How to Continue Therapy During Severe Infections? What Impact Do Genetic Abnormalities Have on Prognosis?

How to Continue Therapy During Severe Infections? What Impact Do Genetic Abnormalities Have on Prognosis?

Source: Sunflower Children's Hospital  

Author: Professional Team  

Editor: Chen L  

Date: June 23, 2023  

Disclaimer:  

The online Q&A is not a substitute for treatment recommendations. Due to the inability to understand the detailed condition of the patient and to conduct face-to-face diagnoses, expert opinions are for reference only. For specific treatment plans, please visit a reputable hospital.

This edition of the "Expert Q&A" features Dr. Li Hua Yang and Dr. Dan Na Lin from the Pediatric Hematology Department at Zhujiang Hospital, Southern Medical University, to answer your questions.

Dr. Yang specializes in chemotherapy for childhood leukemia, lymphoma, brain tumors, and other solid tumors, as well as CART cell therapy and allogeneic hematopoietic stem cell transplantation. She has extensive experience in diagnosing and treating childhood thrombocytopenia, aplastic anemia, thalassemia, neutropenia, hemophagocytic syndrome, and Langerhans cell histiocytosis, among other conditions. She also has rich expertise in treating pediatric hemangiomas, lymphangiomas, and Kame syndrome.

Dr. Lin primarily focuses on clinical work related to pediatric hematological oncology, specializing in chemotherapy and cellular immunotherapy for childhood leukemia and brain tumors.

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Q1: A 7-year-old boy was diagnosed with acute lymphoblastic leukemia (ALL) B at age 6. After the first lumbar puncture, he developed lysis syndrome after receiving prednisone. An MRI showed central nervous system (CNS) involvement, but lumbar puncture results never indicated tumor cells. After 22 days, MRD was below 0.01%, and all genes turned negative, but he had a TP53 mutation with 50% pathogenic germline genes. After 33 days, he was classified as high-risk and underwent chemotherapy according to the 2016 Southern China protocol. He is currently in the second block of high-risk consolidation therapy. After completing the second round of Block 1, he developed a fungal infection, leading to a BNP spike to 38,000, poor kidney function, pneumonia, intestinal obstruction, and required a large amount of glucocorticoids and broad-spectrum antibiotics. The fungal infection has proven difficult to resolve.  

Question: If therapy continues, is the risk of severe infection the same? Can the subsequent therapy still proceed?

A1: Due to the complications caused by the disease itself and high-intensity treatment, the overall survival rate for high-risk (HR) acute lymphoblastic leukemia (ALL) still has significant room for improvement. For patients with suitable donors or persistent positive minimal residual disease (MRD), it is recommended to receive allogeneic hematopoietic stem cell transplantation as soon as possible after MRD turns negative. Increasing survival rates is the key focus of current HR-ALL research, meaning that successfully converting MRD to negative and smoothly bridging to hematopoietic stem cell transplantation is crucial.  

In this case, the child diagnosed with high-risk B-ALL is undergoing the fourth consolidation treatment according to the SCCLG-ALL-2016 protocol but has developed an uncontrollable pulmonary fungal infection. The prognosis of fungal infections is closely related to the patient's immune status. Continuing intensive chemotherapy with a poor immune status makes it even harder to control fungal infections and may worsen the situation. For patients temporarily intolerant to chemotherapy, consider using Blinatumomab (targeting CD19-positive precursor B-ALL) for treatment, and once the fungal infection is controlled, continue with the remaining chemotherapy regimen or directly transition to allogeneic hematopoietic stem cell transplantation. However, if the child also has CNS leukemia (CNSL) (diagnosed if MRI shows an intracranial mass that cannot be explained by other reasons or if immature cells are present in the cerebrospinal fluid), Blinatumomab cannot penetrate the CNS, so close monitoring of the CNSL situation is required, and intrathecal injections can be given during the use of Blinatumomab.  

Since CAR-T cell therapy has shown good efficacy for extramedullary lesions such as the bone marrow, CNS, and testes, theoretically, this child could undergo CAR-T cell therapy followed by bridging to allogeneic hematopoietic stem cell transplantation. However, studies have found that CAR-T cell therapy is relatively less effective for patients with TP53 mutations. This child has a germline TP53 mutation, which is a tumor susceptibility gene, and there is a high risk of secondary tumors from chemotherapy and radiotherapy. Caution is needed when considering cranial radiotherapy (CRT) or total body irradiation (TBI). Additionally, if there are mutations in susceptibility genes like TP53 in relatives, they should not be used as donors.

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Q2: A 3-year-old boy was diagnosed with acute lymphoblastic leukemia (ALL) B at age 1. He underwent chemotherapy according to a low-risk protocol without interruption and completed treatment in mid-March. After the third cycle, the residual was negative. During the first round of maintenance therapy, tests indicated no initial clonotypic sequence detected, and the residual was zero. However, three new clonotypic sequences emerged with mutation frequency.  

Question: What does the emergence of these three new clonotypic sequences indicate?

