DNA Methylation in CML be partially reversed if treatment with decitabine and a combination of decitabine and Imatinib in CML & may show a promising response both in AP and BP of CML, Such drug combinations thus may be relevant even after therapy with second/third-generation Tyrosine kinase inhibitors

DNA Methylation in CML be partially reversed if treatment with decitabine and a combination of decitabine and Imatinib in CML & may show a promising response both in AP and BP of CML, Such drug combinations thus may be relevant even after therapy with second/third-generation Tyrosine kinase inhibitors

Posted by Pranab on 31 Oct 2011 at 06:02 GMT

DNA Methylation in CML be partially reversed if treatment with decitabine and a combination of decitabine and Imatinib in CML & may show a promising response both in AP and BP of CML, Such drug combinations thus may be relevant even after therapy with second/third-generation Tyrosine kinase inhibitors
Professor Pranab Kumar Bhattacharya MD(CAL) FICpath(Inda) , Professor and Head, Dept. of Pathology, In charge- DCP course WBUHS and Miss Upasana Bhattacharya; Rupak Bhattacharya; Ritwik Bhattacharya ;Soumyak Bhattacharya ;Rupsa Bhattacharya ;Dalia Mukherjee; Oindrila Mukherjee; Anuradha Dey; Ranu Roy Biswas, Soma Das: Hriday Ranjan Das; Surajit Sarkar ;
Email corrosponding author -: profpkb@yahoo.co.in
Authors affiliation and Qualifications
*Professor Pranab Kumar Bhattacharya MD(cal), FIC Path(Ind), Professor and Head, Dept. of Pathology Incharge DCP Course WBUHS; *Miss Upasana Bhattacharya – daughter of Prof. P.K. Bhattacharya ; **Rupak Bhattacharya BSc(cal),MSc(JU);**Ritwik Bhattacharya B.com(cal); **Soumyak Bhattacharya BHA;** Rupsa Bhattacharya of residence 7/51 Purbapalli, Sodepur, Kol-110; **Dalia Mukherjee BA(hons) cal, **Miss Oindrila Mukherjee, Debasis Mukherjee BSC(cl) of residence Swamijinagar, Habra *Dr. Anuradha Dey DCP(cal) MD(AIIMS)* Dr, Ranu Roy Biswas MD(cal) Asst Professor Pathology Dr Soma Das MBBS, DCH(cal) Demonstrator Pathology**** Surajit Sarkar Bsc(cal) DMLT(cal)
*Dept of Pathology & microbiology Calcutta School of Tropical Medicine, C.R avenue Calcutta-73, W.B , India** 7/51 Purbapalli; Sodepur; 24 Parganas(north) Kol-110 W.B, India **** Dept of pathology, IPGME&R, Kolkata-20 W.B, India

