Pseudotumor Cerebri in the Setting of Differentiation Syndrome in a Patient with Acute Promyelocytic Leukemia Treated with All-trans Retinoic Acid During Induction Therapy

Introduction: Differentiation syndrome, a well-known complication of all-trans retinoic acid (ATRA) in patients with acute promyelocytic leukemia (APML), can very rarely have ophthalmic manifestations. Pseudotumor cerebri (PC) in the setting of differentiation syndrome (DS) in patients undergoing induction with all-trans retinoic acid has rarely been reported elsewhere. We herein report one such case. Case Presentation: A 28-year-old, non-obese female diagnosed as acute promyelocytic leukemia underwent induction with all- trans retinoic acid and Idarubicin. On day 4 of the treatment, she developed high grade fever (104 – 105 F), dry cough, hypotension, tachycardia, and tinnitus. Chest X ray showed floppy shadows in bilateral lungs. On physical examination, bilateral lower limb edema was noted. She also experienced sudden weight gain of 5 kilogram in 48 hours. After careful exclusion of systemic infection, she was suspected as having DS. She also noticed a reduction in vision in right eye. On eye examination, her best-corrected visual acuity (VA) was 6/60 in the right eye (RE) and 6/6 in the left eye (LE). Fundus evaluation revealed bilateral disc edema with peripapillary hemorrhages along with slight tortuosity of vessels and a yellowish lesion over the fovea in RE. Suspecting DS, she was treated with injection dexamethasone 10 mg twice daily and all- trans retinoic acid was temporarily discontinued. Immediately after its discontinuation, her headache lessened and vision improved gradually. After 2 weeks, her VA was 6/12 in RE and 6/6 in LE which improved to 6/6 in both eyes at 3 months. The patient was also receiving oral voriconazole for fungal prophylaxis and the potentiation effect of all- trans retinoic acid could thus be explained. Conclusion: Pseudotumor cerebri associated with all-trans retinoic acid treatment in acute promyelocytic leukemia, even though frequently reported in pediatric patients, is rare in adults. Ophthalmological evaluation is mandatory in all these patients under all-trans retinoic acid therapy.

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Improvement of prognosis in refractory and relapsed acute promyelocytic leukemia over recent years: the role of all- trans retinoic acid therapy

Annals of Hematology ◽

10.1007/s002770050342 ◽

1997 ◽

Vol 75 (5-6) ◽

pp. 195-200 ◽

Cited By ~ 11

Author(s):

X. Thomas ◽

B. Anglaret ◽

A. Thiebaut ◽

A. Belhabri ◽

D. Treille-Ritouet ◽

...

Keyword(s):

Retinoic Acid ◽

Acute Promyelocytic Leukemia ◽

Promyelocytic Leukemia ◽

Acid Therapy ◽

Trans Retinoic Acid ◽

All Trans Retinoic Acid

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Outcome of Childhood Acute Promyelocytic Leukemia With All-Trans-Retinoic Acid and Chemotherapy

Journal of Clinical Oncology ◽

10.1200/jco.2004.09.008 ◽

2004 ◽

Vol 22 (8) ◽

pp. 1404-1412 ◽

Cited By ~ 91

Author(s):

S. de Botton ◽

V. Coiteux ◽

S. Chevret ◽

C. Rayon ◽

E. Vilmer ◽

...

Keyword(s):

Overall Survival ◽

Retinoic Acid ◽

Acute Promyelocytic Leukemia ◽

Survival Rates ◽

Age Groups ◽

Pseudotumor Cerebri ◽

Promyelocytic Leukemia ◽

Results Of Treatment ◽

Trans Retinoic Acid ◽

All Trans Retinoic Acid

Purpose To determine the results of treatment combining all-trans-retinoic acid (ATRA) and chemotherapy (CT) in childhood acute promyelocytic leukemia (APL). Patients and Methods Children (< 18 years) with newly diagnosed APL were included in the APL93 trial, treated by ATRA followed or combined with daunorubicin-cytarabine, and then randomly assigned between no maintenance, intermittent ATRA, continuous CT, or both. Results Of the 576 patients included in APL93 trial, 31 (5%) were children, including 22 girls (71%) and nine boys (29%). Thirty of the children (97%) obtained complete remission (CR). ATRA syndrome occurred in four children (13%), who all achieved CR, and headaches occurred in 12 children (39%), with signs of pseudotumor cerebri in five children (16%). Seven patients (23%) relapsed. None of the eight patients who received both ATRA and CT for maintenance relapsed. All relapsing patients achieved a second CR. Twenty-two patients remained in first CR after 43+ to 96+ months, six remained in second CR after 17+ to 66+ months, and three patients had died. The 5-year event-free survival (EFS), relapse, and overall survival rates were 71%, 27%, and 90%, respectively. No difference between adults and children included in the APL93 trial was seen for CR rate, 5-year relapse rate, EFS, and overall survival, but significantly better survival was seen in children after adjustment on WBC counts (P = .02) and incidence of microgranular M3 variant (P = .04). Conclusion ATRA combined with CT for induction and also probably for maintenance provides as favorable results in children with APL as in adults and currently constitutes the reference first-line treatment in both age groups.

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Molecular evaluation of response to all-trans-retinoic acid therapy in patients with acute promyelocytic leukemia

Blood ◽

10.1182/blood.v77.8.1657.1657 ◽

1991 ◽

Vol 77 (8) ◽

pp. 1657-1659 ◽

Cited By ~ 62

Author(s):

F Lo Coco ◽

G Avvisati ◽

D Diverio ◽

MC Petti ◽

M Alcalay ◽

...

