A Patient with Acute Promyelocytic Leukemia Treated with Isotretinoin: A Case Report Open Access

Acute promyelocytic leukemia (APL) is a distinct type of acute leukemia characterized by abnormal proliferation of promyelocytes, life-threatening coagulopathy, and the chromosome translocation t(15;17)(q22;q21). Introduction of all-trans retinoic acid (ATRA) and arsenic trioxide (ATO) has improved the prognosis of APL patients significantly [1].

A patient with newly diagnosed APL was treated with ATO and isotretinoin instead of ATRA for several weeks due to a prescription error. Despite this, the patient reached a complete remission (CR) of the APL suggesting that isotretinoin could possibly have a similar effect on APL cells as ATRA.

A 65-year-old woman was evaluated in our hospital because of thrombocytopenia. This finding was determined by her general practitioner after recurrent symptomatic urinary tract infections. She did not note any bruises on her skin. She noticed some recurrent mild bleeding from her nose and sometimes saw traces of fresh blood in the stool.

In the past, the patient suffered from breast cancer, treated with radiotherapy and an aromatase inhibitor. She also suffered from chronic hepatitis B and was on therapy with tenofovir.

Clinically, the patient was in a reduced general condition, slightly obese, with normal blood pressure, normal heart rate, normal oxygen saturation while breathing ambient air, and normal body temperature. Physical examination did reveal palpable spleen, but no hematomas or any other abnormal findings. In the bedside sonography, a slightly enlarged spleen and hemodynamic nonrelevant pericardial effusion were registered. Microhematuria was present.

Hematological examination of the blood sample showed a hemoglobin of 123 g/L (normal range 120–160 g/L), 22 g/L platelets (normal range 150–450 g/L), 3.77 g/L white cells (normal range 3.5–10 g/L), 2.45 g/L of neutrophils (normal range 1.3–6.7 g/L), and 1.11 g/L of lymphocytes (normal range 0.9–3.3 g/L). Coagulation testing revealed INR 1.7 (normal range <1.3), aPPT 32 s (25–34 s), fibrinogen 0.5 g/L (1.7–4 g/L), factor II 51% (70–120%), factor V 44% (70–120%), factor VII 43% (70–120%), and D-dimer >20 (0.19–0.5 μg/mL).

Further laboratory examination showed LDH 579 U/L (normal range 135–214 U/L), ASAT 35 U/L (normal range 11–34 U/L), ALAT 18 U/L (normal range 8–41 U/L), elevated gamma-GT 152 U/L (normal range 6–40 U/L), and creatinine 58 μmol/L (normal range 42–80 μmol/L). Except for gamma-GT, all liver and kidney values remained within normal range during the hospitalization. The elevated gamma-GT remained elevated on approximately the same level.

In the morphological examination of the blood smear, we saw 37% promyelocytic cells. Because of the high suspicion of APL, treatment with ATRA was started before receiving the results of bone marrow examination and genetical testing for promyelocytic leukemia protein-retinoid acid receptor alpha (PML-RARA). Furthermore, the treatment of the severe coagulation disorder compatible with disseminated intravascular coagulation (DIC) was started immediately with intravenous infusions of human fibrinogen, fresh frozen plasma, and platelets. The further treatment and surveillance took place on the hematological ward.

In the blood smear and the FACS from the blood, we saw morphologically and immunophenotypically a constellation of blastoid cells (Fig. 1) fitting to an APL and the PML-RARA fusion gene using nucleic acid amplification technique was clearly positive. As expected, bone marrow morphology showed an 80% infiltration with promyelocytic blastoid cells with the suppression of the physiological hematopoiesis. The fluorescence in situ hybridization analysis and molecular testing confirmed the positivity for PML-RARA fusion transcript, so that the diagnosis of APL was confirmed.

Because of the previous diagnosis and radiotherapy treatment of breast cancer several years earlier, we classified the APL as therapy-associated myeloid neoplasm, APL according to WHO Classification of Tumors of Hematopoietic and Lymphoid Tissues and AML M3 according to FAB. Since her initial white cell count was <10 g/L, the patient was considered as standard risk and the initial therapy with ATRA/ATO was established according to the standard schema of ATRA-ATO arm of Lo-Coco et al. [1] for the first 7 days with the daily dosage of 45 mg/m²/day ATRA.

After the stabilization of disseminated intravascular coagulopathy 7 days after first evaluation, the patient was transferred to the normal general internal medicine ward for further care. There, the patient received isotretinoin instead of ATRA because of a prescription error for nearly 4 additional weeks (and ATO 0.15 mg/kg/day) in the same daily dosage of 45 mg/m²/day for 5 days per week, respectively. After the mistake was registered, isotretinoin was replaced by ATRA. The patient was informed about the isotretinoin application instead of ATRA.

Six weeks later, the bone marrow was reevaluated for the determination of the remission state. Morphologically and histologically CR was confirmed. By flow cytometry, a small population of blastoid cells was seen which were interpreted as regeneration blasts. Additionally, molecular genetics revealed a negative PML-RARA as the MRD marker. The patient was in molecular CR 6 weeks after initiation of treatment where most of the time she received isotretinoin instead of ATRA.

Three months after diagnosis, the blood samples showed hemoglobin of 124 g/L (normal range 120–160 g/L), leucocytes 2.77 g/L (normal range 3.5–10 g/L), platelets 151 g/L (normal range 150–450 g/L), neutrophil counts 1.74 g/L (normal range 1.3–6.7 g/L), and lymphocytes 0.61 g/L (normal range 0.9–3.3 g/L). All coagulopathy markers have started to improve 2 days after start of initial treatment of DIC with transfusions of fresh frozen plasma, fibrinogen, and platelets and were completely normalized 4 weeks later. Only factor VII remained reduced which was highly suspicious for hereditary factor VII deficiency.