DNA methylation in promoter, CPG islands is mechanism of gene silencing, one of drivers of neoplastic transformation through inactivation of critical tumor-suppressor pathways. DNA hypermethylation found in various types of leukemias including AML , ALL[1,5]. CML comprises about 15% of adult leukemias globally. Etiologically, CML is a homogeneous genetic disease, triggered by aberrant tyrosine kinase activity of BCR-ABL translocation [2].Despite genetic homogeneity, there remain heterogeneity in course of CML: it progresses at varying rates, from CP to AP and eventually to Blastic phase{BP}. Imatinib mesylate (Gleevec) though still effective in CP of Ph+ve CML [FDA approved - 2001] in patients with high sokol score [ prognostically still reliable scoring], & 5-years survival rate, today improved from 80- 88%, it is less effective for BP and 2 % of CML [2]. Two TKIs, dasatinib [approved FDA-2006 for adults CML with resistance or intolerance to prior therapy, including imatinib] and nilotinib [approved FDA - 2007 for CP and AP ph +ve adult CML- resistant to or intolerant to prior therapy that included Gleevec ], found be active in some patients with imatinib-resistant disease. Success of TKIs in CML gave patients hope for long disease-free survival in early 2000. However, with prolonged survival time in CML, questions arose about the possibility of late effects of TKI . Imatinib , or Dastinib or combination Imatinib + IFNα included possibility of developing various invasive malignancies, mostly however with imatinib after median time of 40 months survival, BCC, SCC, melanoma,(30% cases), breast cancer[author found 1 case], Prostate cancer[1 Case], GI cancer, GU cancer including RCC even few pancreatic and cholangio carcinomas ,metastatic carcinoma of unknown origin reported in various literatures too[10 ] . These investigators concluded, increased rates of cancers found at large range of sites and for immune deficiency, regardless of mechanism of this deficiency, responsible for such increased risk. There have been scattered reports of co-existence of CML with other lymphoid malignancies such as CLL and multiple myeloma [3,10]. Until 2002, IFN-α was the standard first-line treatment for CP-CML, and allogeneic stem cell transplantation was proposed for patients with low Gratwohl scores CML[4] , the main improvement with imatinib was observed between periods 2000-2007, in patients with intermediate and high Sokal scores, in whom relative survival increased from 65 (53-75) to 95 (82-99) and from 54 (39-67) to 80 (64-89), respectively. Newer therapies with other TKIs (eg, dasatinib, nilotinib, bosutinib now) are effective after imatinib failure [from 2005] and have shown superiority as frontline therapy compared with imatinib mesylate. But Very costly for adherence of medicine
Heterogeneity in disease progression, response to Imatinib therapy is due to molecular events following initial BCR-ABL translocation. Aberrant hypermethylation also had been much previously described in CML [5,6] . Translocated ABL1 promoter showed allele- specific de- novo methylation ,early of disease, unique to CML. Studies showed methylation status of individual tumor-suppressor genes in CML, with results ranging from rare or no hypermethylation (e.g., SFRP1, RASSF1A) [2], to hypermethylation while at progression (e.g., CALCA, CDKN2B, EBF2, ESR, HIC1, TFAP2A, and others), [5]. Hypermethylation of ATG16L2 gene promoter has been associated with a poor response to imatinib treatment[7]. , Imatinib was used due to its additional binding with kIT and PDGF. Imatinib was also approved by FDA[ for patients with KIT-positive(T315I resistance mutation) relapsed AML, where promising results have been seen in early-phase clinical trials]. As, Imatinib, cross -reacts with the PDGF receptor kinase, it has also been repurposed for treatment of dermatofibrosarcoma , systemic mastocytosis, or metastatic malignant GISTs . But use of Imatinib has some limitations as stated. Some CML , show resistance to imatinib during treatment due to point mutations in the BCR-ABL ATP-binding site . Other mechanisms of resistance have been reported, such as BCR-ABL gene amplification, aberrations in other oncogenetic signaling pathways, and persistence of leukemic stem cells and developments of secondary cancers . Extrinsic BM factors contributing to resistance have also been hypothesized, including MDR and Bone marrow micro environmental factors like SDF1 & BAF production, producing B cell turn over increasing IGM CD20+ CD5+ B cells resulting more cell apoptosis factors. These resistant can be overcome by second- and third-generation kinase inhibitors.[8] Some clinical observations suggested, prior IFN α therapy may suppress leukemic relapse on termination of imatinib therapy.[8]Recently, combination therapy with imatinib/IFN-α explored a possible means of deepening the molecular response (4-log reduction in Bcr -Abl/c-Abl ratio) in newly diagnosed CML patients. Two recent studies showed that IFN-α therapy does have this potential, albeit with predicted, with partially manageable, side effects[.8] Although these studies support clinical benefit of adding IFN-α to imatinib therapy, several unanswered questions still remains before authors. First, does IFN- α primarily act against leukemic cells or are other effectors (ie, immune cells) playing a prominent indirect role?. Second, what are potential biochemical mechanisms and intersecting cascades that underlie improved activity of imatinib in presence IFN- α?. It is so may be interesting to consider the fact that DNA methylation can be partially reversed by treatment with decitabine or azacitidine. Though Decitabine has demonstrated single-agent activity in CML [9], a combination of decitabine and imatinib may show a promising response rate in AP and BP . As many patients with blastic-phase CML continue to die of their disease, drug combinations may be relevant even after therapy with second- generation tyrosine kinase inhibitors. However, the best strategy in use of different tyrosine kinase inhibitors in course of the disease still needs to be clarified. Marked impairments were also observed for physical and social functioning as well as overall health status and expectations for health in the future. Fatigue is the most frequently reported symptom and that between 25% and 30% of patients in younger groups then older patients who reported severe symptoms for edema, musculoskeletal pain, muscle cramps, and fatigue with combination.
The survival rate was 89% with imatinib, versus about 70% in previous clinical trials of interferon plus cytarabineHowe ever many people now using either IFN?+ Low doses cytarabine + with Imtainib or imatinib/IFN-?-to initially demonstrate combination of 2 agents was better in reducing cell viability, shows that imatinib potentiated IFN-? signal transduction through effects on one of the IFN-? receptor proteins (IFNAR1) phosporylation.

