1 Definitions

Secondary neoplasia (SN) after HCT includes any malignant disorder occurring after HCT, irrespectively, if related or not to transplantation. For an individual patient, a clear relationship between HCT and SN often cannot be demonstrated. Posttransplant lymphoproliferative disorders are discussed elsewhere (see Chap. 45).

2 Types of Secondary Neoplasia After HCT

 

Therapy-related myeloid neoplasms (t-MN) (Pedersen-Bjergaard et al. 2000)

Donor-derived malignancy (DDM) (Sala-Torra et al. 2006; Wiseman 2011; Engel et al. 2019)

Second solid neoplasms (SSN) (Kolb et al. 1999; Rizzo et al. 2009)

Definition

t-MDS or t-AML after exposition chemo- or radiation therapy

Hematologic neoplasms occurring in grafted donor cells

Solid cancers of any site and histology occurring after HCT

Occurrence

Mainly after auto-HCT

Not excluded after allo-HCT (Yamasaki et al. 2017)

After allo-HCT only

After allo-HCT and auto-HCT

Appearance

Within the first 10 years mainly

Variable

Increasing incidental rate with longer follow-up

Prognosis

Poor

Poor

Depends mainly on the cancer type

3 Pathophysiology

3.1 Therapy-Related Myeloid Neoplasms

t-MN are mainly associated with cytotoxic chemotherapy and radiation therapy that the patient has received either before HCT or as conditioning. The causal role of ionizing radiation in the development of myeloid neoplasms has been demonstrated in atomic bomb survivors of Hiroshima/Nagasaki and in medical radiation workers employed before 1950.

Responsible cytotoxic drugs:

  • Alkylating agents, anthracyclines, and topoisomerase II inhibitors.

  • To a lesser extent antimetabolites and purine analogs.

  • Controversy exists on the role of azathioprine, methotrexate, hydroxyurea, and 6-mercaptopurines used for the treatment of malignant and nonmalignant diseases.

t-MN occur mainly after auto-HCT, where the healthy HCT has been exposed to cytotoxic effect (Diamond et al. 2023). Detecting clonal hematopoiesis mutations in cryopreserved cells before auto-HCT has been associated with a higher risk of t-MN (Gramegna et al. 2022). Rarely t-MN can be observed after allo-HCT. Persistent microchimerism with exposed residual recipient cells or autologous recovery may explain the development of t-MN after allo-HCT (Hoshino et al. 2022). After HCT for sickle cell disease, the 10-year incidence of leukemia and MDS is increased, mainly when conditioned with reduce-intensity and TBI-containing regiment. The onset of t-MN and graft failure after HCT are closely related (Eapen et al. 2023).

Today, increasingly cytotoxic drugs are applied after the allo-HCT, either as GVHD prophylaxis (posttransplant CY) or to prevent disease recurrence (posttransplant maintenance). Posttransplant CY does not seem to increase the risk of t-MN (Majzner et al. 2017; TCT). We do not yet know whether posttransplant maintenance therapy could increase the risk of t-MN after allo-HCT.

A germline cancer predisposition has been demonstrated in 15–20% of t-MNs, and acquired mutagenic effect of cytotoxic therapy with clonal hematopoiesis of indetermined potential (CHIP) is frequently the first step in the multihit development of t-MNs (Voso et al. 2021).

3.2 Donor-Derived Malignancy (DDM)

The pathogenesis of donor-derived hematological malignancies is not fully understood but is likely multifactorial (Sala-Torra et al. 2006; Wiseman 2011; Williams et al. 2021; Gibson et al. 2022):

  • Treatment damage to bone marrow microenvironment from previous chemotherapy, radiation, and treatments to prevent GVHD

  • Transplantation of a malignant clone, or germline or somatic mutations from the donor

  • Stress of rapid clonal expansion after transplant

Reported donor cell leukemia are AML, MDS, ALL, CML, and lymphoid neoplasms including CLL (Engel et al. 2019). The risk of DDM in allogeneic hematopoietic cell transplantation is driven by somatic myelodysplastic syndrome-associated mutations or germline predisposition in donors (Gibson et al. 2022).

Clonal hematopoiesis can be transmitted from a donor to a recipient during allo-HCT. Exclusion of candidate donors with clonal hematopoiesis is controversial since its impact on recipient outcomes and graft alloimmune function is uncertain.

Over 20% of donor-derived myeloid neoplasms carry chromosome 7 abnormalities. Gene sequencing of the donor cells allowed to detect a number of candidate genes that could contribute to the development of DDM (Williams et al. 2021). Malignant clones transferred to the recipient can be of lymphoid origin, observed in older donors, and may evolve into a lymphoid neoplasm in the immunosuppressed host.

3.3 Second Solid Neoplasms (SSN)

Little is known about pathogenesis of SSN after HCT. An interaction between cytotoxic treatment, genetic predisposition, environmental factors, viral infections, GVHD, and its immunosuppression may play a role.

Three main types of SSN (Rizzo et al. 2009):

  • Radiation-related SSN

    • Proven for thyroid, breast, and brain cancers

    • Occur after a long latency (≥10 years after radiation)

    • Is dose related

  • GVHD/immunosuppression-related SSN

    • Squamous cell carcinoma of the skin and oropharyngeal area

    • Short latency

    • Can occur at different localizations

  • Association with viral infection

    • HCV infection associated with hepatocellular cancer

    • HPV-related precancer or second cancer, with increased cumulative incidence for cervical, head and neck, vulvar, vaginal, anal, and penile second cancer (Zhao et al. 2021)

4 Frequency and Risk Factors (See Table 47.1)

4.1 Remarks on SSN

The CI of second solid cancer is 2.2% at 10 years and 6.7% at 15 years (Rizzo et al. 2009).

