Is it best to choose a transplant for combined bone marrow and extramedullary relapse? How long should dasatinib be taken?

[Expert Q&A] Is it best to choose a transplant for combined bone marrow and extramedullary relapse? How long should dasatinib be taken?

Source: Sunflower Children Author: Summer Rain Edited by: Maixm Date: April 7, 2023

In this edition of the "Expert Q&A" column, we have invited Dr. Xu Xiaojun, the Director of the Hematology and Oncology Department at the Children’s Hospital affiliated with Zhejiang University School of Medicine, to answer some questions.

Dr. Xu specializes in the diagnosis and treatment of hematological diseases such as childhood leukemia, lymphoma, aplastic anemia, hemophagocytic syndrome, and thrombocytopenia, as well as common pediatric internal medicine diseases. He is also engaged in immunotherapy for tumor cells and monoclonal antibody targeted therapy.

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Q: An 11-year-old boy was diagnosed with acute lymphoblastic leukemia (ALL) in December 2017, classified as low risk. In June 2022, he experienced a relapse in the bone marrow and testicles, with a positive TEL-AML1 gene. Is it best to choose a transplant for combined bone marrow and extramedullary relapse? Can the transplant address the testicular lesions? If he does not undergo a transplant, how much will the cure rate decrease after relapse?

A: The prognosis and treatment plan for relapsed acute lymphoblastic leukemia vary based on the relapse site and timing. Generally, the earlier the relapse occurs and the poorer the treatment response, the worse the prognosis. Extramedullary relapse usually has a better treatment outcome than bone marrow relapse. Given your child's late-stage combined bone marrow and extramedullary relapse, he falls into the intermediate-risk group for ALL relapse, with a theoretical long-term survival rate of approximately 60-70%. It is generally recommended to consider initial chemotherapy; if the minimal residual disease (MRD) after re-induction chemotherapy exceeds 0.01%, hematopoietic stem cell transplantation (HSCT) is advised. If it is below 0.01%, continuing chemotherapy with local treatment is an option. For unilateral testicular relapse, surgical removal is possible, while bilateral relapses may require radiation therapy. If a secondary relapse occurs, the treatment success rate will significantly decline, potentially down to around 20%.

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Q: A 3-year-old boy was diagnosed with B-ALL at 2.5 years old, classified as intermediate risk. His initial white blood cell count was 77, and by day 19, the MRD was 0.05, turning negative by day 33. He has been undergoing treatment for over 7 months, starting with induction therapy, two rounds of cytarabine, and four doses of high-dose methotrexate. He is currently undergoing re-induction with vincristine, doxorubicin, and asparaginase.

No related fusion genes were detected, and tests for MEF2D and ZNF384 were negative. There was no large fragment deletion in IKZF. FISH testing showed ETV6/RUNX1 negative. The full transcriptome report indicates ETV6-IKZF1 and ETV6-RP11-75N4.2, which may be related to ALL. Should we conduct further checks on these genes? Do they affect prognosis?

A: In full transcriptome testing for hematological tumors, rare fusion genes are often detected. Due to their low occurrence, the clinical value and prognostic significance of these genes are usually unclear, making it difficult to determine prognosis or adjust treatment plans based solely on the presence of these fusion genes. Among various prognostic factors, minimal residual disease (MRD) remains the most critical. While the implications of these genes are not fully understood, their effects typically manifest in MRD levels. Therefore, assessing prognosis and adjusting risk based on MRD is advisable. The significance of these genes will require larger sample sizes for clearer conclusions. Some centers may follow up on changes in these fusion genes, but their value remains uncertain.

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Q: A 5-year-old boy was diagnosed with acute lymphoblastic leukemia L2 type at age 4. No fusion genes were detected, and FISH tests were negative. By day 19, the MRD was <0.01%, indicating low risk, but he has an NRAS gene mutation with a mutation frequency of 39.6%. He is currently being treated according to the CCCG-ALL-2020 (Shanghai) protocol, now in the second cycle of induction. Since diagnosis, he has been taking dasatinib. Does he need to continue taking it after treatment? If so, for how long? Is this gene's prognosis not ideal? Is the relapse rate high?

A: Literature indicates that NRAS mutations with a frequency of over 20% are associated with relatively poor prognosis, but your child's treatment response has been quite favorable, with an MRD of <0.01% by day 19. Considering that, generally, MRD has a stronger prognostic impact than NRAS, I believe your child's future relapse rate should be under 10%. Regarding dasatinib, adherence to the chemotherapy regimen is crucial. Currently, it is generally recommended to continue taking it at least until the completion of maintenance chemotherapy; some patients continue until all chemotherapy is finished, while others may take it for an additional year. The chemotherapy protocol will typically specify the duration for this medication, which should be followed accordingly.

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Column Chief Editor: Wu Xiaoling  

Layout: Summer Rain  

Proofreading: Xiuxiu