References
1] Toyota M, Issa JP (2005) Epigenetic changes in solid and hematopoietic tumors. Semin Oncol 32: 521-530;2005.
2] Jelinek J, Gharibyan V, Estecio MRH, Kondo K, He R, et al. (2011) Aberrant DNA Methylation Is Associated with Disease Progression, Resistance to Imatinib and Shortened Survival in Chronic Myelogenous Leukemia. PLoS ONE 6(7): e22110. doi:10.1371/
3] Dushyant Verma,1 Hagop Kantarjian,1 Sara S. Strom,2 Mary Cortes11 Elias Jabbour,1 Alfonso Quintas-Cardama, et al Malignancies occurring during therapy with tyrosine kinase inhibitors (TKIs) forchronic myeloid leukemia (CML) and other hematologic malignancies Blood , August 16, 2011; DOI 10.1182/blood-2011-06-362889
4] Selim Corm, Laurent Rocheean, J Baptiste Mico, Valérie Coiteux, etal Changes in the dynamics of the excess mortality rate in chronic myeloid leukemia over 1990-,] phase-chr2007: a population study of survival started to fall from 2000 onwards, and percentages Blood October 20, 2011 vol. 118 no. 16 4331-4337
5} Strathdee G; Holyoke TL, Sim A ; Parkr A , Osceir DG etal(2007) I, activation of HOXa gene by hypermethylation in Myeloid in lymhoid malignancy is frequent and associated with Poor prognosis Clin. Cancer Research 13;5048-5055;2007
6] Zeon M, Ben yeuhida D Abraham A Cohen O Wetzler M!1994) Progressive DNA Methylation at the BCR -Abl Locus in the course of Chronic myelogenious leukemia Proc. Natl. Aca Sc. US 91; 10722-26;1994
7] Dunwell T, Hesson L, Rauch TA, Wang L, Clark RE, et al. (2010) A genome -wide screen identifies frequently methylated genes in haematological and epithelial cancers. Mol Cancer 9: 44.
8] Bhatia R, Holtz M, Niu N, et al Persistence of malignant hematopoietic progenitors in chronic myelogenous leukemia patients in complete cytogenetic remission following imatinib mesylate treatment. Blood2003;101(12):4701-4707
9] Issa JP, Gharibyan V, Cortes J, Jelinek J, Morris G, et al. (2005) Phase II study of low-dose decitabine in patients with chronic myelogenous leukemia resistant to imatinib mesylate. J Clin Oncol 23: 3948-3956

10] Roy L, Guilhot J, Martineau G, Larche´e R,Guilhot F. Unexpected occurrence of second malignanciesin patients treated with interferon followedby imatinib mesylate for chronic myelogenousleukemia. Leukemia. 2005;19(9):1689-1692]

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Conflict of Interest:
None declared