administration of IL1RAP antibodies in mice transplanted with chronic and blast phase CML cells resulted in therapeutic effects mediated by murine effector cells. These results provide novel insights into the role of IL1RAP in CML and a strong rational for the development of an IL1RAP antibody therapy to target residual CML stem cells.

Wednesday, September 7, 2016 12:31 PM|Cancer News -- ScienceDaily|Labels: CML
A study in mice combining two inhibitor drugs for treatment of chronic myeloid leukemia has revealed potential for not only stopping the disease completely, but also significantly lowering the cost for treatment.
Monday, August 15, 2016 1:37 PM|Dave Levitan|Chronic Myeloid Leukemia on Cancer Network|Labels: CML, clinical trial
A propensity score–matched comparison of two phase II trials found that dasatinib and nilotinib offer similar responses and outcomes as first-line therapy for patients with chronic-phase CML.
Sunday, August 14, 2016 10:05 PM|Thielen, N., Richter, J., Baldauf, M., Barbany, G., Fioretos, T., Giles, F., Gjertsen, B.-T., Hochhaus, A., Schuurhuis, G. J., Sopper, S., Stenke, L., Thunberg, S., Wolf, D., Ossenkoppele, G., Porkka, K., Janssen, J., Mustjoki, S.|Clinical Cancer Research recent issues|Labels: Bcr-Abl, CML

Purpose: Leukemic stem cells (LSCs) may harbor important resistance to tyrosine kinase inhibitors in chronic myelogenous leukemia (CML). We identified Philadelphia chromosome (Ph)–positive CD34+CD38 bone marrow cells (here denoted LSCs) and addressed their response-predictive value in patients with CML (n = 48) subjected to nilotinib in the ENEST1st trial (NCT01061177).

Experimental design: Two flow cytometry–based cell sorting methods were used with multiparameter-directed CD45- (MPFC) and BCR-ABL1 probe-linked (FISH) identification of Ph-positive cells, respectively.

Results: We observed a positive correlation between the proportion of LSCs at diagnosis and established prognostic markers (blast count, spleen size, Sokal score, and hemoglobin). Conversely, a high LSC burden predicted for an inferior molecular response at 3 (MPFC and FISH), 6 (MPFC), 9 (FISH), and 15 months (FISH). During nilotinib therapy, the proportion of LSCs decreased rapidly. At 3 months, a median of only 0.3% LSCs remained among CD34+CD38 cells, and in 33% of the patients the LSC clone was not detectable anymore (FISH). The response kinetics was similar in LSC fractions as it was in the progenitor and unseparated bone marrow cell fractions.

Conclusions: The proportion of LSCs at diagnosis, as analyzed by two independent methodologies, reflects the biology of the disease and appeared as a prognostic and response-predictive marker in patients with CML subjected to first-line nilotinib therapy. Clin Cancer Res; 22(16); 4030–8. ©2016 AACR.

CONCLUSIONSIn a PS‐matched cohort of patients with newly diagnosed CML‐CP, dasatinib and nilotinib offer similar response and survival outcomes. Both drugs can be considered reasonable standard‐of‐care options as first‐line therapy for patients with CML‐CP. Cancer 2016. © 2016 American Cancer Society. (Source: Cancer)
Sunday, July 31, 2016 10:05 PM|Pratz, K. W., Koh, B. D., Patel, A. G., Flatten, K. S., Poh, W., Herman, J. G., Dilley, R., Harrell, M. I., Smith, B. D., Karp, J. E., Swisher, E. M., McDevitt, M. A., Kaufmann, S. H.|Clinical Cancer Research recent issues|Labels: PARP, CML, MDS

Purpose: DNA repair defects have been previously reported in myeloproliferative neoplasms (MPN). Inhibitors of PARP have shown activity in solid tumors with defects in homologous recombination (HR). This study was performed to assess MPN sensitivity to PARP inhibitors ex vivo.

Experimental Design: HR pathway integrity in circulating myeloid cells was evaluated by assessing the formation of RAD51 foci after treatment with ionizing radiation or PARP inhibitors. Sensitivity of MPN erythroid and myeloid progenitors to PARP inhibitors was evaluated using colony formation assays.

Results: Six of 14 MPN primary samples had reduced formation of RAD51 foci after exposure to ionizing radiation, suggesting impaired HR. This phenotype was not associated with a specific MPN subtype, JAK2 mutation status, or karyotype. MPN samples showed increased sensitivity to the PARP inhibitors veliparib and olaparib compared with normal myeloid progenitors. This hypersensitivity, which was most pronounced in samples deficient in DNA damage–induced RAD51 foci, was observed predominantly in samples from patients with diagnoses of chronic myelogenous leukemia, chronic myelomonocytic leukemia, or unspecified myelodysplastic/MPN overlap syndromes.

Conclusions: Like other neoplasms with HR defects, MPNs exhibit PARP inhibitor hypersensitivity compared with normal marrow. These results suggest that further preclinical and possibly clinical study of PARP inhibitors in MPNs is warranted. Clin Cancer Res; 22(15); 3894–902. ©2016 AACR.

