Background

Acute promyelocytic leukemia (APML) is a biologically and clinically distinct variant of AML. All-trans retinoic acid (ATRA), is the first line treatment in APML where it induces the terminal differentiation of malignant promyelocytes to mature functioning neutrophils. ATRA is generally combined with other agents as remissions induced by ATRA therapy alone are short-lived. When combined with anthracycline, a complete remission (CR) rate of >90% is obtained in the patients with APML (Fenaux et al., 1999; Lo-Coco et al., 2010). Drug toxicities due to ATRA are generally minor. Nasal stuffiness, dry red skin, chapped lips, transient elevations in serum aminotransferases and bilirubin, and hypertriglyceridemia can occur, but rarely require an alteration in treatment (Holmes et al., 2012). However, there are two serious complications that can result from ATRA treatment of APML: (a) differentiation syndrome and (b) Pseudotumor cerebri. In patients with headache, papilledema, and/or vision loss, the diagnosis of PC should be suspected. PC is more common in pediatric age group and adolescents treated with ATRA (Vanier et al., 2003; Naithani et al., 2009), it is rarer in the adults (Castaigne et al., 1990). Herein, we describe a case of ATRA-induced PC in a 25 year old adult female while she was on consolidation treatment for APML.

1 Case Report

A 25-year-old non-obese female patient presented to our hospital with complain of fever and gum hyperplasia since 3 months. On examination, the patient had pallor and bleeding from the gums. Laboratory investigations revealed hemoglobin of 8.5 g/dl, total leucocyte count – 36,000/mm³ (moderate leucocytosis) and platelet count – 41,000/mm³ (moderate thrombocytopenia) with differential count of 70% blast cells + promyelocytes, 3% neutrophils, 27% lymphocytes. The coagulation profile showed normal PT and APTT of 12 sec and 30 seconds respectively. The peripheral blood film showed normocytic normochromic anemia, with predominant blasts and hypergranular promeylocytes. Bone marrow examination revealed 90% blasts + promyelocytes. These blasts were medium to large in size with high nucleus to cytoplasmic ratio, round to indented or lobed nucleus obscured by prominent azurophilic granules with moderate amount of cytoplasm. Many of the cells showed prominent Auer rods. Few faggot cells (cells containing multiple auer rods) were also seen. These cells stained strongly positive with myeloperoxidase and sudan black. Immunophenotypic analysis was performed for confirmation of diagnosis, and it was suggestive of acute myeloid leukemia - FAB M3 type i.e. Acute promyelocytic leukemia with CD13, CD33, CD117, MPO, CD45, CD79a positive and characteristically negative for immature cell markers CD34 and HLA-DR. On Fluorescence in situ hybridization (FISH) 90% of interphase cells were positive for PML-RARa fusion. The patient was started on ATRA 45 mg/m² along with daunorubicin 50 mg/m² for 4 days. After induction chemotherapy, bone marrow was in remission so consolidation treatment was started. Arsenic trioxide 0.15 mg/kg/day 5 days in a week for 5 weeks for two cycles followed by ATRA 45 mg/m² daily for 7 days and daunorubicin 50 mg/m²/day for 3 days given. The patient developed symptoms of headache and diplopia after 5 days of treatment with ATRA. On fundus examination there was bilateral papilloedema. Magnetic resonance imaging (MRI) of brain revealed no significant abnormality. On performing lumbar puncture, cerebrospinal fluid (CSF) an increased opening pressure of 300 mm of water was found without any cytological or biochemical abnormality. CSF cytology was negative and biochemistry revealed CSF protein- 16 mg/dl and CSF glucose- 67 mg/gl. Patient was non-obese and there was no significant history of drug intake such as oral contraceptive pills, minocycline, tamoxifen, lithium, nitrofurantoin or vitamin A. Further lab results revealed hemoglobin of 12.4 g/dl, total leucocyte count – 6300/mm³, platelet count – 4,00,000/mm³; TSH- 1.31 mU/L, Na⁺- 137 and K⁺- 4.5 mmol/l, creatinine- 0.62 mg/dl, Liver function tests including SGOT- 26 U/l, SGPT- 28 U/l, and S. Bilirubin- 0.6 mg/dl. Cortisol levels at 8 am were 300 nmol/l, S. calcium- 10 mg/dl and Parathyroid hormone- 25 pg/ml. Therefore, a probable diagnosis of ATRA induced PC was made, and ATRA was stopped. The patient was started on acetazolamide 500 mg thrice daily and steroids, resulting in complete resolution of the symptoms within 5 days. ATRA was reinstituted after 2 weeks at reduced dose of 25 mg/m² with prophylactic acetazolamide 500 mg/day. Later ATRA was tolerated well by the patient and consolidation therapy was completed.

2 Discussion

Acute promyelocytic leukemia comprises 10% to 15% of acute myeloid leukemia. There is no definite age predeliction but is usually seen in adults. Acute promyelocytic leukemia (APML) is a medical emergency with a high rate of early mortality. Therefore, it is necessary to start treatment as soon as the diagnosis is suspected. For patients with newly diagnosed APML induction therapy is recommended which incorporates all-trans retinoic acid (ATRA) at doses of 45 mg/m² orally until remission is achieved (Castaigne et al., 1990; Tallman et al., 1997).

Though ATRA is considered to be a well- tolerated agent it has many minor side effects including nasal stuffiness, dry red skin, chapped lips, transient elevations in serum aminotransferases and bilirubin, and hypertriglyceridemia. These rarely require an alteration in treatment. Two serious complications which may require an alteration in treatment due to ATRA are differentiation syndrome and Idiopathic intracranial hypertension.

