What Does Positive Fusion Gene Mean? Does It Affect Prognosis?  

What Does Positive Fusion Gene Mean? Does It Affect Prognosis?  

Source: Sunflower Children Author: Sunflower Children Edited by: Gaozx Date: July 6, 2023  

Disclaimer:  

The online Q&A is not a recommendation for treatment plans. As we cannot understand the patient's detailed condition and cannot perform face-to-face diagnosis, expert opinions are for reference only. For specific treatment plans, please visit a regular hospital.  

In this edition of the "Expert Q&A" column, we have invited Dr. Luo Xuequn, the head of the Pediatric Hematology Department at Sun Yat-sen University First Affiliated Hospital, to answer questions.  

Dr. Luo Xuequn is a professor in the Pediatric Hematology Department at Sun Yat-sen University First Affiliated Hospital and an honorary chief expert and doctoral supervisor. He is the head and convener of the "South China Acute Promyelocytic Leukemia Treatment Collaborative Group" for children. He has hosted numerous national natural science grants as well as provincial and municipal research projects, publishing over 100 papers, including more than 30 SCI papers as the first or corresponding author.  

01  

Q: An 8-year-old boy was diagnosed with acute B-lymphoblastic leukemia in September 2022. His initial white blood cell count was 81, categorizing him as intermediate risk. He has been treated according to the CCCG-ALL-2020 protocol, and after 9 days, his MRD was 0.04%, with a negative result at 46 days.  

1. The child developed a venous sinus thrombosis during his first treatment and has been taking rivaroxaban for prevention. Chemotherapy has continued as planned, and the thrombosis has neither worsened nor improved. How long does he need to continue taking rivaroxaban? Are there other measures to improve the thrombosis?  

2. Genetic testing shows the presence of the EP300-ZNF384 fusion gene and the PTPN11 A72T gene mutation. What is the prognosis associated with this gene?  

3. During the use of asparaginase, a low-fat diet is required. How many days before and after the medication should this diet be followed?  

A: 1. Does the child have any symptoms from the venous sinus thrombosis? If the thrombosis is still present, continue with rivaroxaban. The main side effect of rivaroxaban is bleeding, so monitoring and communication with the doctor to adjust the dose is necessary.  

2. In pediatric acute B-lymphoblastic leukemia, no evidence currently suggests that the PTPN11 A72T mutation affects prognosis.  

3. During the use of asparaginase, a low-fat diet is necessary. For children with newly diagnosed leukemia who are receiving asparaginase, if the dose is 2000 units/m² or higher, the effective duration can last for 3 weeks, so a low-fat diet should be maintained for at least 3 weeks. After that, a gradual return to a normal diet is recommended.  

02  

Q: A 13-year-old boy was diagnosed with intermediate-risk acute B-lymphoblastic leukemia on September 28, 2022, and is currently undergoing the sixth cycle of treatment.  

Pre-treatment examinations revealed the CUX1-NUTM1 fusion gene and the NRAS Q61K gene mutation. His MRD was less than 0.01 after 19 days and also less than 0.01 after 46 days. Because the MRD was less than 0.01 at 19 days, only one cycle of cytarabine was used in the second treatment, and the follow-up quantification of the fusion gene was 0.142%. In the third treatment, a high-dose second follow-up showed a quantification of the fusion gene at 0.011%. After the fourth follow-up of the third treatment, the quantification of the fusion gene was 0.000%.  

Is there a need for monoclonal antibody treatment to consolidate and prevent prognosis for this fusion gene? How do this fusion gene and gene mutations affect the prognosis?  

Currently, the child has had a smooth treatment journey from the first to the fourth cycle. Now that he is receiving asparaginase in the fourth cycle and has passed all blood concentration tests, he is preparing for the last phase of the asparaginase treatment (re-induction) before entering the maintenance phase. Since the child's fusion gene only turned negative after the fourth follow-up of the third treatment, is there a need for monoclonal antibody treatment to consolidate and prevent prognosis? How do this fusion gene and gene mutations affect the prognosis?  

A: The CUX1-NUTM1 fusion gene and NRAS Q61K mutation have not been shown to have prognostic significance in pediatric acute B-lymphoblastic leukemia and are currently not used as references for prognosis. The significance of the CUX1-NUTM1 fusion gene for MRD testing is also unclear (your child remains positive after treatment). There are currently no research reports on this. If MRD is accurately detected using flow cytometry (provided that the detection institution has mature and accurate techniques), it is advisable to use the MRD results from flow cytometry to assess prognosis. The mainstream view is that, since the significance of the CUX1-NUTM1 fusion gene is unclear, observation is sufficient, and no special treatment is necessary. There is also no need to use blinatumomab, as it is unclear whether it would be beneficial in this case. However, if the family is concerned and wants to use it, they can discuss it with the attending physician.  