Thursday, July 28, 2016 8:22 AM|Leukemia News -- ScienceDaily|Labels: CML
Researchers have made a world-first breakthrough in the early detection of patients' resistance to a common treatment for chronic myeloid leukemia.
Monday, July 25, 2016 8:16 AM|Uchakina, O. N., Ban, H., Hostetler, B. J., McKallip, R. J.|Glycobiology - Advance Access|Labels: PARP, CML

In the current study we examined the ability of 4-methylumbelliferone (4-MU), which can inhibit hyaluronic acid synthesis, to sensitize K562 chronic myelogenous leukemia (CML) cells to doxorubicin therapy. Exposure of K562 cells to doxorubicin led to increased hyaluronic acid synthase (HAS) gene expression and increased levels of cell surface hyaluronic acid. Furthermore, exposure of K562 cells to exogenous HA caused resistance to doxorubicin-induced cell death. The combination of low dose 4-MU and doxorubicin led to increased apoptosis when compared to higher doses of any agent alone. Additionally, treatment with 4-MU led to a significant reduction in doxorubicin-induced increase in HA cell surface expression. Mechanistically, 4-MU treatment led to an increase in p38 activation and PARP cleavage. The role of p38 in 4-MU/doxorubicin-treated K562 cells was confirmed when p38 inhibitors led to protection from 4-MU/doxorubicin-induced apoptosis. Together, results from this study suggest that treatment with 4-MU increases the sensitivity of CML to chemotherapeutics by decreasing their HA-mediated resistance to apoptosis.

Wednesday, June 29, 2016 10:30 AM|Dave Levitan|Chronic Myeloid Leukemia on Cancer Network|Labels: ALL, CML
Maintenance therapy with TKIs following allogeneic HSCT is feasible and may improve outcomes in patients with high-risk Philadelphia chromosome–positive leukemia.
Monday, June 20, 2016 8:04 AM|Leukemia News -- ScienceDaily|Labels: CML
Biologists present new findings on chronic myeloid leukemia and possible therapeutic approaches, in a newly published article. Chronic myeloid leukemia (CML) develops through chromosomal alterations in blood-forming cells of the bone marrow and usually occurs in older persons. Around 20 percent of adults diagnosed with leukemia suffer from this type of blood cancer.
Thursday, June 16, 2016 11:19 AM|Dave Levitan|Chronic Myeloid Leukemia on Cancer Network|Labels: CML
Two studies show that early deep responses with TKIs yield lasting positive outcomes in CML patients, and that dasatinib outperforms imatinib.
Wednesday, June 15, 2016 3:15 PM|News-Medical.Net Chronic myeloid leukaemia News Feed|Comments|Labels: CML, clinical trial
Research demonstrates the continuing role of allogeneic stem cell transplantation as a salvage option for patients with chronic myeloid leukaemia who progress to accelerated phase or blast crisis after tyrosine kinase inhibitor failure.
Wednesday, June 15, 2016 3:15 PM|News-Medical.Net Chronic myeloid leukaemia News Feed|Comments|Labels: CML
Patients with high-risk chronic myeloid leukaemia who undergo allogeneic haematopoietic stem cell transplantation may benefit from continuing with tyrosine kinase inhibitor therapy, US clinicians believe.
Wednesday, June 15, 2016 3:15 PM|News-Medical.Net Chronic myeloid leukaemia News Feed|Comments|Labels: CML, clinical trial
Final DASISION study findings confirm dasatinib to be an effective, long-term treatment for patients with a new diagnosis of chronic phase-chronic myeloid leukaemia.
Monday, May 23, 2016 2:00 PM|Dave Levitan|Chronic Myeloid Leukemia on Cancer Network|Labels: CML
A 5-year analysis of the DASISION trial showed that dasatinib continued to offer better responses than imatinib in patients with chronic myeloid leukemia.
Wednesday, May 18, 2016 3:15 PM|News-Medical.Net Chronic myeloid leukaemia News Feed|Comments|Labels: CML
Allogeneic hematopoietic stem cell transplantation is associated with a high rate of survival for carefully chosen chronic myeloid leukaemia patients who do not respond well to tyrosine kinase inhibitor therapy, research suggests.
Wednesday, May 18, 2016 3:15 PM|News-Medical.Net Chronic myeloid leukaemia News Feed|Comments|Labels: CML, clinical trial
The primary endpoint of major molecular response at 12 months for ponatinib versus imatinib in patients with newly diagnosed chronic phase-chronic myeloid leukaemia remains undetermined, report the EPIC trial investigators.
Wednesday, May 18, 2016 3:15 PM|News-Medical.Net Chronic myeloid leukaemia News Feed|Comments|Labels: CML
Treatment-free remission may be feasible in many patients with chronic myeloid leukaemia, say researchers who set out clinical and logistical requirements for discontinuing tyrosine kinase inhibitor therapy.
Tuesday, May 3, 2016 1:00 PM|Dave Levitan|Chronic Myeloid Leukemia on Cancer Network|Labels: CML
The addition of pegylated interferon-ɑ2b to dasatinib yielded promising results in a small trial of newly diagnosed chronic myeloid leukemia patients.
Friday, April 22, 2016 9:00 AM|Dave Levitan|Chronic Myeloid Leukemia on Cancer Network|Labels: CML, clinical trial
The efficacy of ponatinib in patients with newly diagnosed CML compared with imatinib remains to be established, as a randomized phase III trial was terminated early due to concerns regarding arterial occlusive events with ponatinib.
Sunday, March 20, 2016 5:00 PM|Cancer|Cancer via|Comments|Labels: CML, clinical trial
CONCLUSIONSOverall, lymphocytosis occurred and persisted in many dasatinib‐treated patients in all phases of CML. Its presence was associated with higher response rates, significantly longer response durations, and increased overall survival, suggesting an immunomodulatory effect. Prospective studies are warranted to characterize the functional activity of these cells and to assess whether an immunologic effect against CML is detectable. Cancer 2016. © 2016 The Authors. Cancer published by Wiley Periodicals, Inc. on behalf of American Cancer Society. (Source: Cancer)