Adolescents and young adults with ALL (AYA) are rare, but the clinical issues encountered are challenging and it is even problematic to define the age range of this group of patients, which is currently generally accepted to be between 15 and 30 years of age. For example, some current pediatric ALL clinical trials allow young adults under the age of 30 to be enrolled, and even more so, some adult institutional clinical trials, including the M.D. Anderson Cancer Center (MDACC), enroll older ALL patients, even up to the age of 55 “young adults”, depending on the executive who writes the study plan.
I. Incidence of acute lymphoblastic leukemia in adolescents and young adults
SEER statistics on the incidence of ALL in young adults in the United States between 2001 and 2005 was 1.6/100,000, between the ages of 15 and 29 years, accounting for approximately 6% of all newly diagnosed aggressive neoplasms, with the lowest incidence of ALL and lower incidence of other leukemias in patients aged 15 to 29 years compared to higher age groups. In the United States, the absolute data of newly diagnosed ALL patients between 15 and 29 years of age is approximately 540 cases.
II. Treatment of adolescent and young adult patients (AYA)
In clinical practice, this group of patients, especially younger adolescents, can present in either the pediatric or adult oncology group, leading to studies comparing outcomes in both groups, with many published studies reporting superior OS and EFS outcomes in the pediatric group compared to the adult treatment group.
There are no comparable studies in the >21 years age group, and the toxicity reported so far with pediatric regimens in this age group appears to be acceptable, with some studies using pediatric regimens in the adult group showing very little grade III-IV toxicity. In MDACC, 30 adults >21 years of age receiving pediatric regimens, excluding expected hematologic toxicities, had approximately 20% grade III-IV adverse events with acceptable and actionable toxicities. The role of pediatric regimens in young adults remains unclear and requires more time and longer follow-up periods to confirm.
Many different factors exist in adult and pediatric clinical trials
(1) Familiarity with the disease, in pediatric patients ALL is the most common malignancy and most pediatric oncologists are very familiar with caring for these patients, providing a therapeutic advantage to pediatric oncologists, on the other hand, ALL is not very common in adults and therefore adult oncologists may not focus on these rare diseases, which are particularly important in ALL, where patient management and treatment are very complex.
(2) Pediatric oncology patients are usually treated in good medical centers, most adult leukemia patients are treated in general wards, and in pediatric leukemia clinical aspects there is a strong emphasis on protocol therapy-trial review is strict, and R21 year old young adults enter trials poorly.
(3) Pediatric patients have parental surveillance and support, unconditional choice, on-time visits to physicians, on-time medication, and a regimen can easily last 3 years.
(4) Finally, pediatric patients have different biological characteristics from young adults with ALL, for example, TEL-AML translocation and hyperdiploidy occurrence are significantly lower than in the pediatric group, while Ph+ ALL, high white blood cell count, and T-cell ALL occurrence are all higher than in the pediatric group.
Adolescent patients with ALL in pediatric leukemia centers, choose effective regimens and, in addition, may receive ongoing national programs, currently the pediatric oncology group regimen, open to patients up to 30 years of age, according to the Berlin-Frankfurt-Muenster (BFM) treatment, in which the study results reported: 81% of patients with rapid response to treatment achieved 6-year EFS and 89% achieved 6-year overall survival, with minimal differences across age groups, with rapid response defined as <25% primary cells after 7 days of treatment and morphologic complete remission at day 28 of induction therapy.
The trial used intensive VCR, meninase and methotrexate, applied to adolescents or other high-risk factors for ALL (at the MDACC Children’s Clinical Center if families do not wish to participate in the national trial protocol), other options known to have significant efficacy in adolescent patients include the Dana Farber Cancer Institute (DFCI), a high-risk ALL regimen and a BFM regimen using high-dose MTX, the DFCI study protocol using intensive menadione therapy in a group aged 15 to 18 years, using 2 consecutive DFCI trials showed 78% EFS in these patients, the DFCI 95-01 protocol using cranial radiation therapy in all patients >15 years of age, and the Children’s Tumor Group (PCG) 9404 protocol also showed significant efficacy in adolescent T-ALL. This trial also applied intensive meninephrine and high-dose methotrexate, and interestingly the recent clinical trial of adolescent T-ALL treatment in high-risk patients achieved similar efficacy to that of pre-B-cell ALL.
