New progress in diagnosis and treatment of childhood ALL and malignant lymphoma

Malignant tumors are one of the major diseases that threaten the lives of children and become the main cause of child deaths. In developed countries such as the United States and Europe, malignant tumors are second only to accidents and are the second most common cause of death for children. In recent years, the mortality rate of malignancies in large cities has also risen to the second most common cause of death in children.

Malignant neoplasms in children are mainly concentrated in the hematopoietic system, central and sympathetic nervous systems, and mesenchymal tissues; they originate from the embryonic residual tissue and mesoderm, and occur in immature cells. Epithelial-derived tumors are rare. The common tumor types are acute leukemia, central nervous system tumors, malignant lymphoma, bone and soft tissue sarcoma, neuroblastoma, nephroblastoma, reproductive system tumor, and retinoblastoma. In the past 40 years, with the advancement of modern medical science and the unremitting efforts of pediatric oncologists, effective and comprehensive treatment has been adopted. About 2/3 of the children's malignant tumors can be cured. The cure rate of childhood acute lymphoblastic leukemia and lymphoma is as follows: Up to 70% to 80%, the 5-year survival rate of most solid tumors in children may exceed 60%, and the curative effect is significantly better than that of adult malignant tumors. This article mainly shares with readers the progress in the diagnosis and treatment of childhood acute lymphoblastic leukemia and malignant lymphoma.

I. Acute lymphocytic leukemia

Refractory and relapsed B-ALL Bortezomib + VXLD Chemotherapy Highly effective acute lymphoblastic leukemia (ALL) is the most common malignancy in children, and it is the highest incidence of childhood cancer. The initial diagnosis of standard and critically ill ALL patients receiving modern standard regimen chemotherapy does not require hematopoietic stem cell transplantation. The 5-year event free survival (EFS) rate reaches 80% to 90%. High-risk ALL adopts strong chemotherapy combined with allogeneic hematopoietic stem cell transplantation. The 5-year survival rate is about 50%. However, despite the combined use of multiple drugs for relapsed and refractory ALL, the complete remission (CR) rate is less than 40%, and the survival rate is low, and new treatments need to be explored.

A study reported by Messinger et al., Children's Hospital of Minnesota, USA, 2011 at the American Society of Hematology (ASH) annual meeting showed that bortezomib in combination with VXLD (vincristine + doxorubicin + L-asparaginase + dexamethasone) is difficult to treat Treatment of relapsed children with B-ALL achieved excellent results, exceeding expected results, and the study was terminated prematurely (Blood, online, May 31, 2012).

The study enrolled patients with relapsed or refractory ALL after 1 to 21 years of age, more than 25% of bone marrow blasts, and two or three drugs combined with chemotherapy. The treatment options were bortezomib 1.3 mg/m2/d1, d4, d8, d11 and combined use of VXLD.

The results showed that 22 patients with relapsed or refractory ALL received this combination therapy and efficacy analysis. A total of 14 patients achieved CR, 2 had CRp (complete remission but no platelet recovery), and a total response rate of 73% (Table 1). The efficacy of B-cell ALL patients was the best. Among 20 patients, 16 patients achieved CR and CRp, and the total effective rate was 80%, while 2 patients with T-cell ALL were ineffective (0%). Three patients (14%) died of bacterial infection, one patient (4.5%) violated the protocol and could not evaluate the efficacy (N/E), and two patients (9%) had severe peripheral neurotoxicity above grade 3 One patient developed mycotic invasive sinus infection and eyelid infection. The treatment was stopped after 14 days of treatment, but the curative effect was CR p. Since 3 patients (14%) died of bacterial infection, vancomycin, levofloxacin, and voriconazole or posaconazole were administered prophylactically in the subsequent 6 patients to prevent further severe fatal infections.

This study shows that bortezomib in combination with VXL D is very effective in relapsed B-ALL patients after combination therapy with multiple drugs, and the effective rate is the highest among all current relapse ALL clinical trials. Prophylactic use of antibiotics can effectively reduce the mortality rate of infection. At the same time, it is necessary to further evaluate the role of bortezomib combination chemotherapy in relapsed and high-risk patients with B-ALL.

Second, malignant lymphoma

1. Long-term follow-up of CCG 5942 with reduced treatment intensity of Hodgkin's lymphoma showed that randomized children with Hodgkin's lymphoma undergoing chemotherapy can be treated with low doses of infringement of wild radiotherapy. Event-free survival can be improved without affecting overall survival. .

