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.