Pseudotumor cerebri (PC) is also commonly called Idiopathic intracranial hypertension (IIH). The PC is a rare disorder with an incidence of approximately 1 case/1 lac population per annum. It primarily affects obese females of reproductive age group. This disorder is characterized by various signs and symptoms produced by raised intracranial pressure i.e. headache, papilledema and vision loss with normal cerebrospinal fluid composition along with no evident cause of intracranial hypertension on neuroimaging or other laboratory investigations. A long list of medications have been reported to be associated with PC. The evidence linking growth hormone treatment, retinoids, and tetracycline antibiotics is strongest; however, the mechanisms by which these might produce PC is not known. Other than obesity, the association between other medical conditions such as Cushing’s disease, hypoparathyroidism, hypothyroidism, chronic kidney disease, anemia and PC is not proven.

Diagnosis-modified Dandy criteria is used for diagnosis of PC; each of the following apply.

Symptoms and signs of increased intracranial pressure (i.e. headache, transient visual obscurations, pulse synchronous tinnitus, papilledema, visual loss);

No other neurologic abnormalities or impaired level of consciousness;

Elevated intracranial pressure with normal cerebrospinal fluid (CSF) composition;

A neuroimaging study that shows no etiology for intracranial hypertension;

No other apparent cause of intracranial hypertension

3 Pathogenesis

The pathogenesis of PC is unknown. There may be association between PC and venous sinus stenosis. Many studies at present suggests that apparent venous sinus narrowing is not the primary cause in most cases but is secondary to elevated intracranial pressure. Other theories include increased cerebrospinal fluid outflow resistance; obesity-related raised abdominal and intracranial venous pressure; altered sodium and water retention mechanisms; and abnormalities of vitamin A metabolism.

ATRA at high doses increases the production of cerebrospinal fluid and delays CSF absorption at arachnoid villi due to alteration of the lipid constituents of the arachnoid villi. There is a progressive age-related decline in the RAR expression in the central nervous system explaining the decreased risk of PC in the adult patient of APML as compared to the pediatric age group (Visani et al., 1996).

4 Conclusions

As all-transretinoic acid can cause pseudotumour cerebri, careful consideration should be given to the patients of acute promyelocytic leukemia if they complain of headache, blurring of vision and altered visual acuity. Pseudotumor cerebri is suspected then regular follow-up visits with serial examinations including visual acuity, visual field testing and a fundus examination are required until they stabilize, to prevent sequelae of raised intracranial pressure such as optic atrophy and vision loss. As in most patients, symptoms worsen slowly and with treatment, gradual improvement and/or stabilization occurs, but they may not have necessarily complete recovery; many patients have persistent papilledema, elevated intracranial pressure as documented on lumbar puncture, and residual visual field deficits.

Authors’ contributions

There was no conflict of interest.

Acknowledgments

Financial support and sponsorship- Nil

References

Castaigne S., Chomienne C., Daniel M.T. et al., 1990, Alltransretinoic acid as a differentiation therapy foracute promyelocytic leukemia, I. Clinical results, Blood, 76(9): 1704-1709

PMid:2224119

Fenaux P., Chastang C., Chevret S., Sanz M., Dombret H., Archimbaud E. et al., 1999, A randomized comparison of all transretinoic acid (ATRA) followed by chemotherapy and ATRA plus chemotherapy and the role of maintenance therapy in newly diagnosed acute promyelocytic leukemia, The European APL Group, Blood, 94(4):1192-1200

PMid:10438706

Holmes D., Vishnu P., Dorer R.K., and Aboulafi D.M., 2012, All-Trans retinoic acid-induced pseudotumor cerebri during induction therapy for acute promyelocytic leukemia: a case report and literature review, Case Rep Oncol Med., 2012:313057

https://doi.org/10.1155/2012/313057

PMid:22701192 PMCid:PMC3371673

Lo-Coco F., Avvisati G., Vignetti M., Breccia M., Gallo E., Rambaldi A. et al., 2010, Front-line treatment of acute promyelocytic leukemia with AIDA induction followed by risk-adapted consolidation for adults younger than 61 years: results of the AIDA-2000 trial of the GIMEMA Group, Blood, 116(17):3171-3179

https://doi.org/10.1182/blood-2010-03-276196

PMid:20644121

Naithani R., Kumar R., and Mishra P., 2009, Pseudotumor cerebri in a child in early phase of induction therapy for APL with ATRA, Indian J Pediatr., 76(4):439-440

https://doi.org/10.1007/s12098-009-0134-x

PMid:19412592

Tallman M.S., Andersen J.W., Schiffer C.A. et al., 1997, Alltrans-retinoic acid in acute promyelocytic leukemia, N Engl J Med., 337(15): 1021-1028

https://doi.org/10.1056/NEJM199710093371501

PMid:9321529

Vanier K.L., Mattiussi A.J., and Johnston D.L., 2003, Interaction of all trans-retinoic acid with fluconazole in acute promyelocytic leukemia, J Pediatr Hematol Oncol., 25(5):403-404

https://doi.org/10.1097/00043426-200305000-00010

PMid:12759628

Visani G., Bontempo G., Manfroi S., Pazzaglia A., D’Alessandro R., and Tura S., 1996, All-trans-retinoic acid and pseudotumor cerebri in a young adult with acute promyelocytic leukemia: a possible disease association, Haematologica, 81(2):152-154

PMid:8641645