Case Challenges

A 46-year-old female with graft failure after HSCT

A 46-year-old female presented with abdominal pain and was found to have cholecystitis.

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.

Tim McCarthy

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 globulin.

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 pancytopenic.

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% donor cells.

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.

Case Discussion

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 × 106/L.

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.

Conclusion

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 benefit.

Negative prognostic indicators include lack of initial engraftment or dysfunction occurring shortly after initial transplant, or lack of partial donor chimerism.

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.

References:

  • Aversa F. N Engl J Med. 1998;339:1186-1193.
  • Qazilbash MH. Cancer. 2006;106:1084-1089.
  • Urbano-Ispizua A. Blood. 2001;98:2352-2357.
  • Wolff SN. Bone Marrow Transplant. 2002;29:545-552.

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 disclosures.

A 46-year-old female presented with abdominal pain and was found to have cholecystitis.

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.

Tim McCarthy

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 globulin.

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 pancytopenic.

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% donor cells.

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.

Case Discussion

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 × 106/L.

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.

Conclusion

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 benefit.

Negative prognostic indicators include lack of initial engraftment or dysfunction occurring shortly after initial transplant, or lack of partial donor chimerism.

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.

References:

  • Aversa F. N Engl J Med. 1998;339:1186-1193.
  • Qazilbash MH. Cancer. 2006;106:1084-1089.
  • Urbano-Ispizua A. Blood. 2001;98:2352-2357.
  • Wolff SN. Bone Marrow Transplant. 2002;29:545-552.

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 disclosures.

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