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You Make the Call: How would you treat a patient with acute promyelocytic leukemia and CNS disease?

March 26, 2024

April 2024

Harry P. Erba, MD, PhD  Professor of Medicine  Leukemia Program Director  SWOG Leukemia Committee Chair  Duke Cancer InstituteHarry P. Erba, MD, PhD
Professor of Medicine
Leukemia Program Director
SWOG Leukemia Committee Chair
Duke Cancer Institute


Sanghee Hong, MD  Assistant Professor of Medicine  Duke University School of MedicineSanghee Hong, MD
Assistant Professor of Medicine
Duke University School of Medicine




I have a 20-year-old female patient with acute promyelocytic leukemia (APL). She had an unusual presentation with a right clavicular mass that had been growing very slowly for one year, as well as intermittent symptoms of sciatica. Her blood counts and coagulation labs were normal. Initially, her diagnosis was consistent with an Ewing sarcoma, but a biopsy of the clavicular mass showed APL with t(15;17) and trisomy 8 (confirmed by fluorescence in situ hybridization [FISH] and positive for PML-RARA by reverse transcription polymerase chain reaction [RT-PCR]). A PET scan only showed avidity in the clavicular mass and sacrum, and MRI of the brain and spine showed soft tissue expansion of the sacrum into the spinal canal (extradural) that was causing the sciatica. A posterior iliac crest bone marrow biopsy had normal morphology, karyotype, and FISH results for t(15;17), but was positive for PML-RARA by RT-PCR.

She was started on induction therapy with the APML4 regimen of all-trans-retinoic acid (ATRA), idarubicin, and intravenous arsenic trioxide (IV ATO; ATRA 45 mg/m2 daily plus idarubicin 12 mg/m2 on days 2, 4, 6, and 8, followed with IV ATO 0.15 mg/kg daily starting on day 9). She has tolerated this regimen well, with no differentiation syndrome.

She also had screening lumbar puncture (LP) with concurrent intrathecal (IT) chemotherapy (50 mg of cytarabine) to check for central nervous system (CNS) involvement. The spinal fluid analysis showed a white cell count of 17 x 106/L, red blood cell count of 4 x 106 /L, and morphology of cells that was concerning for promyelocytes. Based on these results, I believe she has CNS involvement.

Before knowing about the CNS disease, I planned to use APML4 induction, followed by four cycles of ATRA plus ATO consolidation (as per the APML4 ALLG trial), but no maintenance. Now, in light of the CNS disease, how should I treat her?


This patient presents with extramedullary involvement of APL, which is found in less than 5% of APL cases. It is even more remarkable that the bone marrow did not show morphologic evidence of disease. There are more reported cases of CNS relapse isolated or concurrent with bone marrow relapse, particularly (~4%) for high-risk disease,1 defined as an initial white blood cell (WBC) count greater than 10 x 109/L. However, CNS manifestation of APL at diagnosis is extremely rare with fewer than 10 reported adult cases.2 Because of the rarity, European LeukemiaNet and the National Com­prehensive Cancer Network do not recommend routine cerebrospinal fluid (CSF) analysis and IT treatment. In this case, the presentation with extramedullary disease (EMD) alone, soft tissue extension into spinal canal by MRI, and sciatic symptoms support the possibility of CNS involvement.

Overall, we agree with the concern for an unusual initial presentation of APL with CNS disease. The patient has EMD of the bone and paraspinal space, increasing the risk of CNS disease as well. We typically would order an MRI to evaluate for leptomeningeal enhancement, which could help confirm the results in an ambiguous situation. Because ATO and ATRA are water-soluble medicines with limited penetration to the blood-brain barrier, they cannot reach therapeutic levels in the CSF. When giving typical oral doses of ATO, CSF drug levels are only 17.7% of the plasma levels.3 Idarubicin does not cross the blood-brain barrier as well.4

At this juncture, the patient would benefit from both high-dose chemotherapy and IT therapy. There are reported cases that high-dose cytarabine (HiDAC) consolidation is effective in controlling CNS disease in APL.2,5 Also, in the APL 2000 trial, high-risk populations with initial WBC greater than 10 x 109/L received five doses of IT chemotherapy (combination of methotrexate, cytarabine, and steroids) upon count recovery from induction and 2 g/m2 of HiDAC, a combination that may have contributed to preventing CNS relapse.6

Extrapolating the effectiveness of HiDAC in CNS APL and the general approach to CNS leukemia, we suggest treating the patient with two cycles of HiDAC (e.g., a consolidative dose of 2 g/m2 IV cytarabine over three hours every 12 hours on days 1-3). We also suggest alternating HiDAC cycles with the ATRA/ATO consolidations so the patient benefits from both CNS and systemic treatments. Until her CSF clears the APL, she should be considered for frequent (twice weekly) IT cytarabine 70 mg and checked for CSF leukemia by flow cytometry. In each ATRA/ATO consolidation cycle, we recommend repeating the LP with IT cytarabine 70 mg. IT cytarabine was reported as safe and effective in a small case series of intracranial APL.7 We have used this approach in our patients because HiDAC has been successful in treating CNS relapse of APL.


  1. de Botton S, Chevret S, Coiteux V, et al. Early onset of chemotherapy can reduce the incidence of ATRA syndrome in newly diagnosed acute promyelocytic leukemia (APL) with low white blood cell counts: results from APL 93 trial. Leukemia. 2003;17:339-342.
  2. Harrer DC, Lüke F, Einspieler I, et al. Case report: extramedullary acute promyelocytic leukemia: an unusual case and mini-review of the literature. Front Oncol. 2022;12:886436.
  3. Au WY, Tam S, Fong BM, et al. Determinants of cerebrospinal fluid arsenic concentration in patients with acute promyelocytic leukemia on oral arsenic trioxide therapy. Blood. 2008;112(9):3587-3590.
  4. Berg SL, Reid J, Godwin K, et al. Pharmacokinetics and cerebrospinal fluid penetration of daunorubicin, idarubicin, and their metabolites in the nonhuman primate model. J Pediatr Hematol Oncol. 1999;21(1):26-30.
  5. Morra E, Lazzarino M, Brusamolino E, et al. The role of systemic high-dose cytarabine in the treatment of central nervous system leukemia. Clinical results in 46 patients. Cancer. 1993;72(2):439-445.
  6. Adès L, Chevret S, Raffoux E, et al. Is cytarabine useful in the treatment of acute promyelocytic leukemia? Results of a randomized trial from the European Acute Promyelocytic Leukemia Group. J Clin Oncol. 2006;24(36):5703-5710.
  7. Duarte RF, Arnan M, Sánchez-Ortega I, et al. Clinical experience using intrathecal liposomal cytarabine to manage neoplastic meningitis in three patients with acute promyelocytic leukemia. Leuk Res. 2011;35(7):e128-e130.


My hematology colleagues and I are being referred pregnant patients with borderline microcytic or normocytic anemia and ferritin levels of less than 10 µg/L. Obstetrics literature suggests we treat these patients with oral or intravenous iron to increase ferritin levels to greater than 30 µg/L. Is there a hematologic justification for this recommendation?

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Disclaimer: ASH does not recommend or endorse any specific tests, physicians, products, procedures, or opinions, and disclaims any representation, warranty, or guaranty as to the same. Reliance on any information provided in this article is solely at your own risk.


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