A2: The efficacy of low-risk (LR) acute lymphoblastic leukemia (ALL) is approaching a cure. The key focus of LR-ALL research is to reduce chemotherapy intensity to avoid related adverse effects and improve quality of life. Of course, due to limitations in detection technology, LR-ALL is not necessarily genuinely low-risk, nor can the possibility of relapse be completely excluded. This emphasizes the importance of dynamic monitoring of minimal residual disease (MRD) and timely adjustment of treatment plans. Currently, MRD monitoring techniques for ALL primarily include multiparameter flow cytometry and RT-qPCR or next-generation sequencing (NGS) targeting fusion genes and immunoglobulin/TCR genes.  

In 2020, China’s drug administration released guidelines for monitoring minimal residual disease in clinical trials of acute lymphoblastic leukemia, noting that NGS monitoring methods still lack uniform standards and require integration and validation with other detection projects for clinical significance. Immune repertoire monitoring is suitable for patients without specific fusion genes as monitoring targets, requiring the determination of IGH oligoclonality and TCR rearrangements at diagnosis and regular PCR monitoring thereafter. During treatment, clonal evolution may occur, and the significance of MRD should be comprehensively analyzed in conjunction with flow cytometry. It is suggested to monitor using both techniques regularly; if the copy number continues to rise and MRD turns positive in flow cytometry, it indicates a significant risk of leukemia relapse, necessitating timely intervention.

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Q3: A 12-year-old girl was diagnosed with acute lymphoblastic leukemia (ALL) B at age 10, rated as intermediate risk, and is currently undergoing maintenance treatment according to the 2015 protocol.  

Question: Previously, due to fever, she stopped taking mercaptopurine, and methotrexate was delayed. Now that she is ending treatment, should she supplement 14 days of mercaptopurine, and does she also need to supplement methotrexate?

A3: Currently, the research goal for intermediate-risk (IR) acute lymphoblastic leukemia (ALL) is to bring its cure rate closer to that of the low-risk group. The main treatment methods include chemotherapy and targeted therapy. Oral methotrexate and mercaptopurine (which have a synergistic effect) are also important components of the maintenance therapy protocol. The continuity of maintenance treatment and accumulated drug dosage both affect the patient’s long-term prognosis, needing to be maintained for a total of 2.5 years. Dosages should be adjusted based on blood cell counts (especially neutrophils and platelets), and at the end of treatment, the duration of mercaptopurine and methotrexate should be supplemented as needed (i.e., accumulated dosage).  

Of course, some patients require personalized medication plans due to heterozygous or homozygous mutations in drug metabolism genes like TPMT and NUDT15. The drug dosages these patients can tolerate are often less than 1/8 of the standard dose, emphasizing the continuity of treatment rather than necessitating full accumulated doses for the entire maintenance therapy cycle. The goal of low-intensity maintenance chemotherapy is to prevent relapse while restoring the patient's immune function as much as possible, ultimately relying on the immune system to eliminate residual leukemia cells. 

There are many factors influencing disease relapse, such as the emergence of drug resistance genes, the amplification of leukemia subclones, extramedullary lesions, and the immune status of the body. Therefore, parents should not be overly anxious about the two-week treatment duration difference.

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Q4: An 11-year-old boy was diagnosed with acute lymphoblastic leukemia (ALL) B at age 10, with positive fusion genes BCR::ABL (P190) and ETV6::RUNX1. He is undergoing treatment according to protocol 20 + Dasatinib, with MRD negative at 19 days and 46 days. He has just completed the third phase of the fourth cycle, and the medication administration process has been smooth each time.  

Question: What is the prognosis for a child with this fusion gene when taking Dasatinib? How often should the fusion gene be tested? Does MRD turning negative at 19 days mean that both the BCR::ABL (P190) and ETV6::RUNX1 fusion genes are also negative?

A4: Philadelphia chromosome-positive (Ph+) acute B-lymphoblastic leukemia (B-ALL) has been shown through a large number of clinical studies that the combination of tyrosine kinase inhibitors (TKI) with chemotherapy can achieve long-term efficacy comparable to or even better than allogeneic hematopoietic stem cell transplantation if the patient's BCR/ABL fusion gene-MRD can turn negative timely. Of course, TKI must be taken continuously throughout the entire treatment period. Dasatinib, with multiple targets and strong effects, can penetrate the blood-brain barrier, and the CCCG-ALL-2015 protocol study found that the efficacy of second-generation TKI Dasatinib is significantly better than that of first-generation TKI Imatinib.  

Current research focuses on the timing of TKI withdrawal and the mechanisms of TKI resistance. There are no unified standards for TKI treatment duration among various cooperative groups. Some groups require stopping TKI along with chemotherapy when MRD is negative, while others require maintaining a deep MRD remission for two years before TKI withdrawal. ETV6::RUNX1 is an independent favorable prognostic factor; cases with ETV6::RUNX1 accompanying BCR::ABL (P190) are rare, and there are no relevant reports about the prognosis. However, theoretically, the ETV6::RUNX1 fusion gene does not worsen the prognosis based on Ph+.  

