Non-infectious complications after bone marrow transplant: graft failure

What every physician needs to know about non-infectious complications after bone marrow transplant: graft failure:

Graft failure

Graft failure (GF) is a life threatening complication of hematopoietic stem cell transplantation (HCT).

GF can be observed early post-transplant (primary, failure to establish hematologic engraftment) or late (loss of an established graft).

GF occurs following either autoHCT (autologous hematopoietic stem cell transplantation) or alloHCT (allogenic hematopoietic stem cell transplantation). Its incidence after marrow ablative therapy is less than 5%. However, it can be higher (10 to 15%), following umbilical cord blood (UCB) transplantation.

GF or rejection (dysfunction) can be associated with primary disease relapse, but careful search for signs of persistent marrow disease can inform management decisions.

GF should be considered in patients with persistence of low blood counts, transfusion requirements longer than expected post-transplant (greater than 30 to 40 days). In late or secondary graft failure, significant and persistent fall in blood counts follows previous hematologic recovery.

What features of the presentation will guide me toward possible causes and next treatment steps:

Symptoms

Patients with pancytopenia may have fatigue, bleeding tendency or infections.

Physical examination findings

Pallor, ecchymoses, or signs of infection.

What laboratory studies should you order to help make the diagnosis and how should you interpret the results?

Initial tests

Complete blood count (CBC)

– CBC with differential will reveal pancytopenia. Relative lymphocytosis (with absolute neutropenia) can be present.

Anemia without reticulocytosis

– Relative or absolute reticulocytopenia without signs of blood loss or hemolysis.

Peripheral blood smear

– Hypoplastic anemia usually has a bland, transfusion dependent erythrocyte morphology. Dysplastic features (for example, hypochromic macrocytes or pseudo Pelger-Huet cells) can suggest myelodysplastic syndrome (MDS), macrocytosis, and granulocyte hypersegmentation suggest folic acid or unlikely Vitamin B12 deficiency; macrocytosis may indicate hypothyroidism, and microcytosis may suggest iron deficiency (unexpected after HCT).

Vitamin B12 and folic acid levels
Iron studies
Thyroid function tests
Lactate dehydrogenase levels
Increased levels can occur with fragmentation hemolysis that can accompany cyclosporine or tacrolimus.

See also “When do you need to get more aggressive tests” below.

What conditions can underlie non-infectious complications after bone marrow transplant: graft failure:

Differential diagnosis

Active infections (mostly viral or bacterial)

– Human herpesvirus (HHV-6) infection may result in GF. Parvovirus infection can yield erythropoietic failure (pure red cell aplasia [PRCA].

Nutritional factors

– Folic acid deficiency may accompany post-HCT malnutrition.

Hypothyroidism
Acute graft-versus-host disease (GVHD)

– Requires other symptoms and signs (skin rash, nausea, diarrhea, elevated liver function tests).

Myelosuppressive drugs

– Mycophenolate mofetil or ganciclovir can cause cytopenias.

Hypersplenism
Myelodysplastic syndrome (MDS)

– Persistent or acquired after autologous HCT.

Veno-occlusive disease (VOD)

– Veno-occlusive disease (VOD) of the liver may induce thrombocytopenia.

Microangiopathic anemia/thrombotic thrombocytopenic purpura (MAHA/TTP)

– MAHA/TTP will present with anemia (hemolytic associated with reticulocytosis and high LDH).

When do you need to get more aggressive tests:

More aggressive tests are needed at the same time as initial blood tests.

Bone marrow aspirate and biopsy

Morphologic examination for cellularity, evidence for primary malignancy, myelodysplasia, or fibrosis. Evaluate iron stores. Vacuolization in erythroblasts may indicate copper deficiency; giant erythroblasts may suggest parvovirus infection.

Flow cytometry for evidence of primary malignancy
Fluorescence in situ hybridization (FISH) and cytogenetics for chromosomal abnormalities associated with primary malignancy or emerging myelodysplastic syndrome (MDS)
Polymerase chain reaction (PCR) based tests for molecular abnormalities associated with primary malignancy
Chimerism studies (percentage of donor and recipient cells, sort cells for T lymphocytes and granulocytes) Chimerism studies from peripheral blood (in sorted T cells and granulocytes)
Microbiologic studies (if suggested); granulomatous disease (mycobacterium) or viruses (HHV-6) can lead to GF

What imaging studies (if any) will be helpful?

Abdominal computed tomography (CT) scan or ultrasound to rule out splenomegaly and associated hypersplenism.

What therapies should you initiate immediately and under what circumstances – even if root cause is unidentified?