In the adult clinical group, adolescents are often placed in the adult ALL regimen group, such as the hyper-CVAD regimen, where the hyper-CVAD alternating regimen uses fractionated cyclophosphamide, vincristine, glucocorticoids and adriamycin alternating with medium-dose methotrexate and high-dose cytarabine, including intrathecal therapy, by CNS disease risk and first lumbar puncture cerebrospinal fluid status. This regimen achieved at least a 95% complete remission rate; except for spinal cord neurological invasion, without cerebrospinal radiotherapy, with a CNS relapse rate <5% and a published hyp-CVAD 5-year EFS at 38% (including all patients), a similar complete remission rate was achieved with intensive treatment of ALL using relatively high-dose anthracyclines, as well as high-dose Ara-c and methotrexate.
The duration of treatment is relatively short compared to pediatric regimens, without prolonging the maintenance period, and Pre-B-ALL treated with this regimen achieves a 5-year EFS of approximately 52% in all patients, with such efficacy not achieved in patients with high leukocytes or MLL gene rearrangements, and the Oncology and Leukemia Group (CALGB) 8811 case study showed a 5-year EFS at 69% for Pre-B-ALL <30 years of age. However, the results of the larger ECOG study group were not encouraging, and in this trial included 4-drug combination induction chemotherapy. Immediately following phase 2 induction using cyclophosphamide and cytarabine, this initial treatment was very similar to the pediatric ALL treatment regimen, while the later treatment differed from the pediatric regimen using moderate doses, with a 5-year overall survival rate of 44% in patients aged 15 to 19 years treated in the ECOG trial group, and interestingly, in patients aged 20 to 29 years OS was similar to the adolescent group with OS at 45%.
Third, disease-specific treatment
Adult ALL treatment strategies are entering a rapid phase and are being tried for different subtypes, formerly B-ALL expressing CD20, adult patients treated with anti-CD20 monoclonal Meroval plus hyper-CVAD improved disease-free survival (62% versus 28%) in patients <30 years old compared to the results of a retrospective study of non-T-CD20+ ALL.
However, there was no statistically significant improvement in OS and DFS in patients at higher ages; therefore, the addition of anti-CD20 monoclonal antibody to standard chemotherapy in adolescent-onset and young adult ALL may be an attractive option and more cases need to be accumulated. Many adult groups for ph+-ALL,currently use the addition of lysine kinase TKIS at the same time as chemotherapy. Adult studies have shown that imatinib can be added at the time of chemotherapy if the ph chromosome is detected and is well tolerated. In a long-term follow-up study of a group of ph+-ALL with a mean age of 51 years (17 to 84 years) using hyper-CVAD in combination with imatinib, 93% of patients achieved complete morphologic remission, molecular response by nested PCR in 52% of patients, and significantly improved 3-year DFS and OS compared with hyper-CVAD alone (66% vs 14% and 55% vs 15% P<0.001). The second-generation TKI, dasatinib in combination with hyper-CVAD is being used in ph+-ALL too early to draw definitive conclusions. Young adult T-ALL using hyper-CVAD in combination with nelarabin is similar to the treatment strategy of the pediatric oncology group (COG), adding nelarabin to BFM and treating the combined high-dose methotrexate
IV. Central nervous system treatment
All strategies used to treat ALL prevent CNS relapse or have a therapeutic effect on CNS leukemia, but how many courses of treatment are needed for CNS? What kind of patients need to be treated for CNS leukemia? Recently, several research groups using BFM as a base treatment have suggested that cranial radiotherapy is important to maintain a high cure rate, and the BFM group found that radiotherapy was not needed for the intermediate risk group of pre-B-ALL patients. The intermediate-risk group includes adolescent patients with pre-B-ALL who respond well to hormones, the Children’s Oncology Group (COG) clinical trials used advance BFM treatment, although the radiation doses were small and did not include spinal radiation therapy all showed early responses, some clinical trials included cranial radiation therapy, while other treatments did not use cranial radiation therapy even in patients with previous CNS leukemia at diagnosis, and used cranial radiation therapy in patients with cerebral white Compared with patients treated with hyper-CVAD regimen plus intensive intrathecal injection and with radiotherapy, the CNS relapse rate was lower in the group treated with hyper-CVAD, possibly related to the application of high-dose cytarabine. Thus, partial cure can be achieved in adolescents and young adults with ALL using combination chemotherapy alone without cranial irradiation.
