A 46-year-old female presented with abdominal pain and was found to have
A cholecystectomy showed pathology consistent with a human T-cell
leukemia virus-1 lymphoproliferative disease, and PET/CT showed lung nodules
and liver involvement.
She underwent treatment with cyclophosphamide, doxorubicin, vincristine,
prednisone and etoposide. At that time, her course was complicated by the
development of a pleural effusion, which required a chest tube.
She achieved complete remission and subsequently was evaluated for
allogeneic stem cell transplant. At that time, no suitable donors were
available, and only double umbilical cord blood units were available as an
alternate donor source.
She initially declined transplant; however, approximately 13 months
after her diagnosis, she developed a gluteal mass. PET/CT showed active uptake,
and biopsy showed a recurrence of the lymphoma. She received two cycles of
salvage chemotherapy with ifosfamide, carboplatin and etoposide, which resulted
in a second complete remission. Repeat PET/CT showed resolution of the gluteal
lesion with stable lung lesions.
At that point, she was admitted to undergo allogeneic hematopoietic stem
cell transplant (HSCT) from double umbilical cord blood units. The double
umbilical cord blood units were determined to be appropriately matched and had
an appropriate number of cells.
She initially underwent conditioning with fludarabine and melphalan, and
graft-versus-host disease prophylaxis included mycophenolate and tacrolimus.
She underwent transplant; however, she showed no evidence of engraftment by day
35 post-transplant and was considered to have graft failure.
After a conditioning regimen of fludarabine, cyclophosphamide and
alemtuzumab (Campath, Ilex Pharmaceuticals), she underwent a second double
umbilical cord blood transplant. She continued to exhibit graft failure,
despite support with granulocyte colony–stimulating factor and
immunosuppression with tacrolimus, mycophenolate mofetil and anti-thymocyte
She remained pancytopenic, requiring transfusion support, and her course
was complicated by development of BK virus cystitis. On day 33 from the second
transplant, she was started on IV immunoglobulin and dexamethasone to increase
immunosuppression and potentially lead to engraftment. However, she remained
She also developed vancomycin-resistant enterococci in the urine, and
she was treated with daptomycin (Cubicin, Cubist Pharmaceuticals) and
gentamicin. A restriction fragment length polymorphism (RFLP) study showed 100%
On day 53 from the second transplant, she was found to be
galactomannan-positive. She was started on treatment with micafungin (MyCamine,
Astellas Pharma), besides the voriconazole that she had previously been on for
invasive aspergillosis infection. On day 55, romiplostim (Nplate, Amgen) was
added. She continued to remain pancytopenic and died on day 57 post-second
allogeneic double cord blood transplant.
This case demonstrates one of the major complications of HSCT —
that of graft failure.
There are several definitions of engraftment. Practically, engraftment
can be defined as maintaining a neutrophil count ≥500 ×
Graft failure is the inability to sustain donor cell engraftment. This
also can be seen as a complication as graft rejection, in which there is a
substantial loss of donor cells after initial successful engraftment. As seen
in this case, failed engraftment can be a fatal complication. Fortunately, this
occurs with an overall frequency of less than 5%.
Broadly speaking, graft failure may be due to an inadequate number of
transplanted HSCs or failure of an adequate number of cells to survive.
Contributing factors to failed engraftment may include immunologic-mediated
destruction, infections, a poor marrow microenvironment and toxic effects of
drugs. Other risk factors include human leukocyte antigen disparity and T-cell
depletion, besides low cell dose.
Graft dysfunction also is seen more commonly with disparate donor
transplants with reduced-intensity conditioning regimens. Infectious agents
known to contribute to graft failure include HHV-6, HHV-8 and cytomegalovirus.
Graft dysfunction management
In an effort to manage graft failure or rejection, it is important that
the dysfunction be recognized early and appropriate interventions be made.
Management options include:
- Addition of growth factors without infusing additional HSCs.
Hematopoietic growth factors may be used to lead to engraftment after
graft failure or dysfunction. Reports of using both granulocyte-macrophage
colony–stimulating factor and G-CSF have shown many patients respond to
cytokines with an increase in absolute neutrophil count, with some responders
maintaining counts after discontinuation of the growth factors. In these
reports, the best results were found in patients who had at least a partial
donor mixed chimerism.
- Boosting by infusion of HSCs without cytotoxic therapy.
The success of HSC engraftment has been found to be related to the
number of cells infused. There is no definitive dose established in allogeneic
transplants, although in one study a mean of >10 × 106/kg
of CD34+ cells were used. This study demonstrated engraftment after large doses
of peripheral blood HSCs and second HSC transplants for those who underwent
graft failure. Although a higher dose is associated with engraftment, an exact
threshold has not been established. A retrospective study suggested there may
be less survival with increasing HSC dose in allogeneic transplants and higher
rates of graft-versus-host disease.
- A complete second transplant with pre-infusion conditioning.
A second HSC transplantation offers survival potential to patients. As
mentioned prior, an attempt should be made to understand the cause of the
initial graft failure, such as insufficient number of cells or insufficient
immunosuppression. Other considerations include further obstacles to
engraftment, such as severe splenomegaly, inadequate graft-versus-host disease
prophylaxis, infection such as cytomegalovirus, HHV-6, HHV-8 or parvovirus, or
evidence of residual host immunity from T cells or natural killer cells
directed against donor cells.
If no cause is identified, consideration must be given to an immunologic
mechanism, and the second transplant should be performed with increased
immunosuppressive measures directed toward host immune mechanisms for marrow
dysfunction. These may include anti-T-cell serotherapy and the use of
additional cytotoxic immunosuppressive therapy. In addition, any infections
associated with graft dysfunction should be controlled before proceeding with a
second HSC transplant.
Graft failure is a significantly daunting complication in HSC
transplants. Although there are potential options for management, a second HSC
transplant for graft dysfunction often is necessary and may provide survival
Negative prognostic indicators include lack of initial engraftment or
dysfunction occurring shortly after initial transplant, or lack of partial
In this case, despite a second HSC transplant and evidence of 100% donor
cells on RFLP, the use of hematopoietic growth factors and augmented
immunosuppression, the patient remained pancytopenic with no engraftment and
ultimately died due to overwhelming infection.
Unfortunately, the options in this setting of graft failure after second
HSCT continue to be limited, and continued investigation is necessary.
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For more information:
- Tim McCarthy, MD, is an internal medicine resident physician at
Robert Wood Johnson Medical School in New Brunswick, N.J. He will start his
fellowship in hematology/oncology this summer at the University of North
Carolina at Chapel Hill. Disclosure: Dr. McCarthy reports no relevant financial