Urgent treatment

Platelets or red blood cells (RBC) transfusions as needed
Neutropenic fever: Immediate work-up, intravenous antibiotics and fluids
Granulocyte-colony stimulating factor (G-CSF) or erythropoietin, but if no response after some time, these may be discontinued

What other therapies are helpful for reducing complications?

Preventative measures for patients with high risk for GF

Graft source

Human leukocyte antigen (HLA) identical sibling donor HCT rarely leads to GF
Avoid donor: Recipient HLA mismatch in host-versus-graft (HVG) direction
Screen for pre-HCT anti-HLA (anti-donor) antibodies which increase GF risk

Conditioning regimen

Donor graft T cell depletion increases risk of GF
More potent immunosuppression or in vivo depletion of functioning host T cells (for example, anti-thymocyte globulin [ATG] and/or total lymphoid irradiation) may limit risks of GF
Myeloablative regimens reduce risks of GF

Dose of stem cells

Hematopoietic stem cells or even megadose

– A high number of hematopoietic stem cells or even megadose (greater than 10 x 10⁶/kg CD34+ cells/kg) may overcome graft resistance. These higher doses may also immunosuppress the recipient via higher infused number of T cells (CD3+, CD8+), dentritic cells, or natural killer (NK) cells.

Double cord grafts

– In umbilical cord blood (UCB) transplant, double cord grafts have improved engraftment and studies pursuing ex vivo expansion or marrow homing techniques might do the same.

Immunosuppressive drugs

Early intensification of the post-transplant immunosuppression reduces GF
Aggressive diagnostic measures for early detection of GF: Closely follow chimerism studies, particularly in T-cells

What should you tell the patient and the family about prognosis?

Therapy

Cytokine therapy (G-CSF or GM-CSF).

Decrease immunosuppression when secondary GF or decline in chimerism is detected. This may increase risks of severity of GVHD.

Infusion of a booster dose of donor hematopoietic stem cells to support hematopoietic engraftment. If primary GF has occurred, added pre-boost immunosuppression (often with ATG) is required.

Donor lymphocyte infusions (DLI) (10^5-7 CD3+/kg) to enhance T cell engraftment and promote transition to full donor chimerism. This is feasible if no active GVHD is present.

Prognosis

The prognosis of GF depends on severity of pancytopenia, percentages of donor cells, relapse of primary disorder, donor availability for collection and reinfusion of more cells, and the patient’s current clinical status (for example, active infection or bleeding. The prolonged pancytopenia can be fatal.

“What if” scenarios.

In refractory cases

A second allogeneic transplantation may be needed.In some cases conditioning with reduced doses of cytotoxic agents or further immunosuppression with ATG, corticosteroids, plus cyclosporine is given before the second infusion.

For second graft infusions, these reduced intensity conditioning (RIC) regimens are associated with less toxicity and better survival than myeloablative regimens.

In unrelated donor (URD) transplant, second transplant might be difficult, because of unavailability of the original donor. Transplantation from another donor or umbilical cord blood (UCB) might be an option.

In UCB transplantation, only UCB cells from a different UCB, a volunteer URD, or haploidentical transplantation may be used for a second transplant.

Pathophysiology

Risk factors

Insufficient number of stem cells

Autologous bone marrow transplantation

– To establish autologous engraftment, approximately 2 × 10⁴ colony-forming cells/kg recipient weight are needed. This can be accomplished by infusing minimum of 1 × 10^6 autologous marrow mononuclear cells (MNC)/kg, at least a dose of MNC of 2 × 10⁸/kg .

It is generally agreed that a minimum dose of 2.5 x 10⁶ CD34+ cells is necessary for successful engraftment but reinfusion of 5.0 x 10⁶ CD34+ cells is preferred for autologous stem cell transplant (autoSCT)
Autologous peripheral stem cell transplantation

– G-CSF with or without myelosuppressive chemotherapy such as cyclophosphomide is used to mobilize stem cells for apheresis. Plerixafor (AMD3100), an inhibitor of the interaction between stromal cell-derived factor 1 (SDF-1) and its receptor, C-X-C chemokine receptor type 4 (CXCR4) plus G-CSF increases the success of stem collection in difficult patients.

Allogeneic stem cell transplantation

– Growth factors alone are used to mobilize a graft from healthy donors. 5 × 10⁶ CD34+ cells/kg is the usual target collection for a donor allograft.

UCB grafts with a total nucleated cell (NC) dose of greater than or equal to 2.5 × 10⁷ cells/kg have a greater probability of successful engraftment.