Keyword(s):

Retinoic Acid ◽

Acute Promyelocytic Leukemia ◽

High Frequency ◽

Southern Blot Analysis ◽

Molecular Level ◽

Promyelocytic Leukemia ◽

Acid Therapy ◽

Trans Retinoic Acid ◽

All Trans Retinoic Acid ◽

Leukemic Clone

Abstract The advent of retinoic acid (RA) in the treatment of acute promyelocytic leukemia (APL) has led to a high frequency of short- lasting complete remissions (CR). We studied the response to RA by molecularly analyzing the RA receptor alpha (RAR alpha) locus, which has recently been shown to be rearranged in all APLs. Southern blot analysis demonstrated that the RAR alpha rearrangements persisted in the APL samples containing maturing myeloid cells 2 to 3 weeks after the start of RA treatment, but disappeared after 5 to 8 weeks, when the patients achieved CR. Our investigations provide clear evidence that CR occurs at molecular level and that there is reconstitution of an apparently normal, nonclonal hematopoiesis. Further, it shows that RA acts by triggering differentiation rather than by exerting a cytotoxic effect on the leukemic clone.

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All-trans-retinoic acid–induced pseudotumor cerebri in acute promyelocytic leukemia

Journal of Neurosciences in Rural Practice ◽

10.1055/s-0039-1700329 ◽

2014 ◽

Vol 05 (03) ◽

pp. 273-275

Author(s):

T. M. Anoop ◽

Nidhi Jain ◽

Sreejith G. Nair ◽

Geetha Narayanan

Keyword(s):

Retinoic Acid ◽

Acute Promyelocytic Leukemia ◽

Induction Therapy ◽

Treatment Strategy ◽

Pseudotumor Cerebri ◽

Promyelocytic Leukemia ◽

Trans Retinoic Acid ◽

All Trans Retinoic Acid

ABSTRACTAll-trans-retinoic acid is an integral part in the treatment strategy of acute promyelocytic leukemia (APL). Here we describe a case of pseudotumor cerebri associated with all-trans-retinoic acid (ATRA) during the induction therapy in an adult with acute promyelocytic leukemia (APL).

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Gangrenous cheilitis associated with all-trans retinoic acid therapy for acute promyelocytic leukemia

International Journal of Hematology ◽

10.1007/s12185-009-0468-1 ◽

2009 ◽

Vol 91 (1) ◽

pp. 132-135 ◽

Cited By ~ 1

Author(s):

Mariko Tanaka ◽

Noriyasu Fukushima ◽

Hidekazu Itamura ◽

Chisako Urata ◽

Masako Yokoo ◽

...

Keyword(s):

Retinoic Acid ◽

Acute Promyelocytic Leukemia ◽

Promyelocytic Leukemia ◽

Acid Therapy ◽

Trans Retinoic Acid ◽

All Trans Retinoic Acid

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Pseudotumor Cerebri Associated with All-Trans Retinoic Acid Treatment During Induction Therapy for Acute Promyelocytic Leukemia: A Case Report and Literature Review

Blood ◽

10.1182/blood.v118.21.4264.4264 ◽

2011 ◽

Vol 118 (21) ◽

pp. 4264-4264

Author(s):

Dylan Holmes ◽

David M. Aboulafia

Keyword(s):

Retinoic Acid ◽

Intracranial Pressure ◽

Literature Review ◽

Acute Promyelocytic Leukemia ◽

Pseudotumor Cerebri ◽

Promyelocytic Leukemia ◽

Induction Treatment ◽

Fluid Composition ◽

Trans Retinoic Acid ◽

All Trans Retinoic Acid

Abstract Abstract 4264 Pseudotumor cerebri (PC) is a rare disorder characterized by elevated intracranial pressure with normal cerebrospinal fluid composition, normal cranial imaging findings, and symptoms and signs of increased intracranial pressure. A number of medications have been linked to PC including vitamin A and its derivative all-trans-retinoic acid (ATRA). Herein, we describe the case of a 38-year-old woman who was diagnosed with PC during standard induction treatment for acute promyelocytic leukemia (APL). Her neurologic complaints of severe headache and diplopia improved slightly after ATRA was discontinued and she was treated with acetazolamide, but symptoms did not abate until fluconazole was held five days later. Through a literature review, we identified 41 case reports of APL patients with ATRA-associated PC, 23 of which provided details of clinical presentation and follow-up. The median age at diagnosis of PC was 27 for females and 16 for males; the female-to-male ratio was 1.3:1. All 23 patients complained of headache; papilledema was present in all 21 instances (100%) where a retinal exam was described. ATRA was held due to PC in 20 cases (87%), and neurologic symptoms resolved without further intervention in 7 of 20 (35%). The remaining 13 patients were treated with diuretics (11 of 13 cases, 85%), high-volume lumbar punctures (5, 38%), corticosteroids (4, 31%), and/or analgesics (3, 23%). Including our index patient, eight patients were rechallenged with ATRA after neurologic improvement, and 5 (63%) required further interventions to resolve recrudescent symptoms. We identified one other patient whose neurologic complaints persisted despite dose reductions in ATRA. This patient improved only after fluconazole was discontinued. Because both ATRA and fluconazole are metabolized by the cytochrome P-450 system, we suggest that if taken concurrently, they may exacerbate the risk of PC. Physicians should be aware of this interaction between ATRA and fluconazole and consider discontinuing both fluconazole and ATRA in APL patients who develop PC. Disclosures: No relevant conflicts of interest to declare.

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