The number of intrathecal injections is controversial and may depend on the systemic chemotherapy regimen chosen, with intrathecal injections ranging from 8 to 25 on the hyper-CVAD regimen and above for patients with slow early response treated with pediatric regimens, with the majority of intrathecal injections in the middle. Currently, young adults with pre-B-ALL treated at MDACC centers receive 15 intrathecal injections for patients treated with boosted BFM and menadione regimens. In addition, during CNS prophylaxis lumbar puncture due to injury may bring leukemic cells into the CNS, there are reports of worse prognosis in ALL patients with injury initiation intrathecal injection ALL patients, as the AYA population is becoming more obese sheath injection injury is increased, it is recommended for obese patients to delay the first intrathecal injection until the circulating primitive cells are cleared, reducing the chance of CNS contamination.
The most concerning toxicity in young adult patients with a pediatric-based approach appears to be acceptable, as mentioned above based on intensive menadione based therapy, which is well tolerated, and the standard 4-5 drug combination induction combined with intrathecal injection can be well executed, achieving a high rate of complete remission after induction therapy, and the pediatric regimen requires a shorter hospital stay overall compared to the adult regimen, in which Whether the addition of TKIS, melphalan or nelarabine is safe and effective remains unclear, and these studies may be conducted in the near future.
V. Hematopoietic stem cell transplantation
Transplantation is currently recommended in pediatric protocols for very high-risk pre-B-ALL patients, a group that includes the following: failure of induction according to morphologic criteria or persistence of microscopic residual disease (MRD); ph chromosomes, MLL rearrangement for poor response to therapy, subdiploid chromosome 44 or DNA index <0.81 in leukemic primitive cells, if there is a paired-related donor or An antigenically unrelated donor, except for the HLA-DR locus, in remission after initial chemotherapy for patients entering the transplant procedure.
What is the role of bone marrow transplantation in adolescent and young adult ALL? Adult ALL has an overall transplant EFS of 30-40% after first remission and worse after the second CR phase, EFS varies in different age groups, but in other studies, age does not affect survival, and other investigators have found that LFS is higher in the <30 years age group than in the 30 years age group in patients in first remission, and that post-transplant LFS may be better than post-chemotherapy LFS.
In studies of high-risk groups with adult ALL, stem cell transplantation is strongly recommended after first remission in these cases where the leukocytes are high at initiation, ph chromosome positive, slow to respond to chemotherapy or resistant to primary induction, or contain MLL rearrangements that are very poor to chemotherapy, in contrast to the pediatric group where subdiploidy is not frequently mentioned as a high-risk feature of adult ALL. The pediatric regimen is applied to the young adult population, for which there is no analysis of the effectiveness of new chemotherapy strategies compared with stem cell transplantation, and it is necessary to add transplantation to new chemotherapy regimens for high-risk young adults.
VI. Relapsed and refractory ALL
After relapse of ALL in young adults, treatment revolves around bone marrow transplantation with a second remission if an acceptable donor is available, followed by transfer to a transplantation procedure as soon as possible, the greatest difficulty lies in deciding on a donor and inducing another remission, after the first relapse it is very difficult to maintain the remission status despite the patient’s transplantation. Because of the few data on CNS relapse, intensive intrathecal chemotherapy combined with systemic systemic therapy can successfully achieve remission, but long-term survival is very poor. hyper-CVAD regimens with VCR, menadione and dexamethasone achieve second remission in approximately 45% of patients. This is a viable option for young adults after relapse with the pediatric regimen, and conversely, patients who relapse with the hyper-CVAD regimen may be effective with the pediatric regimen-based induction regimen.
VII. Summary
Young adult ALL (AYA) treatment is at the crossroads of pediatric and adult regimens, leading to this group being assigned to either the adult or pediatric group, and there may be benefits at the crossroads, not just for young adult patients, but also for ALL in all age groups, with intermediate groups of young adult ALL, patients having the potential to combine adult and pediatric trials, driving new trials in both young and older ALL populations. For example, the early application of TKI to ph+ALL treatment has recently been added to pediatric ALL treatment. Second-generation and late-stage TKIS are in clinical trials in the AYA population and, if successful, would strongly support the advancement of these agents for use in cutting-edge pediatric ph+-ALL treatment. Another example anti-CD20 monoclonal antibody, Meroval, has been shown to provide benefit in young adult ALL treatment and may be worthy of trial application in high-risk pediatric CD20+ non-T-ALL, and in adult acute leukemia, current interest lies in the application of pediatric-like chemotherapy regimens to adults, potentially improving survival and reducing hospital days, in addition to pediatric focus on late effects, particularly cognitive function, while also being MRD, adult and pediatric groups are investigating how to apply MRD for ALL. transplantation may be considered for adolescent and pediatric ALL and persistent MRD.