Dear Editor,
Despite recent advancements, the survival in pediatric acute myeloid
leukemia (AML) continues to remain dismal.1 Various
molecular and genetic alterations and minimal residual disease (MRD) are
frequently used for risk stratification. Salvage intensive
chemotherapies have been recommended to bring remission before
proceeding to hematopoietic stem cell transplant (HSCT). These come with
prolonged duration of neutropenia and higher infective
mortality.2 There is need for identification of novel
therapeutic targets.
Leukemic blasts commonly express CD38, daratumumab, a recombinant
monoclonal antihuman CD38 antibody approved for myeloma therapy, has
been suggested to be also potent in acute lymphoblastic
leukemia.3 We report possibly first case of pediatric
AML who achieved MRD negative remission with single agent daratumumab.
A 2 years old male presented with history of recurrent fever, which was
not responding to conventional antibiotics. Routine blood investigations
revealed anemia with hypereosinophilia. CBC revealed hemoglobin 8.3g/dl,
white blood cell counts 32.5 x 109/microlit and
platelet count of 320 x 109/microlit. Absolute
eosinophil count was 10.6 x 109/microlit. USG abdomen
documented abdominal lymphadenopathy and splenomegaly. Hematology
opinion was sought for eosinophilia. Child underwent a lymph node biopsy
under sedation and in same sitting a bone marrow aspirate and biopsy
were performed. Bone marrow revealed 71% blasts. The flowcytometry
scatter parameters and antigenic expression profile of bone marrow along
with morphology are consistent with Acute Myeloid Leukemia with CD 38
(dim expression) and aberrant expression for CD56. Abdominal lymph node
biopsy was suggestive of round cell tumor with histomorphology and
immunostaining were consistent with hematolymphoid (Myeloblast)
malignancy. Ki67 was 70%. Cytgenetics revealed tetraploidy (XXXY) on
chromosomal analysis. He was administered induction chemotherapy ADE as
per AAML0531 protocol. Child attained morphologic remission but MRD
assessment revealed 0.57% clonal cells. He went on to receive phase II
of ADE therapy. Subsequent cycles were continued as per protocol. At end
of intensification II protocol bone marrow MRD assessment revealed
0.48% clonal cells in April 22. There was delay in subsequent therapy.
BMA at this point revealed 7% blasts. These clonal cells had dim CD 38+
expression.
Parents were counselled regarding need for allogeneic bone marrow
transplantation. Gemtuzumab ozogamicin is not available in India.
Daratumumab at a dose of 16 mg/kg was started in view of CD 38
expression. After 4 weekly doses of daratumumab, child attained MRD
negative (<0.1) remission. BMT was delayed due to logistic
issues and lack of consent from family. Therefore, weekly doses of
daratumumab were continued. MRD remained negative even after 1 month
(After 8 doses of Daratumumab) in June 22 <0.1%. Dosing
schedule was changed to once in 2 weeks after this.
At the time when he was due to for 10th dose of
daratumumab, he complained of right leg pain which worsened with
restricted movement and local tenderness. MRI hip and leg showed marrow
edema with periosteal reaction in right tibia suggestive of myeloid
leukemia changes. Histobiopsy from tibial lesion and bone marrow both
revealed florid relapse. MRD was 21.9%.
Child underwent a salvage chemotherapy with FLAG and attained
morphologic remission. MRD at this time was 1.72%. He underwent a
haploidentical (donor sister) hematopoietic stem cell transplant in Oct
22. At present child is 5 months post BMT with MRD negative status and
100% donor chimerism.
Most AML blasts show high CD38 expression without obvious correlation
with cytomorphological and genetic characteristics.4
Daratumumab is a fully human IgG1-kappa monoclonal antibody that
directly binds to CD38 has been confirmed to be safe and effective in
patients with relapsed and refractory multiple
myeloma.5 Daratumumab has multiple mechanisms of
action Daratumumab significantly induces antibody dependent phagocytosis
in AML and shows interference with AML cell trafficking in vivo in a
xenograf transplantation model.6
Previous reports on daratumumab in acute lymphoblastic leukemia have
used a dose of 16 mg/kg which is typical myeloma
protocol.7 MRD negative remission induction is fast as
happened with this child who attained MRD negative remission after 4
weekly doses. This remission was sustained for 10 weeks which provides a
very good window to proceed with HSCT as curative therapy. One important
consideration is that our child had a dim CD 38 expression. Daratumumab
promotes antitumor immune responses, rather than targeting the cancer
directly [10]. Daratumumab can inhibit cytotoxic
T-lymphocyte–associated antigen 4 (CTLA-4) and programmed cell death
protein 1 (PD-1) to promote T-cell expansion and enhance T-cell
activation, resulting in prolonged survival and delayed disease
recurrence in patients with advanced solid tumors and hematologic
malignancies.8 Therefore, it is possible that other
mechanism of action may have been useful in inducing remission. This
opens up possibility of its usage in CD 38 dim/negative negative AML
also. Daratumumab and venetoclax combination has been added to a
preparative regimen among 20 children with chemorefractory acute myeloid
leukemia who underwent haploidentical HSCT yielding a 2-year EFS of
44%.9
Present report highlights efficacy of daratumumab as a single agent in
inducing short lived MRD negative remission in a child with dim CD 38
expression.