The most important prognostic assessment method is the MRD of the two fusion genes. This child’s PCR-MRD was negative at both 19 days and 46 days, indicating that the patient is sensitive to chemotherapy and TKI. Throughout the treatment period, PCR-MRD should be monitored every three months, and if the copy number increases, the monitoring interval should be shortened, and treatment strategies should be adjusted promptly.

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Q5: A 7-year-old boy was diagnosed with acute lymphoblastic leukemia (ALL) B in December 2021 after experiencing joint pain for over two months. His MRD was 0.42% at 19 days, and after 50 days, flow cytometry MRD turned negative, with the transcription gene TCF3::ZNF384 testing positive. He is undergoing chemotherapy according to the Shanghai 2020 protocol. During the second cycle of intensification, he received 0.1g of Imatinib daily, and he is now in the maintenance phase.  

Question: Is TCF3::ZNF384 a high-risk gene? Does he need a transplant now? Should other treatments be added?

A5: The ZNF384 gene rearrangement is caused by the t(12;19) chromosomal translocation, with an incidence of 5% in childhood ALL and about 10% in adolescent ALL. Patients with this type of childhood ALL often have high white blood cell counts at diagnosis and respond poorly to steroids.  

Whether to classify a patient as high-risk can vary by cooperative group definitions. The St. Jude Children's Research Hospital (SJCRH) - ALL-16 protocol classifies it as intermediate risk. The prognosis for EP300::ZNF384 fusion gene types is better than for other rearrangements, while patients with TCF3::ZNF384 and TAF15::ZNF384 fusion genes may have a later relapse.  

This child had a positive PCR-MRD at day 50 of treatment, indicating a high-risk classification. If the flow cytometry MRD or PCR-MRD is ≥0.1% before consolidation treatment (W12), there are indications for allogeneic hematopoietic stem cell transplantation. Before transplantation, Blinatumomab can be used to help convert PCR-MRD to negative, reducing the risk of relapse after transplantation.

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Q6: A 6-year-old boy was diagnosed with acute lymphoblastic leukemia (ALL) B at 5.5 years old due to an IK6 heterozygous deletion. He was treated according to the 2018 intermediate-risk protocol, with a white blood cell count of 47 at diagnosis, a high hyperdiploid subtype, and a triploid complex karyotype. His PCR-MRD was 1.3668% on day 15, 0.0008% on day 33, and flow cytometry MRD was less than 0.01%, with gene tests turning negative. The chemotherapy process went smoothly without infection; after re-induction, PCR-MRD was negative, and he is now in the second month of maintenance.  

Questions: 1. On day 15, without flow cytometry MRD testing, the PCR-MRD was 1.3668%. What would the flow cytometry MRD result roughly be if converted? Was the residual too high on day 15?  

2. Does the IK6 heterozygous deletion affect prognosis? Is the intermediate-risk treatment intensity sufficient?  

3. The child's head MRI was normal at diagnosis, and the cerebrospinal fluid has remained normal. The doctor said to perform intrathecal injections 17 times, but the intermediate-risk protocol states 24 times. Is 17 times enough?

A6: The tumor suppressor gene IKZF family includes IKZF1, IKZF2, IKZF3, IKZF4, and IKZF5. Among them, IKZF1 consists of eight exons, coding a zinc finger protein that forms ten isoforms (IK1-IK10) through different splicing. IK1-IK3 are functionally normal isoforms, while IK4-IK10 are mutant isoforms. This child has the IK6 mutant isoform, which has a loss of function. Its impact on prognosis is influenced by other background genes; for example, patients with the BCR::ABL1 fusion gene have a poorer prognosis, while those with DUX4 gene rearrangements tend to have a better prognosis.  

Different cooperative groups have varying standards for risk stratification. For instance, the Southern China ALL-2023 protocol includes IKZF1 deletions without DUX4 rearrangement in the high-risk group. The NCCN guidelines include IKZF1 deletions in the high-risk group, while the CCLG-ALL-2018 protocol classifies patients as high-risk if d15 MRD ≥ 1×10^-1 or d33 MRD ≥ 1×10^-4 or if pre-consolidation treatment MRD ≥ 1×10^-4 without ETV6::RUNX1 co-occurrence.  

This child's PCR-MRD of 1.3668% at day 15 would be classified as intermediate risk according to most cooperative groups. The sensitivity of flow cytometry MRD monitoring differs from PCR-MRD monitoring (10^-4 versus 10^-6), and as they monitor different subjects and methodologies, direct conversion is not feasible. The child has a favorable hyperdiploid karyotype, with PCR-MRD below 10^-1 at day 15 and below 0.01% at day 33, indicating a good treatment response. He is currently in the maintenance treatment phase, and it is recommended to monitor MRD regularly, ensuring the continuity and intensity of maintenance therapy. Since the child has had no CNS leukemia during onset or treatment, diagnosed as CNS1, according to the CCLG-ALL-2018 protocol, the standard recommendation for intrathecal injections is indeed 17 times.