Stem Cell Transplant Patients Face Lifelong Cancer Risk

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Even 20 years after receiving a hematopoietic stem cell transplant (HSCT), patients have a dramatically increased risk of developing a secondary malignancy compared with the general population, say experts who underline the need for counseling in this vulnerable population.

Transplant patients may experience a number of complications following treatment, said Gesine Bug, MD, University Hospital Frankfurt, Germany.

Although the risk decreases over time in the majority of cases, the likelihood that patients will develop a second solid cancer increases continuously throughout the decades following HSCT, with the outcome depending on the type of malignancy, she said.

Bug was speaking here at the at the European Society for Blood and Marrow Transplantation (EBMT) Annual Meeting 2019.

At the meeting, Tal Schechter, MD, the Hospital for Sick Children, University of Toronto, Canada, presented data on the rate of secondary malignancies in almost 450 stem cell transplant patients treated over a 22-year period.

The data showed that approximately 8% of their patients developed second neoplasms. The cumulative incidence was 7.5% at 15 years and 18% at 20 years.

Although mortality rates among patients with secondary malignancies were not higher than those seen in other patients, those who did die from the secondary cancer did so within 8 months of diagnosis.

Schechter said their results show that young survivors of stem cell transplant have "a high rate" of secondary malignancies.

She noted that there are several risk factors in the development of secondary malignancies, including being diagnosed with acute lymphoblastic leukemia (ALL) and female sex.

"Future studies should focus on the causal relationship between diagnosis, prior therapy, the stem cell transplant conditions, and the development of secondary malignant neoplasm," Schechter concluded.

Bug said that patients "must be counseled that they need lifelong screening for solid tumors after transplant."

She added that "two thirds of patients are not aware that they are at higher risk of developing some cancers, and some of them think their risk is smaller because they already had a cancer."

Bug underlined the fact that the literature shows that this is not the case — patients develop up to five cancers after stem cell transplant.

High Survival After Transplant

Bug began her presentation by noting that, "luckily, more and more of our patients survive" stem cell transplants.

However, "that means patients will develop comorbidity," she said. She noted that "most patients, especially if they are older, will go into transplant with some problems, but they will go on to develop further problems, and these are very diverse."

Problems include neuropsychological effects, such as depression and neurocognitive deficits; pulmonary, cardiovascular, liver, kidney, and bone diseases; endocrine conditions; gonadal dysfunction; and secondary malignancies.

Bug said that malignant complications, which are considered very late events after HSCT, are responsible for 25% of deaths more than 5 years after allogeneic HSCT and 15% of post-autologous HSCT deaths.

She explained that secondary neoplasms fall into four categories:

• Therapy-related myeloid neoplasms (t-MNs) — neoplasms related to pretransplant chemotherapy and radiotherapy
  
  
• Solid secondary neoplasms — cancers of any site and histology following HSCT
  
  
• Donor-cell leukemia — hematologic neoplasms arising from grafted donor cells
  
  
• Posttransplant lymphoproliferative disorder — uncontrolled proliferation of B-cell lymphocytes infected with Epstein-Barr virus

Bug pointed out that there is a notable difference between the incidence curves of t-MNs and solid secondary neoplasms.

Although the cumulative incidence of t-MNs rises to around 6.5% at 15 years post transplant and then plateaus, the incidence of solid secondary neoplasms continues to rise throughout follow-up, reaching more than 15% at 25 years.

Delivering a keynote lecture on long-term survivorship at the meeting, Hélène Schoemans, MD, Department of Hematology, UZ Leuven, Belgium, noted that the most frequent cancers following HSCT occur in the head and neck.

For example, esophageal cancers occur at a standardized incidence ratio (SIR) of 8–11 in comparison with the general population; thyroid cancers occur at an SIR of 3; ear, nose, and throat (ENT) cancers at an SIR of 7–27; and brain cancers at an SIR of 4–10.

Moreover, following HSCT, there is an increased risk for liver cancer (SIR, 6–28), sarcoma (SIR, 6–13), and skin cancer (SIR, 7).

Schoemans said the occurrence of ENT, esophageal, thyroid, brain, liver, and skin cancers is related to total body irradiation prior to HSCT.

ENT, esophageal, thyroid, and skin cancers are also linked to graft-vs-host disease. Sarcoma and thyroid and brain cancers are more frequent in individuals who underwent HSCT as a child.

