DISCUSSION
Despite current long-term remission with leukemia-free survival of ALL reaching above 90% in children 1, 12, relapsed ALL and adult cases are still the most important obstacles for the cure of ALL patients. The relapse rate is about 10-15% of ALL in children, but substantially higher (about 25-30%) in high-risk subgroups13, 14. An estimated 40% to 50% of adult patients with ALL experience relapse 15. DS patients with ALL even have high relapse rate,6 partially due to poor tolerance to anti-leukemia drugs.16 DS patients more frequently develop severe infectious complications.16
Although high dose Mitoxantrone plus Cytarabine were effective in achieving remission in refractory leukemia, the duration of the remission was only about half a year 17 and still about 50% of ALL patients do not respond to salvage therapy prior to the ALL R3 protocol 18. The British ALL R3 protocol utilizes Mitoxantrone to confer a significant response in progression-free and overall survival in children with relapsed ALL4. Our patient, who had a bone marrow relapse about 20 months after the completion of his initial chemotherapy, was considered to have late bone marrow relapse (defined as relapse occurring 36 months after the first diagnosis or more than 6 months after the end of front-line therapy). He was treated as per the ALL R3 protocol and had positive MRD of 0.2% after Reinduction and negative MRD after Consolidation. Per the ALL R3 protocol, patients with B-precursor ALL with late bone marrow relapse and low MRD (<0.01%) at the end of induction had favorable outcomes with chemotherapy without undergoing stem-cell transplantation. Patients with higher MRD (>0.01%) required allogeneic stem-cell transplantation. But after long-term follow-up of the late bone marrow relapse patients for 7 years, the second relapse rate was about 23% in the high MRD group even after stem cell transplant. We had discussed this as a group for our patient and thought that his transplant related mortality (TRM) would be too high given his toxicities with initial chemotherapy and his Down syndrome status. We chose to continue chemotherapy per ALL R3. In the low MRD group with chemotherapy, second relapse rate was about 27%19. The progression-free survival at 5 years was significantly lower in the high MRD group comparing with that in the low MRD with 56% versus 72%19. Our case is unique in that the patient was still complicated with several systemic infection after only receiving two phases of chemotherapy per the ALL R3 protocol for his first relapse, but remained in remission for nearly two years.
Patients with Down syndrome are well-known to have 10- to 20-fold increased risk of developing B-cell precursor ALL.20The Ponte di Legno study group showed that DS-ALL patients had higher 8-year cumulative incidence of relapse than non-DS patients (26% vs 15%) 6. AYA patients with ALL have favorable outcomes when they are treated with pediatric protocols.11Treatment-related mortality, primarily from infection, increased in all protocols in DS-ALL, which made both the five-year event-free and overall survival inferior in patients with DS-ALL 21, 22. Current COG protocols have made modifications to limit toxicities. Our patient had multiple infections during his initial chemotherapy per AALL1131. He also developed multiple severe infections after two phases of chemotherapy per the ALL R3 protocol following disease relapse. Given the significant toxicity that he experienced, a decision was made for cessation of therapy, which we thought would benefit the patient better and was approved by patient’s parents. Over time, more options are becoming available for patients with relapsed ALL that confer less toxicity. Currently, antibody-targeted therapies, such as bispecific (CD3/CD19) T-cell-engaging antibody Blinatumomab, Inotzumab, and CD19-directed chimeric antigen receptor (CAR) T –cell therapies are major breakthroughs in the management of relapsed leukemia23.
Spontaneous or transient remission of acute lymphoblastic leukemia during severe infection has been described in a few cases and case series reports with averaged ten weeks in duration 7-9, 24. The proposed mechanism was due to increased cortisol production during stress or infection combined with an immune-mediated process thereby generating anti-leukemic effects 7, 8, 25. Cytokines, including tumor necrosis factor-alpha, interferon-alpha, and interleukin-2, released during infection can directly inhibit the residual blast proliferation or through increased activity of T lymphocytes, macrophages, and natural killer cells leading to an anti-leukemia effect 26, 27. Similar phenomena and mechanisms have been discussed and reported in several cases and case series in acute myeloid leukemia patients 28, 29. Our patient’s long-term remission may be attributed to a combination of the two phases of chemotherapy per ALL R3 protocol with the systemic stress related to his multiple severe infections.