To The Editor
MLL-rearranged (MLL-r) infant Acute lymphoblastic leukemia (ALL) is an
aggressive leukemia with poor prognosis. The 4-year event-free survival
is 47%.1 Inotuzumab Ozogamicin (InO) is a
CD22-targeted antibody-drug conjugate approved to treat relapsed ALL.
There is limited data on InO in infant leukemia.2,3Here we present a case of MLL-rearranged pre-B infant ALL with multiple
relapses and eventual long-term response to InO.
Our patient was diagnosed at 9-month-old of age with MLL-rearranged
pre-B ALL. He presented with leukemia cutis, leukocytosis and was CNS2.
He was enrolled in COG study AALL15P1.4 He had an
isolated bone marrow relapse 5 months into the treatment. He was then
enrolled on the COG relapse protocol AALL1331 and randomized to receive
chemotherapy with plans for bone marrow transplant. However, had a
second marrow relapse before he could receive a transplant.
Blinatumomab was then given as a bridging therapy while awaiting Car-T.
Ironically, on the day of admission for CAR-T therapy, he was found to
have CNS relapse and extra medullary disease. Thus, CAR-T was postponed
and at this time he was given InO along with triple intrathecal
chemotherapy for CNS 3 disease.
Our patient had an excellent response to InO. After two cycles of InO,
he was able to receive Car-T therapy. Unfortunately, while his marrow
remained MRD negative, his 28-day post-Car T evaluation showed CNS and
extramedullary relapse.
After having so many treatment failures within a span of 15 months, his
family chose to prioritize quality of life over the unlikelihood of
cure. InO was then resumed for palliative purposes. He was also treated
with triple intrathecal therapy followed by cranial radiation (1200Gy)
for his CNS disease. Surprisingly, our patient tolerated the InO well
and received 9 total cycles over the following year, his longest
treatment related remission, maintaining negative MRD. Dosing of Ino was
given weekly for 3 weeks/month for the first 5 cycles, then spaced
bi-weekly and then monthly for the remainder of the treatment.
Complications during InO treatment included moderate but persistent
pancytopenia, mucocutaneous bleeding, and one admission for localized
pseudomonas cellulitis.
As his mucocutaneous bleeding seemed out of proportion to the level of
thrombocytopenia (platelet count 40-50k), investigations were done to
identify other potential causes of bleeding. Coagulation studies, which
were normal at diagnosis, showed prolongation of PTT (45sec, ref
range:25-35), with no correction of mixing studies (42sec). Factor VIII,
IX, XI levels and Vitamin C, and K levels were normal. Workup for Von
Willebrand disease was negative. Dental evaluation was also normal.
Aminocaproic acid for persistent episodes of gingival bleeding was given
with some improvement, but the bleeding and bruising ultimately resolved
as InO dosing was spaced out.
Aside from thrombocytopenia, there are no previous reports of
coagulation abnormalities associated with InO.5,6 Due
to our patient’s mucocutaneous bleeding, we suspect InO may have
precipitated some degree of platelet dysfunction. Platelet aggregation
studies were not done during this time period but would have been
helpful to better delineate this cause. Additionally, we did not test
for inhibitors which may have caused the prolonged PTT.
Due to the risk for VOD with InO, his hepatic function was monitored
closely. Bilirubin levels remained normal, and AST, ALT and GGT were
only mildly elevated (grade 1). He was treated with prophylactic
Actigall (10mg/kg) BID for liver protection.
Our patient had an excellent quality of life with few complications
during prolonged InO treatment. Because of his unexpected and prolonged
remission, after 1 year of therapy, his parents elected to pursue a
curative stem cell transplant with a haploidentical paternal donor. His
conditioning regimen for transplant included Fludarabine and
Cyclophosphamide with post-transplant Cyclophosphamide. Unfortunately,
one month after transplant, his bone marrow was found to have complete
autologous reconstitution. He remains in complete remission and MRD
negative with a detection level of 10-6.(done by
CloneSeq), with recent bone marrow surveillance done 14 months after
stopping InO therapy.
After 4 prior relapses on conventional treatment protocols, our patient
has achieved a prolonged and ongoing remission with Inotuzumab. His
disease control can be attributed primarily to the prolonged treatment
of InO, as he has had disease recurrence after every other agent.
Although he was treated with Cytoxan and Fludarabine as a part of the
conditioning regimen for transplant it is unlikely this chemotherapy had
an impact on his disease as he was already in remission. Because he had
100% autologous reconstitution after transplant, there is no graft vs.
leukemia to explain this prolonged response. Since InO has poor CNS
concentration, as it does not cross the blood-brain
barrier,7 intrathecal therapy as well as cranial
radiation was instrumental in maintaining our patient’s excellent
response.
This is the first reported
case of prolonged MRD negative remission using Inotuzumab in a patient
with heavily treated, multiple relapsed, MLL-r infant ALL. InO was
effective in maintaining disease control and was well tolerated.
Surprisingly, disease control has persisted even after the cessation of
InO. InO could be considered as an alternative therapy for
relapsed/refractory CD22+ infant ALL, either as a bridge to curative
therapy or as an option for life prolongation therapies.