– The required dose is higher for greater HLA mismatched alloHCT: CD34+ cell counts are also better correlated with engraftment. Greater than 1.7 x 10⁵ CD34+ cells/kg is associated with faster neutrophil recovery. Double unit UCB transplant is widely used in adults with more frequent and faster engraftment.

Transplantation

Conditioning regimen

– Low busulfan blood exposure, insufficient immunosuppression, T-lymphocyte depletion of donor marrow increase risks of GF.

HLA-mismatch

– In URD, HLA mismatch, especially at HLA-C, is associated with GF.

Graft source

– UCB, the overall incidence of graft failure is greater.

Post-transplantation

Residual recipient NK cells can mediate graft rejection
Early graft failure can be accompanied by emergence of host cytotoxic T lymphocytes, presumably reflecting immune-mediated graft rejection
Drugs: Acyclovir, ganciclovir, trimethoprim-sulfamethoxazole, and mycophenolate mofetil are associated with poor graft function or GF

Complications of transplantation augmenting GF risks

Viral infections, including Cytomegalovirus (CMV) and HHV-6

What other clinical manifestations may help me to diagnose non-infectious complications after bone marrow transplant: graft failure?

N/A

What other additional laboratory studies may be ordered?

N/A

What’s the evidence?

Demirer, T, Buckner, CD, Appelbaum, FR. “Rapid engraftment after autologous transplantation utilizing marrow and recombinant granulocyte colony-stimulating factor mobilized peripheral blood stem cells in patients with acute myelogenous leukemia”. Bone Marrow Transplant. vol. 15. 1995. pp. 915-922. [One of the first studies showing peripheral stem cell transplant is feasible and successful.]

Jillella, AP, Ustun, C, Robach, E. “Infectious complications in patients receiving mobilization chemotherapy for autologous peripheral blood stem cell collection”. Journal of Hematotherapy & Stem Cell Research. vol. 12. 2003. pp. 155-160. [Demonstrates chemotherapy based mobilization regimens are associated with infections.]

Ozcelik, T, Topcuoglu, P, Beksac, M. “Mobilization of peripheral blood stem cells (PBSCs) with chemotherapy and recombinant human G-CSF: a randomized evaluation of early vs late administration of recombinant human G-CSF”. Bone Marrow Transplant. vol. 44. 2009. pp. 779-783. [Demonstrates late administration of G-CSF is also effective to collect stem cells.]

Stiff, P, Micallef, I, McCarthy, P. “Treatment with plerixafor in non-Hodgkin's lymphoma and multiple myeloma patients to increase the number of peripheral blood stem cells when given a mobilizing regimen of G-CSF: implications for the heavily pretreated patient”. Biol Blood Marrow Transplant.. vol. 15. 2009. pp. 249-256. [Demonstrates plerixafor efficacy in stem cell collection.]

Jillella, AP, Ustun, C. “What is the optimum number of CD34(+) peripheral blood stem cells for an autologous transplant?”. Stem Cells and Development. vol. 13. 2004. pp. 598-606. [Reviews stem cell number in autologous transplantation.]

Bensinger, WI, Martin, PJ, Storer, B. “Transplantation of bone marrow as compared with peripheral-blood cells from HLA-identical relatives in patients with hematologic cancers”. New England Journal of Medicine. vol. 344. 2001. pp. 175-181. [Compares stem cell transplantation with bone marrow transplantation.]

Champlin, RE, Schmitz, N, Horowitz, MM. “Blood stem cells compared with bone marrow as a source of hematopoietic cells for allogeneic transplantation”. Blood. vol. 95. 2000. pp. 3702-3709. [Compares stem cell transplantation with bone marrow transplantation.]

Weisdorf, D, Miller, J, Verfaillie, C. “Cytokine-primed bone marrow stem cells vs. peripheral blood stem cells for autologous transplantation: a randomized comparison of GM-CSF vs. G-CSF”. Biology of blood and marrow transplantation : journal of the American Society for Blood and Marrow Transplantation.. vol. 3. 1997. pp. 217-223. [Compares stem cell sources.]

Wagner, JE, Barker, JN, DeFor, TE. “Transplantation of unrelated donor umbilical cord blood in 102 patients with malignant and nonmalignant diseases: influence of CD34 cell dose and HLA disparity on treatment-related mortality and survival”. Blood. vol. 100. 2002. pp. 1611-1618. [Demonstrates the importance of stem cell number in UCB transplant.]

Smith, AR, Wagner, JE. “Alternative haematopoietic stem cell sources for transplantation: place of umbilical cord blood”. British Journal of Haematology. vol. 147. 2009. pp. 246-261. [Reviews the importance of stem cell number in UCB transplant.]

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Non-infectious complications after bone marrow transplant: graft failure