To the Editor,
Immune-mediated cytopenias (IMCs), including immune thrombocytopenic
purpura (ITP), autoimmune hemolytic anemia, and autoimmune neutropenia,
have been newly highlighted as a significant complication after
allogeneic hematopoietic cell transplantation (HCT), with a cumulative
incidence of 2.1% to 52.6%.1,2 Major risk factors
for post-transplant IMC include younger recipient age at HCT,
non-malignant disease, cord blood transplantation, unrelated donor, and
a reduced-intensity conditioning (RIC) regimen.1,2Post-transplant IMCs are occasionally resistant to conventional
first-line therapy, i.e., corticosteroid and/or intravenous
immunoglobulin (IVIG) therapy in combination with supportive therapy,
such as granulocyte colony-stimulating factor, thrombopoietin receptor
agonist (TPO-RA), and transfusion. Rituximab, an anti-CD20 monoclonal
antibody (mAb), mycophenolate mofetil, bortezomib, and daratumumab, an
anti-CD38 mAb, have been used as second-line or subsequent therapies for
refractory or recurrent cases.1–5
A 17-year-old boy with adrenoleukodystrophy underwent allogeneic bone
marrow transplantation (BMT) from a human leukocyte antigen (HLA) 7/8
allele-matched unrelated donor using a RIC regimen consisting of
fludarabine (125 mg/m2), melphalan (140
mg/m2), rabbit anti-thymocyte globulin (5 mg/kg), and
total body irradiation of 4 Gy. Tacrolimus and short-term methotrexate
were administered as prophylaxis for graft-versus-host disease (GVHD).
Myeloid lineage cell engraftment and complete chimerism were achieved on
days 20 and 28, respectively. No significant GVHD was observed.
On day 118, he was readmitted to our hospital with oral bleeding and
cutaneous purpura, and was diagnosed with ITP. The clinical course after
onset of ITP is shown in the Figure. Soon after re-admission, frequent
red blood cell and platelet transfusions were required to treat massive
gastric mucosal bleeding. Since various treatments, such as IVIG,
prednisolone, methylprednisolone, TPO-RAs (eltrombopag and romiplostim),
and four courses of 375 mg/m2/week rituximab, failed
to improve thrombocytopenia, he received one course of 16 mg/kg
daratumumab on day 191, after the approval for use as an unapproved drug
from the Patient Safety Unit of Kyoto University Hospital. His platelet
counts soon exceeded 100×109/L but suddenly decreased
7 months later while he was receiving romiplostim therapy. Since the
effect of the three courses of daratumumab was transient and serial flow
cytometric analyses demonstrated the reemergence of CD20+ B cells, which
had disappeared after rituximab therapy, just before the recurrence of
ITP, he received four courses of rituximab in combination with
prednisolone (1 mg/kg/day) and romiplostim. His platelet counts
gradually increased and reached more than 100×109/L 1
month after initiation of the second rituximab treatment, while he was
still undergoing therapy with prednisolone and romiplostim.
The pathophysiology of post-HCT IMCs is still poorly understood.
However, it has been speculated that immune dysregulation caused by
conditioning regimens, infections, GVHD, immunosuppressive agents,
reduced and dysfunctional regulatory T cells, and/or HLA mismatched
donor-derived naïve T cells trigger the development of post-HCT IMCs
mainly via auto-antibody production to hematopoietic
cells.1,2,6 High-throughput single-cell bioassay of
antibody-secreting cells of ITP patients has recently demonstrated the
existence and dissemination of autoreactive plasma cells in multiple
hematopoiesis organs, such as spleen, bone marrow, and lymph nodes,
which might reduce the efficacy of B cell depletion by
rituximab.5 In the present case, CD38-targeting
therapy using daratumumab quickly improved the first episode of
rituximab-refractory ITP, suggesting the presence of autoreactive plasma
cells. By contrast, additional rituximab therapy was effective in
counteracting the recurrence of daratumumab-refractory ITP, implying the
presence of remnant autoreactive B cells. Thus, sequential or
combination therapy with rituximab and daratumumab appears to be a
promising therapeutic option for refractory post-transplant IMCs, which
might be caused by multiple antibody-secreting cell populations.