Non-infectious complications after bone marrow transplant: secondary cancer

Non-infectious complications after bone marrow transplant: secondary cancer

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

Bone marrow transplant is carried out in order to cure a hematologic malignancy; however, by itself it can cause other cancers. Post-transplant malignancy can occur because of either relapse of primary cancer or emergence of a secondary cancer. These malignancies are summarized below.

Relapse of primary cancer

Early relapse perhaps remains the most important complication of hematopoietic stem cell transplantation (HCT) (auto [autologous] HCT, in hematological malignancies, in particular acute leukemia). In acute leukemias, relapse is more common after autoHCT compared to allo (allogenic) HCT due to the absence of a graft-versus-leukemia effect. Relapse of acute leukemia is uncommon beyond 2 to 3 years after HCT.

Late relapse (beyond 2 years) can occur in around 13% of patients after MAC (myeloablative conditioning regimen) alloHCT and cause mortality in 50%.

Secondary cancer

Compared with the general population, HCT survivors have a 4 to 13 fold higher risk for developing secondary malignancies. These malignancies can be categorized as solid tumors, secondary (treatment induced) acute myeloidleukemia (AML)/ myelodysplastic syndrome (MDS), and post-transplant lymphoproliferative disease (PTLD). Risks of cancers are increased after HCT compared with the general population in skin, thyroid, oral cavity, esophagus, liver, nervous system, bone and connective tissues.

Solid tumors (ST):

ST mostly involve skin. Other common sites are oral cavity, esophagus, liver, breast, lung, thyroid, connective tissue, brain, uterine, bone. ST occur a median of 6 years post HCT, and their cumulative incidence (CI) increases with time from 0.2% at 5 years to 3.1% at 10 years and 4% at 15 years.

Hematologic malignancies (HM):

Most of HM are secondary leukemias and myelodysplastic syndrome (MDS) and limited to recipients of autoHCT. The incidence of hematologic malignancies peaks between 2 to 5 years post-transplant. Rarely, new leukemias in donor cells can occur after alloHCT.

PTLD:

The vast majority of PTLD are originated from B-cells. The incidence of PTLD after HCT ranges from 0.5 to 1.0%. The highest incidence is in the first year after transplantation, then decreases significantly. PTLD incidence is approximately 2 to 3% following umbilical cord blood (UCB) transplantation, similar to the incidence after marrow or peripheral blood stem cell grafts.

Risk factors

ST:

Younger age at HCT, use of total-body irradiation (TBI) in conditioning, Myeloablative TBI, young age at HCT, prolonged immunosuppressive treatment beyond 24 months and chronic graft-versus-host disease (cGVHD) are risk factors for ST. In a recent Japanese study, patients with a history of lymphoma had higher incidence of ST, compared to other diagnoses.

HM:

Older age, exposure to alkylating agents or topoisomerase II inhibitors pre-transplant, and use of higher dose of TBI (greater than or equal to13.2Gy) in conditioning are associated with higher incidence of HM. In addition, in some series, PBSC or in vitro graft purging may increase risks of MDS/AML post-transplant.

PTLD:

Unrelated or human leukocyte antigen (HLA) mismatched related donor and chronic GVHD are risk factors for PTLD. In vitro or in vivo T-cell depletion with ATG use increases the occurrence of PTLD in UCB transplantation (up to 21%). Alemtuzumab use is also associated with high rate of Epstein-Barr virus (EBV) reactivation and PTLD.

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

Clinical symptoms

Constitutional symptoms (for example, fatigue, decreased appetite, and weight loss), organ related symptoms (e.g.,, dry cough/dyspnea for lung cancer, headache or alteration of mental status in brain cancers, bone pain, etc.), tendency for infections or hemorrhage can occur.

Signs

New skin lesions, pallor due to anemia, breast mass, icterus due to liver involvement can be detected.

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

Complete blood count (CBC) with red blood cell (RBC) or white blood cell (WBC) dysplasia, leukoerythroblastosis may indicate bone marrow metastasis by a ST. Complete metabolic panel with liver function tests (elevated liver enzymes, particularly GGT [gamma-glutamyl transpeptidase] may indicate liver metastasis). EBV polymerase chain reaction (PCR) for PTLD.