Retrospective Analysis

To examine how common subsequent malignant neoplasms are after stem cell transplants, Schechter and colleagues conducted a retrospective analysis of patients who survived at least 2 years after receiving a transplant for a malignant condition during childhood, adolescence, or young adulthood.

The team evaluated transplants performed in Ontario between 1992 and 2014 in patients aged ≤30 years. The investigators linked the stem cell transplant databases to the regional cancer registry and healthcare utilization data from the Institute for Clinical Evaluative Sciences.

Schechter told the audience that in Ontario, stem cell transplants are performed in children and adolescents in one center, and in adults in three centers, "and we had the data from two of these three centers and all of the pediatric data."

By using each patient's unique health number, the team was able to obtain data on all cancer diagnoses in stem cell transplants, "because every cancer and biopsy is reported to the Ontario cancer registry...so we’re pretty sure we didn't miss any cancer in the province."

In all, they were able to obtain complete data on 446 stem cell transplant patients, of whom 51.8% were treated for myeloid malignancies, 42.6% for ALL, and 4.2% for lymphoma.

The majority of patients (59.4%) were male; 70.3% of patients received their stem cell transplant when they were 0 to 18 years of age.

Bone marrow was the most common source of stem cells for transplant (68.2% of cases). A small majority of donors (52%) were related; the rest were unrelated.

During a median follow-up of 15.1 years, 36 of the stem cell transplant patients (8.1%) developed 45 secondary malignant neoplasms, at a mean age of 28.9 years.

The researchers calculated that the 10-year cumulative incidence for secondary malignant neoplasms was 4.0%; the incidence rose to 7.5% at 15 years and 18.0% at 20 years.

The most common neoplasm was papillary carcinoma of the thyroid (11 patients), followed by a secondary leukemia/lymphoma (10 patients), squamous cell carcinoma (nine patients), and adenocarcinoma (five patients).

The following were significant risk factors for the development of a secondary malignant neoplasm:

• Being aged 19–29 years at the time of the stem cell transplant (P < .01)
  
  
• History of acute graft-vs-host disease (P = .038)
  
  
• Female sex (P = .034)
  
  
• A diagnosis of ALL

Indeed, when the team analyzed the data for patients who had ALL, they found that the cumulative incidence of a secondary malignant neoplasm was 4.9% at 10 years and 25.0% at 20 years, nearly double the rates (2.7% and 13.4%, respectively) seen in patients with myeloid malignancies (P = .040).

Schechter suggested that this difference may be due to the fact that ALL patients undergo total body irradiation as part of their treatment.

During follow-up, 73 of the patients (16.4%) in the study died.

These included nine of the patients (25.0%) with secondary malignant neoplasms. These patients died a median of 0.64 years (7.68 months) after diagnosis.

Analysis showed, however, that there was no difference in survival rates between stem cell transplant patients with and those without secondary malignant neoplasms (P = .554).

When the team compared survival between their cohort and that of 131 patients who underwent stem cell transplant for nonmalignant indications, they again found no significant difference (P = .941).

Annual Checkups

Bug emphasized that to catch secondary malignancies as early as possible, physicians should perform a physical examination for signs and symptoms during annual checkups.

If cancer is suspected, patients should be referred to a dermatologist or other relevant specialists, and "if in doubt, take a biopsy."

She also said that mammography should start "early" in women, at 25 years of age or 8 years after radiotherapy, and not later than age 40 years, which is "much earlier than in the normal population."

Bug also underlined that patients "must avoid unprotected ultraviolet skin exposure, and they should stop smoking and passive tobacco exposure, and they should drink alcohol only moderately."

Asked when stem cell transplant patients should be counseled for secondary malignancies, Bug said that it should not be during early posttransplant consultations, because "patients cannot cope with all the problems at one time."

She said that it should perhaps be left until the patients return to work and are being seen every 6 months or a year, at which point "you must be sure that these patients know."

Bug added that counseling regarding secondary neoplasms is "important" prior to transplant and that all the risks must be explained, "but then they forget, and later on, you have to come up with this topic again."

Bug has received research grants from Novartis Pharma; travel grants from Astellas Pharma, Celgene, Jazz Pharmaceuticals, Neovii, and Gilead; honoraria from Novartis Pharma, Celgene, Amgen, and Jazz Pharmaceuticals; and advisory board membership for Eurocept, Sandoz/Hexal, and Pfizer Pharma. Schechter's study was supported by the C17 Research Network.

European Society for Blood and Marrow Transplantation (EBMT) Annual Meeting 2019: Abstract OS1-3; keynote lecture NG04-6. Presented March 25, 2019.

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