As consolidation therapy, the patient received 7 cycles of ATRA/ATO treatment according to the Lo-Coco et al. [1] scheme. A bone marrow biopsy performed after completion of consolidation therapy showed further MRD negativity. We continued to see the patient for regular follow-up consultations, and PML-RARA from peripheral blood remained consistently negative.

The patient received tenofovir alafenamide 25 mg daily without ritonavir for chronic hepatitis B. There are no pharmacokinetic or pharmacodynamic interactions known between tenofovir alafenamide and ATRA or ATO. A pharmacist checked drug-drug interactions during hospital stay without notable results.

The suspicion that the reason for thrombocythemia in this patient could be an APL came from the initially seen DIC. The therapy with ATRA and ATO was started immediately, and after the improvement of DIC, the patient was transferred from the hematological ward, where she has been under intense surveillance, to a general internal medicine ward. From then on, she was treated with isotretinoin instead of ATRA for the next 4 weeks. Within this time, the patient experienced several complications such as possible differentiation syndrome, which was treated with dexamethasone, and fever without an infectious focus, and once again because peripherally inserted central venous catheter associated cellulitis requiring antibiotics. The patient recovered from these complications, and the hematological reevaluation showed a CR 6 weeks after initial treatment.

ATRA is a vitamin A derivate which was established as a therapy for APL based on studies from China in the 1970s and 1980s [2, 3]. ATRA efficacy was shown by achieving CR in APL patients, but also in vitro by introducing differentiation of the malignant cells. ATRA is targeting the RARA part of the PML-RARA fusion gene. Regimens with addition of ATO or standard chemotherapy were established since remission with ATRA alone often was not durable. Especially ATO, targeting the PML-Part of PML-RARA, has molecular synergism with ATRA which makes the combination of these two drugs highly effective. Isotretinoin is one of the agents for therapy of acne vulgaris. The mechanism by which isotretinoin is effective in acne is not known [4]. In its chemical structure, isotretinoin is the stereoisomer of ATRA. It is therefore very similar to ATRA and is also a vitamin A derivate.

In 2020, Alkhaldy et al. [5] reported a case where the patient was treated with isotretinoin due to unavailability of ATRA because the patient could not be transported to the specialized center. Initially, abnormal promyelocytes were seen in the peripheral blood smears, leucocytes were elevated, and there was a coagulation disorder. The parameters started to improve 5 days after treatment with isotretinoin, suggesting that this agent is effective in APL.

Breitman et al. [6] showed in 1980 that they were able to induce and measure the differentiation of human promyelocytic leukemia cells after the treatment with isotretinoin in vitro, suggesting that retinoids generally are able to play a role in the treatment of acute myeloid leukemia in a similar biochemical way. In 1983, Flynn et al. [7] described a case where 13-cis-retinoid acid was applied in a patient with APL which was resistant to chemotherapy. After several days of treatment, the samples showed clear increase of maturing myeloid cell counts, severe neutropenia started to improve, and white blood count increased confirming the potential effectiveness of isotretinoin in APL. A similar report was published by Nilsson [8] in 1984 showing again that retinoid acid other than ATRA has a potential to induce the differentiation in APL. Takeshita et al. [9] showed in a more recent clinical study that tamibarotene, a synthetic vitamin A derivate other than ATRA, could be even superior to ATRA in certain cases.

Our case was not experimental compared to the cases quoted here, but it does suggest that either the patient was not harmed by not having the right therapy with ATRA in the subacute phase of the disease or isotretinoin indeed might have possibly positive effect on the APL cells. The spectrum of adverse effects of isotretinoin is known from the experience in the patients with acne.

The limiting aspect to our case discussion is possibly the strong effectiveness of ATO alone in APL as shown by Soignet et al. [10] and Ghavamzadeh et al. [11]. Even without ATRA, ATO seems to have a good potential to induce CR, so we have to be also critical to suggest effects of isotretinoin based on the presented case. On the other side, the standard therapy for APL is still the combination of ATO with ATRA and not ATO alone, because of synergistic effects of both [1, 12, 13]. The vitamin A derivate ATRA plays an important role in a standard therapy scheme to achieve the CR and in the consolidation phase.

Our case shows the importance of clinical drug prescription security tools to avoid application mistakes. IT-tools like special apps integrated into clinical software and four-eyes principles could help avoid such errors. The establishing of a Critical Incident Reporting System (CIRS) could help learn from such mistakes.

Our case and cases from the past do suggest the possible need for further investigation of isotretinoin in clinical trials to further understand the effect of isotretinoin on APL cells, whether it could have a potential to be a further option for the treatment of APL. The CARE checklist has been completed by the authors for this case report, attached as online supplementary material (for all online suppl. material, see https://doi.org/10.1159/000541328).

The authors thank the treating team from the Hematology Clinic.

Ethical approval is not required for this study in accordance with local or national guidelines. Written informed consent was obtained from the patient for publication of the details of their medical case and any accompanying images.

The authors have no conflicts of interest to declare.

The authors have no funding sources to declare.

Ilja Goldin wrote the initial manuscript. Edits and recommended changes were provided by Michael Medinger, Jakob Passweg, and Delia Halbeisen. Ilja Goldin, Michael Medinger, and Jakob Passweg were involved in the treatment of the patient. Delia Halbeisen gave pharmaceutical support.

All data generated or analyzed during this study are included in this article and its online supplementary material files. Further inquiries can be directed to the corresponding author (M.M.).