Is Acute Promyelocytic Luekemia Is a Curable Disease ?

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

Correspondence article

 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

N Engl J Med 2016; 374:1197-1198March 24, 2016 DOI: 10.1056/NEJMc1513710 

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) 2^nd 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/m² daily 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 NFK_B inhibitor. AS₂O₃ can 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 2^nd remission. If relapses occur after 2^nd 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

 References

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