The main treatment for Hodgkin's lymphoma in children is chemotherapy and/or radiation therapy. With the current standard of treatment, the cure rate has reached 80% to 90%. Whether it can be based on the current efficacy, reduce the intensity of treatment to further reduce the long-term side effects are worthy of attention.

Recently, the US Children's Cancer Research Group (COG) reported a randomized randomized clinical study of CCG 5942 in patients with Hodgkin's lymphoma who were randomized to chemotherapy after radiotherapy. Long-term follow-up results showed that CR patients received low chemotherapy after chemotherapy. Dosage infringement of wild radiotherapy may increase the EFS rate but does not affect the overall survival (OS) rate (J Clin Oncol, May 29, 2012 online).

In the study, 826 patients were enrolled from January 1995 to December 1998. 490 patients who received CR chemotherapy were randomly assigned to receive either low-dose (15 to 25 Gy) invasive radiotherapy or observation groups. EFS and OS counted from the time of random enrollment.

The results showed that the 10-year EFS and OS of the whole group were 83.5% and 92.5%, respectively. Among the patients who received randomization after CR treatment, the 10-year EFS in the radiotherapy and observation groups was 91.2% and 82.9%, respectively (P=0.004), and the 10-year OS was 97.1% and 95.9%, respectively (P=0.50). Large masses, B symptoms, and nodular sclerotic pathologic types are risk factors for EFS.

With a median follow-up of 7.7 years, low-dose invasive radiotherapy significantly increased the patient's EFS but did not improve OS. The risk of recurrence and the long-term side effects of radiotherapy need to be considered comprehensively for individualized patients. A comprehensive consideration of the patient, the characteristics of the disease, and the early response to chemotherapy will help determine which patients benefit from radiotherapy.

2. Late B-NHL rituximab has been added to a strong chemotherapy regimen to improve survival. COG reports that rituximab plus high-intensity chemotherapy can benefit advanced childhood B-cell non-Hodgkin's lymphoma in children and adolescents.

Both Burkitt's lymphoma (BL) and diffuse large B-cell lymphoma (DLBCL) are mature B-cell non-Hodgkin's lymphomas (B-NHL) and are highly invasive malignant tumors. Internationally, the same treatment strategies are used. And programs, stratified by risk factors. According to the current standard chemotherapy regimen, the 5-year event-free survival rate in early stage patients is more than 90%, and that in late stage patients is 70%-80%. Both of these two types of lymphomas express high levels of CD20. The addition of rituximab, which targets the CD20 monoclonal antibody, to a late-stage B-NHL intensive chemotherapy regimen in children is a concern for doctors.

US COG reported the clinical study of rituximab combined with high-intensity chemotherapy for advanced childhood B-NHL at the ASH Annual Meeting in December 2011 and the American Society of Clinical Oncology (ASCO) in June 2012. The results showed that there was no clinical study. Compared with the rituximab FAB/LMB/96 regimen, rituximab combined with high-intensity chemotherapy can benefit B-NHL in late childhood adolescents, especially in patients with central aggression (ASH2011; ASCO 2012; J Clin Oncol 2012, 30: Suppl 9501).

This study prospectively studied children with untreated stage III/IV or high-risk [bone marrow and/or centrally infiltrated] B-cell non-Hodgkin's lymphoma. Labriase was used to prevent tumor lysis while a combination of the modified FAB/LMB/96 protocol and rituximab was used. Hydration with non-alkaline fluid was performed 4–24 h before chemotherapy, with Raflate (0.2 mg/kg) followed by COP regimen (cyclophosphamide + vincristine + prednisone). Rituximab was administered at 375 mg/m2 each time. The FAB B4 or C1 protocol was added. Each induction course was used twice, and each consolidation session was used once.

The results showed that in 40 cases of advanced maturation B-NHL, 15 cases were central violations, and all 15 cases were Burkitt's lymphoma. There were only 5 deaths in the whole group, of which 2 were toxic and 3 were tumor related. The three-year EFS rates in patients with stage III/IV and group C (bone marrow/central infiltration) were 95% and 89%, respectively. Interestingly, 2 of 4 patients with primary mediastinal disease relapsed, while 19 patients with LDH less than 2 times normal had no recurrence or toxicity-related death. In 15 patients with central aggression, 14 survived. Compared with the FAB/LMB/96 regimen without rituximab (Table 2), the 3-year EFS at stage III/IV was 95% and 84%, respectively, with central infiltration. The 3-year EFS for patients was 93% and 72%, respectively. This immunotherapy plus chemotherapy is excellent for patients with central involvement.