Successful clearance of chemorefractory leptomeningeal disease by craniospinal irradiation followed by venetoclax maintenance in a patient with isolated central nervous system relapsed acute promyelocytic leukemia

INTRODUCTION

Central nervous system (CNS) involvement is a rare but difficult to treat complication of acute promyelocytic leukemia (APML). In patients with relapse disease who are refractory to conventional APML-directed therapies such as all transretinoid acid (ATRA), arsenic trioxide (ATO), anthracyclines, and cytarabine, there is no standard of care. We, hereby, describe a case of 71-year-old male with no known comorbidities, who was diagnosed with high-risk APML and was treated with ATRA, ATO, and daunorubicin-based induction and maintenance therapy and had a medullary relapse (Bone marrow relapse) after 1 year of completion of therapy. He was salvaged by gemtuzumab ozogamicin (GO)-based chemotherapy followed by autologous transplant. The patient had a second isolated CNS relapse after 1 year of autologous stem cell transplant (SCT) and was salvaged by craniospinal irradiation followed by venetoclax maintenance. The patient continued to be in remission on maintenance venetoclax since past 1 year. Craniospinal irradiation is generally efficacious for lymphoblasts. There are very little data on the radiation sensitivity of promyelocytes. This case is being presented to highlight successful clearance of promyelocytes by craniospinal irradiation and maintaining remission on venetoclax since 1 year.

CASE REPORT

A 71-year-old male was first diagnosed with high-risk APML in April 2020 when he presented with hemorrhagic phenomenon. He was treated with ATRA, ATO, and Daunorubicin-based induction and consolidation and achieved complete molecular response. His end of induction cerebrospinal fluid (CSF) was negative for any blasts. One year after initial presentation, he had medullary relapse which was salvaged with GO and ATO followed by autologous SCT.

One year after his transplant, he was found to have molecular relapse while on 6-mercaptopurine/methotrexate/ATRA maintenance. He was treated with ATO in combination with first idarubicin and then mitoxantrone but continued to have low-level molecular positivity. He also developed neurological symptoms with headaches, memory loss, and slurred speech. CSF examination revealed frank CNS involvement [Figure 1]. His CSF was positive for abnormal promyelocytes that constituted 97% of total cells (150 cells/µL) and CSF glucose and protein were 59.3 mg/dL and 40.8 mg/dL, respectively. CSF polymerase chain reaction for promyelocytic leukemia- retinoic acid receptor alpha (PML-RARA) could not be done due to non-availability of the test. He was then treated with high-dose cytarabine and four sessions of twice weekly triple intrathecal chemotherapy but developed worsening neurological symptoms. Serial CSF examination did not show any clearance of abnormal promyelocytes [Table 1]. He was then started on a course of craniospinal irradiation and received a total of 24 gy to the cranium and 18 Gy to the spine over 3 weeks. In this duration, he was severely pancytopenic and required significant transfusion and antibiotic support. However, the CSF completely cleared after completion of irradiation. He also showed clinical improvement which coincided with complete clearance of CSF. His PML-RARA transcript which had been persistently positive in peripheral blood also became undetectable. Subsequently, he was started on maintenance oral venetoclax and has received four cycles so far. He continues to be in CNS remission till date, 12 months after the craniospinal radiation.

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Figure 1:

Cerebrospinal fluid examination with abnormal promyelocytes in case of central nervous system involvement of acute promyelocyte leukemia (May- Grunwald giemsa, ×40).

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DISCUSSION

For patients with relapsed APML, treatment options include anthracyclines, ATO with or without ATRA, cytarabine, and/or GO regimens. The treatment choice depends on the first-line regimen used for induction and whether the relapse occurred during therapy.^[1,2] Despite a high CR2 rate observed with the ATO-based regimen among APL relapse cases, the second relapse rate remained high. Optimal post-remission treatment is essential for prolonging remission.^[1,2] In our case, the consolidation post 1^st relapse was done by auto hematopoietic stem cell transplantation (HSCT) and the patient remained in remission for 1 year. However, he had CNS symptoms 1 year post auto HSCT and was diagnosed with isolated CNS relapse. Even after trial of ATO, anthracyclines and multiple triple intrathecals given twice a week; however, his CSF continued to be positive for blasts. No consensus has been established on post-remission treatment strategies after CR2. Thus, a empirical trial of radiotherapy was given for which there is paucity of data in the literature. The CNS is the most common site of extramedullary relapse, for which no recognized effective treatment exists.^[3] There are enough data that lymphoblasts are sensitive to radiation. However, there is paucity of data regarding the myeloblasts that may be amenable to treatment with radiation; however, Furuya et al., have described role of intracranial irradiation in patients with CNS release.^[4] Case report by Patel et al.,^[5] reported the case of a patient with relapsed AML (non-APML) who presented with cranial nerve palsies unresponsive to intrathecal cytarabine and methotrexate, requiring emergent whole-brain radiotherapy and was successfully managed. However, such data are lacking in regards to APML. Venetoclax, a highly selective BCL-2 inhibitor, has recently been shown to cross the blood-brain barrier.^[6] Zhang et al., demonstrated that venetoclax with IT injection support resulted in remission in patients with PML::RARA-positive APML with CNS involvement^.[7] It is also worth examining whether venetoclax can enter the CSF and whether its concentration changes in the CSF. Studies have shown that venetoclax can be detected in the CSF and that its concentration is approximately 1/300^th–1/1000^th of that in the plasma.^[6,7]

CONCLUSION

This case exemplifies the fact that chemorefractory leptomeningeal involvement in APML can still be exquisitely radiation sensitive. Craniospinal irradiation can be continued in patients with cytopenias as long as good supportive care is continued in parallel followed by maintenance venetoclax is an effective treatment option for relapsed refractory APML.