Title- “ Is Acute Promyelocytic Leukemia is a curable disease?
Author
Professor Dr Pranab Kumar Bhattacharya MD(University of Calcutta) FIC path(India) Professor Department of Pathology Murshidabad District Medical College Behrampore Station Road ; Behrampore Court; Dist Murshidabad West Bengal Now Posted as Professor of Pathology ( detailment) at Calcutta School of Tropical Medicine 110 CR Avenue Kolkata-700073 West Bengal India
2) Dr Ronok Voyas DCP Student Calcutta School of Tropical Medicine 110 CR Avenue Kolkata -70073 West Bengal India
This article submitted as / correspondence or letter to Editor to New Eng Journal of Medicine against the article under manuscript No NEJM 16-04395 on dated 30.03.2015
Targeted Therapy Alone for Acute Promyelocytic Leukemia
by authors
Francesco Lo-Coco, M.D.University Tor Vergata, Rome, Italy francesco.lo.coco@uniroma2.itLaura Di Donato, M.Sc.
Gruppo Italiano Malattie Ematologiche dell’Adulto (GIMEMA) Foundation, Rome, Italyfor GIMEMARichard F. Schlenk, M.D.University of Ulm, Ulm, Germanyfor the German–Austrian Acute Myeloid Leukemia Study Group and Study Alliance Leukemia
The Editor
Sir , I went through the correspondence article “ Targeted therapy alone for Acute Promyelocytic leukaemia “ published in NEJM[1]
AML, alone is about 15-2-% of Acute Leukaemia (AL) in children and 80% of AL in adults. Acute Promyelocytic Leukaemia (APL) is around 10% of all AML cases. In FAB morphology, APL shows high percentage of Promyelocytes ( >20%) with auer rods and some have multiple bundles of auer rods specially when seen in peroxidise stain. Leukemic cells resembles promyelocytes and they have large atypical primary granules, kidney shaped nucleus and branched or adherent auer rods. Immunological phenotypes are CD9, CD13, CD 15& CD 33+ve and CD34 and HLA Dr- ve. So targeted anti CD33 antibody therapy may be beneficial in this leukaemia
APL are of two types i) macro granular whose peroxidise stain are intensely positive , where hypo fibrinogenmia and haemorrhage from coagulopathy, DIC etc are very common and cells are HLA DR-ve and II) 2nd type is micro granular (M3v) whose leukemic cells are mature promyelocytes and contain RAR-α gene and they do response to All Trans Retinoic Acid ( ATRA) thrapy and anti CD33 antibody therapy or in combination. This micro granular variants is approx 20% of patients with APL . In these patients auer rods may be present but less evident. Within this variant, rarely cells contain eosinophilic or basophilic granules and basophilic variants are again non responsive to ATRA, virulent and relapses common in them. Cytogenetically PML-RAR –α fusion and t( 5:7) , NPM- RARα fusion confer Retinoic acid sensitive when PLZF- RAR –α fusion is usually seen ATRA resistant.
AML results from a series of mutations in either a hematopoietic multi potential cells or occasionally a more differentiated lineage- restricted progenitor cells[2]Some cases of APL and AML in younger individual more likely arise in progenitor cells with linage restrictions. These mutations results from chromosomal translocations in majority patients. The mutant protein products often are a transcription factor or element in the transcription pathways that disrupts the regulatory sequences controlling growth rate or survival of blood cells progenitors and differentiation and maturation. In most APL such translocation involves chromosome 17 t (15:17) that contain RAR α gene or t(15:17). In APL , PML- RAR-α fusion protein represses Retinoic Acid inducible gene which prevent appropriate maturation of Promyelocyte. The Induced disruption involves co receptor histone- deacetylation complexes results APL[3]
The break point on chromosome 17 within the gene for RAR- α and the break point on chromosome 15 within the locus of a gene originally referred MYL is now called as “PML gene” This gene encodes a unique transcription factor. The translocation may results two new chimeric gene i) RAR-α- PML which is actively transcribed in APL. II) PML-RAR-α which is also transcribed and accounts for aberrancy in haematopoiesis. The PML- RAR-α gene has again two iso forms that can produces a short and long type fusion m RNA. And patients of APL with short mRNA iso-form have worst outcome on ATRA or As2O3
ATRA is a standard component of induction therapy in APL when used alone the drug can induce a short remission in 80% APL. However ATRA when combined with anthracyclin groups of drugs like Idarubicin or Gemtuzumab , combined therapy can induce remission in 85-90% patients for 50 months. A typical induction regimen for APL is ATRA 45 mg/m2daily in divided doses with Idarubicin 12mg/m2 daily for 4 days. ATRA induces maturation of leukemic cells; suppression of malignant cells clone; synthesis of a protein that selectively degrade PML-RAR-α fusion gene, induces activity of STAT-1. But APL with leukemic cells that have PML-RAR-α break point fusion site in PML exon no 6 have less responses to ATRA. ATRA combined with chemotherapy is associated with bone marrow suppression ,severe infection ,death from sepsis and secondary leukaemia develop[1] . The combination therapy with ATRA with AS2O3 rather results more rapid responses in remission for long PML-RAR-α transcript mRNA level after either agents used alone. Actually AS2O3 can be useful for patients with relapses with ATRA or ATRA with Idarubicin. AS2O3 trigger apoptosis of promyelocyte leukemic cells at high concentration and maturation at low concentration and this apoptosis occur through activation of caspase -1 & caspase -8. It also function through NFKB inhibitor. AS2O3can be so combined with Idarubicin and ATRA but toxic effect of AS2O3 + ATRA are again prolongation of QT interval, marked elevation of liver enzymes secondary leukaemia [1] and event free survival in AS2O3 in 96% patients for 50 months
Causes of death in APL is haemorrhage as a result of coagulopathy or DIC . Hyper coagulable clotting tendency may occur during first months of ATRA[5] Another cause of death id Retinoic acid syndrome- a rapid increase of total blood leukocyte count as high as 80x 10 9 / litter in first several weeks of therapy( usually by 11-47 days). Similar syndrome has been described when treated with As2O3
Bone marrow transplant is not generally recommended for patients in APL in first or 2nd remission. If relapses occur after 2nd remission, allogeneic stem cell transplant is done for advanced APL in patients with persistent disease detected by PCR [4] and stem cells must be negative for PML-RAR-α gene
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