03  

Q: A 5-year-old boy was diagnosed with acute B-lymphoblastic/myeloid mixed leukemia at 5 years old. He is currently undergoing consolidation after two treatment cycles, and his flow cytometry shows complete remission. What should the next steps of the treatment plan be?  

A: For acute B-lymphoblastic/myeloid mixed leukemia, it is important to determine if it is biphenotypic or biclonal, with most cases being biphenotypic. Biphenotypic acute B-lymphoblastic/myeloid mixed leukemia is typically treated with the acute lymphoblastic leukemia protocol, which has shown good efficacy, but this depends on treatment response, including leukemia minimal residual disease (MRD), especially after the induction treatment of the first cycle. However, you did not provide the MRD data after the induction treatment of the first cycle. If the treatment response is good, the subsequent treatment should continue with the acute lymphoblastic leukemia protocol.  

04  

Q: A 5-year-old girl was diagnosed with low-risk acute lymphoblastic leukemia at age 4. Her MRD was less than 0.01% at both 19 and 46 days, and her bone marrow smear was normal. After two high-dose methotrexate treatments, her initial fusion gene was CBFA2T3-PIEZO1 (level 2), with gene mutations FLT3 A680V (level 1) and KMT2D A5010_E5014fs (level 2), and hyperdiploidy. In the 30th week, her bone marrow showed MRD less than 0.01%, normal smear, and the CBFA2T3-PIEZO1 fusion gene at 0.05%. By the 41st week, her bone marrow showed MRD less than 0.0017%, with the CBFA2T3-PIEZO1 fusion gene at 0.08%.  

What does it mean that this fusion gene, CBFA2T3-PIEZO1, has remained positive until now? How does it affect prognosis? Is there a risk of relapse?  

A: The prognostic significance of the CBFA2T3-PIEZO1 fusion gene in acute lymphoblastic leukemia has not yet been confirmed and is currently not considered a reference for prognosis. The significance of the CBFA2T3-PIEZO1 fusion gene for MRD testing is also unclear (your child remains positive after treatment). There are currently no research reports on this. If MRD is accurately detected using flow cytometry (provided that the detection institution has mature and accurate techniques), it is advisable to use the MRD results from flow cytometry to assess prognosis. The mainstream view is that, since the significance of the CBFA2T3-PIEZO1 fusion gene is unclear, observation is sufficient, and no special treatment is necessary.  

05  

Q: A 16-year-old girl was diagnosed with acute lymphoblastic leukemia in March 2015, with a positive BCR-ABLP190 fusion gene. After a year of chemotherapy, she completed treatment without a transplant. Since the onset of her illness, she has been taking dasatinib, and only in 2022 did she test negative; all other tests have been positive, with values below 0.0001%. Additionally, her hemoglobin has consistently been around 74.  

Can she stop taking dasatinib under these circumstances? What can be done about her low hemoglobin?  

A: Currently, the standard detection method for BCR-ABLP190 is quantitative PCR, which has a sensitivity of only 0.01%. The new detection method, digital PCR (ddPCR), also has a sensitivity of only 0.001%. If your child's BCR-ABLP190 is detected at below 0.0001%, what method was used for this test? If it was one of the aforementioned methods, it should be considered negative. It is advisable to send her to another testing institution to confirm the negative result, and if confirmed, she can stop the medication and be monitored with regular check-ups.  

Low hemoglobin may be related to dasatinib; it is recommended to perform a blood test to check the trough and peak concentrations of dasatinib. Based on the blood concentration, the dasatinib dosage can be adjusted to reduce the side effects of anemia if continued medication is necessary.  

06  

Q: A 3-year-old boy was diagnosed with low-risk acute B-lymphoblastic leukemia at 2 years old, with high hyperdiploid subtype. His MRD was 0.69 at 19 days and turned negative at 46 days. Due to the residual disease at 19 days, he received an additional cycle of CAT treatment. During the second CAT treatment, when administering the third dose of asparaginase, his blood concentration did not reach the required level. Later, he switched to two cycles of Erwinia asparaginase for re-induction therapy.  

Should he receive the third dose of asparaginase to address the insufficient blood concentration before transitioning to the maintenance phase? What is the prognosis in this situation?  

A: If the blood enzyme activity (blood concentration) has not reached the required level after administering asparaginase, the efficacy may be somewhat affected, but the extent of the impact depends on how many further cycles of Erwinia asparaginase are planned and whether the case is considered low, medium, or high risk. Generally, low-risk cases are less affected. If additional cycles of Erwinia asparaginase are needed, it is possible to supplement the treatment. Different treatment protocols have different supplementation methods, which should be determined by your physician. We use the South China protocol (SCCLG-ALL protocol), and low-risk patients can supplement at the end of the re-induction CAM cycle.  

Chief Editor | Xiao Xiang  

Layout | Ying Tao  

Proofreader | Ya Li