Ancillary tests such as high lactate dehydrogenase (LDH) and beta-2 microglobulin may indicate PTLD or other lymphoma; serum protein electrophoresis may show monoclonal or oligoclonal abnormalities associated with PTLD.

What conditions can underlie non-infectious complications after bone marrow transplant: secondary cancer

Differential diagnosis

MDS:

Rule out vitamin B12, folic acid, copper deficiencies, as well as thyroid dysfunction. Cytopenias can result from drug toxicities such as immunosuppressive or antiviral drugs. Viral or other infections may be myelosuppressive. Chimerism after allo HCT (to distinguish relapse in recipient cells) and cytogenetics for MDS/AML are useful. Consider donor originated MDS/AML if diagnosis is correct, but chimerism shows 100% donor cell DNA.

ST or PTLD presenting with a mass:

Rule out infections such as nocardiasis and invasive fungal infections.

Abnormal central nervous system (CNS) findings by an magnetic resonance imaging (MRI) scan:

Rule out infections (viral (for example, herpes simplex virus [HSV], fungal, or parasites such as toxoplasmosis), drug toxicities (calcineurin inhibitors) can induce posterior reversible encephalopathy syndrome (PRES).

When do you need to get more aggressive tests:

Tissue biopsies (where the lesion is) are the ultimate tests for diagnosis. Bone marrow aspirate and biopsy with flow cytometry, chimerism, morphologic, and cytogenetic analyses.

If CNS malignancy is suspected by symptoms or MRI finding, spinal tap with cytology, flow cytometry, EBV PCR.

What imaging studies (if any) will be helpful?

Radiology

• Mammograms for breast cancer

• Computed tomography (CT) scan of the chest for lung cancer

• CT or MRI of the liver for hepatic primary or metastatic cancer

• MRI of brain and/or spinal cord to show CNS cancer or PTLD

• Bone scans for primary or metastatic (e.g., prostate, lung, and breast, etc.) bone cancers

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

Management and outcome

ST:

Screening patients for ST is the most important factor in management to detect ST in early stages. In this regard, careful evaluation for skin cancers, breast, thyroid, and lung cancers, particularly in patients receiving TBI are critical.

AML/MDS:

Response to conventional chemotherapy in therapy-related AML/MDS is uniformly poor (e.g., OS is approximately 6 months). AlloHCT is the most frequently attempted salvage therapy and may rescue 13-30% of these patients. Early stage MDS patients have a better chance of survival.

PTLD:

Tapering off immunosuppressive drugs and administration of rituximab are the current first line treatments with a success rate of around 60-75%. Systemic chemotherapy is recommended as a second line treatment. Mammalian target of rapamycin (mTOR) inhibitors such as sirolimus because of their antiproliferative and antiangiogenic effects may be useful; antiviral treatment and EBV specific cytotoxic T-lymphocytes are being investigated, and can be effective for prevention and treatment of PTLD.

What other therapies are helpful for reducing complications?

Preventive measures

ST:

Conventional preventive measures such as smoking cessation before transplant, using sunscreen, diet, regular physical activity should be advised. Regular skin, oral, thyroid, and pelvic examinations are essential. Close age appropriate screening for HCT recipients with established methods, including mammograms and colonoscopy is important to detect early ST. Female patients receiving chest or TBI (greater than or equal to 800cGy) should have annual mammogram screening starting at age 25, or 8 years after radiation (whichever occurs later), as per pediatric cancer survivors guidelines.

PTLD:

Avoiding T cell depletion, tapering immunosuppressive drugs as soon as possible, monitoring EBV DNA in high risk patients are recommended. In a recent study, it has been shown that rituximab administration may prevent PTLD development in patients with EBV DNA in the blood.

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

As mentioned in management section above, prognosis is generally poor in patients with MDS/AML and better in patients with PTLD.

Prognosis, of course, varies in patients with ST depending on diagnosis and stage.