Table 47.1 Frequency and risk factors
Full size table

Increased risk for SSN after HCT has been demonstrated from breast, thyroid, skin, liver, lung, oral cavity and pharynx, brain and CNS, bone and connective tissue cancers and malignant melanoma.

An individual patient can present several subsequent different SSN after HCT. Up to five different solid cancers have been observed in a patient treated with allo-HCT.

Digestive system and particularly colorectal cancers have not been proven to be increased after HCT (Heydari et al. 2020). In non-transplanted cancer patients, second colorectal cancers are increased when treated with abdominal radiation (Henderson et al. 2012; Rapiti et al. 2008; van Eggermond et al. 2017).

So far there are few long-term data on SSN after RIC. A single-center study shows an increased rate of SSC compared to MAC during the first 10 years post-HCT (Shimoni et al. 2013). The 10-year cumulative incidence of SSC following RIC reached 12.9%, with an overall SIR of 1.03–1.9, mainly significant for head and neck and bladder cancers. Second malignancy seems to be higher than expected in treated allo-HCT recipients conditioned with RIC but still longer follow-up time with larger cohorts is needed for definitive assessment (Del Galy et al. 2022).

The outcome of SSC is mainly dependent on the type of second cancer. Standardized mortality ratio was higher, compared with de novo solid cancers, for melanoma, prostate, breast, kidney, bladder, colorectal, and endometrial cancers but not for the other cancers (Tichelli et al. 2019). Most subsequent solid cancers occurred at younger ages than primary cancers, emphasizing the need for cancer screening at younger ages (Inamoto et al. 2018).

5 Screening (Majhail et al. 2012; Inamoto et al. 2015) (See Also Chap. 21)

5.1 Therapy-Related Myeloid Neoplasms

Annual monitoring of full peripheral blood counts during the first 10 years after auto-HCT (most t-MN occur within 10 years after HCT).

If unexpected abnormalities in the blood count are observed (increased MCV, cytopenia, dysplasia in peripheral blood, thrombocytosis, leukocytosis, monocytosis), extended analysis of blood and bone marrow is warranted, including cytogenetics and NGS (Bachiashvili et al. 2022).

5.2 Donor-Derived Malignancy

Chimerism monitoring of the malignant cells is needed in case of “relapse” or new hematological malignancy after allo-HCT.

Whether to search for clonal hematopoiesis, lymphoid malignant clone, and germline mutations in the donor in case of DDM remains controversial.

5.3 Second Solid Cancer (Socie and Rizzo 2012; Inamoto et al. 2015)

Lifelong screening for SSN is recommended after auto-HCT and allo-HCT.

General recommendations are as follows:

  • During annual control, clinical screening and reviewing for possible symptoms of SSN.

  • Follow country-specific or international guidelines for cancer screening recommendations for the general population.

  • Be informed and counselled about the risk of SSN.

Specific recommendations are included in Table 47.2.

Table 47.2 Screening for second solid cancer after HCT
Full size table

6 Treatment

Neoplasm

Treatment

t-MN

Same treatment than de novo myeloid neoplasms

Early donor search and rapid allo-HCT (Finke et al. 2016; Kroger et al. 2011; Metafuni et al. 2018)

Decision-making including consideration of cumulative toxicity due to previous HCT, age, and comorbidity

DDM

No standard treatment

Treatment depends on the nature of disease

Reported treatments (Engel et al. 2019)

• Retransplantation

• Conventional chemotherapy

• DLI

• Palliation

SSN

Should be treated as de novo cancers of the same type

7 Outcome

Neoplasm

Outcome

t-MN

Generally very poor

Median survival of 6 m

Identical outcome than t-MN in general

DDM

Few data available

In most cases, mortality high and OS poor

In a small series of 47 DDM, median survival 32.8% months

Death mainly due to progression or relapse of DDM

SSN

Mainly dependent on the type of SSN (Ehrhardt et al. 2016; Tichelli et al. 2019; Inamoto et al. 2018)

Favorable outcome

• Thyroid, breast, prostate, melanoma, cervix

Intermediate outcome

• Oropharyngeal, colorectal, bladder, renal, ovarian, endometrial

Poor outcome

• Pancreas, lung, brain, hepatobiliary, esophageal

Key Points

  • Three types of secondary neoplasia may occur after HCT: therapy-related myeloid neoplasms (t-MN), mainly after auto-HCT; donor-derived malignancy (DDM) after allo-HCT; and second solid neoplasia (SSN) after auto-HCT and allo-HCT.

  • Pretreatment or conditioning with radiation and/or chemotherapy including alkylating agents, anthracyclines, and topoisomerase II inhibitors is mainly responsible for t-MN.

  • DDM are extremely rare and are either transmitted from the donor or newly transformed in the host.

  • Non-squamous second solid cancers (breast, thyroid, brain, etc.) are strongly related to local radiation or TBI and occur with long delay after HCT. Squamous cell carcinoma of the skin, the oral cavity, and the pharynx is related with chronic GVHD and can occur early after HCT. Conditioning with RIC does not seem to reduce the risk of second cancer.

  • Outcome of t-MN is poor, and allogeneic HCT represents the only curative treatment.

  • Outcome of SSN depends mainly on the type of second cancer; second solid cancer should be treated as a de novo cancer of the same type.