Abstract

The characteristic of acute promyelocytic leukaemia (APL) is a reciprocal translocation between chromosomes 15 and 17 resulting in a chimeric PML and retinoic acid receptor alpha (RARA) oncogene. The fusion protein (PML/RARA) formed as result is thought to block the differentiation of the bone marrow cells arrested at the promyelocytic stage. It has been documented by both in vivo and in vitro studies that a large number of APL cells undergo granulocytic maturation after all-trans retinoic acid (ATRA) therapy. The case report presented here is a rare case of PML/RARA positive APL patient exhibiting extensive monocytic differentiation after ATRA therapy as documented by morphology and FISH studies.

Introduction

Acute promyelocytic leukaemia harbours the unique chromosomal translocation t (15;17) which involves the retinoic acid receptor alpha gene (RARA) on chromosomal 17 and PML, the gene of a putative transcription factor on 15 and is thought to be the pathognomonic abnormality of this disorder. This chromosomal translocation causes maturation arrest of the leukaemic cells at the promyelocyte stage by making them insensitive to retinoic acid. However these cells are paradoxically more sensitive to high concentrations of retinoic acid than normal cells, and can be successfully induced to differentiate towards mature neutrophils by ATRA both in vitro and in vivo.1 However there are very few cases documented in literature where the APL cells show monocytic differentiation following ATRA therapy.

We present one such rare case of an APL patient with t (15; 17) showing monocytic along with granulocytic differentiation of APL cells after ATRA therapy.

Case Report

Fig. 1 : Peripheral smear showing the raised total count and myeloblasts.		Fig. 2 : Bone marrow smear showing the promyelocytes showing reniform nuclei and auer rods in the cytoplasm, highlighted in the inset.
Fig. 3 : Peripheral smear showing monocytoid cells following ATRA therapy.		Fig. 4 : Peripheral smear showing normalization of count and mature granulocytes.

Our patient was a 13 year old boy who presented with history of fever since fifteen days and bleeding gums, melaena and ecchymotic patches all over the body since 4 days prior to hospital admission. A complete haemogram done on admission showed anaemia, marked thrombocytopenia and a total WBC count of 35,000/cmm with 58% promyelocytes and 22% myeloblasts (Fig. 1). A bone marrow aspirate smear showed features of acute promyelocytic leukaemia with abnormal promyelocytes with reniform nuclei showing prominent granulation and at times Auer rods (Fig. 2). Interphase FISH studies show 10% cells positive for the PML/RARA, fusion indicative of the classical (15;17) translocation, characteristic of APL. On the basis of the reports standard ATRA therapy was initiated followed by idarubicin therapy. The patient on the fourth day of admission went into DIC and had to be given platelet concentrates. He developed symptoms of the ATRA syndrome with fever and mild dyspnoea along with subarachnoid haemorrhage. Subsequently ATRA was stopped on the 8th day of treatment. From day 10 the patient showed clinical improvement and ATRA was restarted. The total WBC counts from day 15 showed a progressive fall. On day 20 the total WBC count was 11,000/cmm with the differential count showing 71% granulocytes, 22% monocytes and 7% lymphocytes (Fig. 3). The counts repeated after a week showed a total WBC count of 9,800/cmm and the monocytosis was resolved (Fig. 4).

Discussion

It is well known that APL cells differentiate to mature neutrophils following ATRA therapy.2,3 Very few cases in literature report cases of classical APL showing in vivo evidence of marked monocytic differentiation following ATRA therapy. Various studies done previously on haemopoietic colonies derived from the bone marrow of APL patients, have shown that the PML/RARA fusion transcript was found on the more mature CD34/CD38+ progenitors giving rise to both BFU-E and CFU-GM.3 Based on this observation it has been hypothesized that APL arises from the neoplastic transformation of a more differentiated cell type with the capacity to differentiate into either neutrophils or monocytes. FISH analysis for the PML/RARA fusion gene was done to determine whether the monocytes observed after ATRA therapy were derived from the blasts carrying the t (15;17). The high number of positivity (35%) of monocytes determined by FISH analysis gives a clear evidence that a large number of monocytes seen in the peripheral blood smear have differentiated from the leukaemic cells which had retained the underlying cytogenetic abnormality of t (15;7).

The implications of this change seen following ATRA therapy are that the marked monocytosis observed following ATRA therapy should not be of much clinical concern and secondly it supports the theory that the APL cells evolve from an early myeloid cell whose progeny have the dual capacity to differentiate into either granulocytes or monocytes both of which were seen in our case.

Thus to conclude monocytosis observed during ATRA therapy of APL is due to an intrinsic capacity of the leukaemic cells to undergo monocytic differentiation rather than the differentiation of increased numbers of normal haematopoietic cells into monocytes.⁴

References

1. Miyauchi J, Ohayashiki K, Inatomi Y, et al. Neutrophil Secondary - Granule deficiency as a Hallmark of All-Trans Retinoic Acid-Induced Differentiation of Acute Promyelocytic Leukemia Cells. Blood 1997; 90 (2) : 803-13.
   
2. Chomienne C, Fenaux P, Degos L. Retinoid differentiation therapy in promyelocytic leukemia. Faseb J 1996; 10 : 1025-30.
   
3. Signaling pathways activated by all-trans retinoic acid in acute promyelocytic leukemia cells. Leuk Lymphoma 2004; 45 : 2175-85.
   
4. Naeem M, Harison K, Barton K, et al. A unique case of acute promyelocytic leukemia showing monocytic differentiation after ATRA (all-trans retinoic acid) therapy. Eur J Haematol 2006; 76 (2) : 164-66.
   

*Associate Professor, **Resident, Department of Ophthalmology, T.N.M.C and B.Y.L. Nair Hospital, Mumbai - 400 008.