DISCUSSION
Despite current cure rates of ALL above 90% 1,9,
relapsed ALL is still the most important obstacle for the cure of
pediatric ALL patients. The relapse rate is about 10-15% of ALL in
children, but substantially higher (about 25-30%) in high-risk
subgroups 10,11. An estimated 40% to 50% of adult
patients with ALL experience relapse 12. 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 13 and still about 50% of ALL patients do
not respond to salvage therapy prior to the ALL R3 protocol14. The British ALL R3 protocol utilizes Mitoxantrone
to confer a significant response in progression-free and overall
survival in children with relapsed ALL 3. 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 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. In the
low MRD group with chemotherapy, second relapse rate was about
27%15. 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%15. Our case is unique in
that the patient remained in remission for nearly two years after only
receiving three phases of chemotherapy per the ALL R3 protocol for his
first relapse.
Children with Down syndrome are well-known to have increased risk of
developing B-cell precursor ALL. The 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%) 16.
Treatment-related mortality, primarily from infection, is increased in
all protocols in DS-ALL, which made both the five-year event-free and
overall survival inferior in patients with DS-ALL17,18. 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 three 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. 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 leukemia19.
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 duration5-7,20. The proposed mechanism was due to increased
cortisol production during stress or infection combined with an
immune-mediated process thereby generating anti-leukemic effects5,6,21. 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 22,23.
Similar phenomena and mechanisms have been discussed and reported in
several cases and case series in acute myeloid leukemia patients24,25. Our patient’s long-term remission may be
attributed to a combination of the three phases of chemotherapy per ALL
R3 protocol with the systemic stress related to his multiple severe
infections.