Pathophysiology

Conditioning regimens, including alkylating agents and radiation mainly induce single or double breaks, as well as repairing damage in DNA. These genetic alterations can cause mainly hematologic malignancies seen after transplantation.

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

These patients should be regularly and thoroughly examined for new skin or mucosal lesions in the mouth for skin and oral cancers. New lesions concerning for a malignancy should be biopsied.

EBV DNA analysis in blood or cerebrospinal fluid, wherever the lesion is, can be useful to diagnose post-transplantation lymphoproliferative disease.

What’s the Evidence?

DiNardo, CD, Tsai, DE.. “Treatment advances in post-transplant lymphoproliferative disease”. Curr Opin Hematol.. vol. 17. 2010. pp. 368-7. (Discusses recent advances in management of PTLD.)

Lowe, T, Bhatia, S, Somlo, G.. “Second malignancies after allogeneic hematopoietic cell transplantation”. Biol Blood Marrow Transplant.. vol. 13. 2007. pp. 1121-34. (Discusses secondary malignancies in alloHCT.)

Styczynski, J, Einsele, H, Gil, L, Ljungman, P.. “Outcome of treatment of Epstein-Barr virus-related post-transplant lymphoproliferative disorder in hematopoietic stem cell recipients: a comprehensive review of reported cases”. Transpl Infect Dis.. vol. 11. 2009. pp. 383-92. (Describes treatment outcome with preemptive use of rituximab and EBV-cytotoxic T lymphocytes (CTL) in PTLD.)

Abou-Mourad, YR, Lau, BC, Barnett, MJ. “Long-term outcome after allo-SCT: close follow-up on a large cohort treated with myeloablative regimens”. Bone Marrow Transplant.. vol. 45. 2010. pp. 295-302. (Describes the long term adverse effects including ST after alloHCT.)

Seshadri, T, Pintilie, M, Kuruvilla, J. “Incidence and risk factors for second cancers after autologous hematopoietic cell transplantation for aggressive non-Hodgkin lymphoma“. Leuk Lymphoma.. vol. 50. 2009. pp. 380-6. (Demonstrates the incidence of secondary cancers following autoHCT.)

Bhatia, S, Louie, AD, Bhatia, R. “Solid cancers after bone marrow transplantation”. J Clin Oncol.. vol. 19. 2001. pp. 464-71. (Demonstrates the incidence of ST after HCT in a large series.)

Kalaycio, M, Rybicki, L, Pohlman, B. “Risk factors before autologous stem-cell transplantation for lymphoma predict for secondary myelodysplasia and acute myelogenous leukemia”. J Clin Oncol.. vol. 24. 2006. pp. 3604-10. (Demonstrates the risk factors for developing MDS/AML after autoHCT.)

Darrington, DL, Vose, JM, Anderson, JR. “Incidence and characterization of secondary myelodysplastic syndrome and acute myelogenous leukemia following high-dose chemoradiotherapy and autologous stem-cell transplantation for lymphoid malignancies”. J Clin Oncol.. vol. 12. 1994. pp. 2527-34. (Demonstrates increased risk of MDS/AML after autoHCT and discusses risk factors.)

Armitage, JO, Carbone, PP, Connors, JM, Levine, A, Bennett, JM, Kroll, S.. “Treatment-related myelodysplasia and acute leukemia in non-Hodgkin’s lymphoma patients”. J Clin Oncol.. vol. 21. 2003. pp. 897(Demonstrates increased risk of MDS/AML after autoHCT.)

Friedman, DL, Rovo, A, Leisenring, W. “Increased risk of breast cancer among survivors of allogeneic hematopoietic cell transplantation: a report from the FHCRC and the EBMT-Late Effect Working Party”. Blood.. vol. 111. 2008. pp. 939-944. (Describes risk of breast cancer after alloHCT.)

Inamoto, Y, Shan, N, Savani, B. “Secondary solid cancer screening following hematopoietic cell transplantation”. Bone marrow transplantation. vol. 50. 2015. pp. 1013-1023. (Describes risk factors for and how to screen patients for secondary cancers after HCT.)

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