Heart Transplantation for Adriamycin Cardiomyopathy

Corresponding Author

Heart transplant cardiologists are in the business of making predictions, addressing 3 critical questions during the heart transplant evaluation: Is this patient sick enough to warrant heart transplantation? Is the rest of the body well enough to derive improved quality of life and survival from transplantation? Does the patient have adequate caregiver support to sustain him or her through the arduous process? Some answers are based on science but many on judgment and experience. The evaluation process culminates in the heart transplant selection committee meeting, where often ardent debates ensue, focused on whether the patient is in that magical window of sick enough but well enough for transplantation—where the heart is the problem, and the rest of the body is not.

These discussions, aimed at the appropriate allocation of the scarce resource of a donor heart, are especially fraught for patients with prior malignancies. For these patients, lightning has struck multiple times: they have had the bad luck to get cancer, the good luck to survive it, but the bad luck to be faced with yet another hurdle: heart failure requiring the consideration of advanced heart failure therapies. At this fork in the road, the heart transplant selection committee becomes the arbiter of the lighting strike: will the good luck that sustained these cancer survivors hold out? Are such patients viable candidates for heart transplantation?

Cancer survivors pose significant challenges given the variable natural history of their pre-existing malignancy in the context of immunosuppression, raising the stakes of the critical prediction: will these patients thrive with the scarce resource of a donor heart? The ethical dilemma looms large. Inappropriate allocation of the donor heart not only harms the transplant recipient but also other candidates on the waiting list, on borrowed time, whose lives might have been saved if they had received a heart instead. The most recent International Society of Heart and Lung Transplantation listing guidelines offer only vague guidance: “Cardiac transplantation should be considered when tumor recurrence is low based on tumor type, response to therapy, and negative metastatic workup. The specific amount of time to wait to transplant after neoplasm remission will depend on the aforementioned factors and no arbitrary time period for observation should be used” (1). Thus, in balancing these multiple competing individual and societal interests, the decision is based, in large part, on the culture of individual programs, driven by the anchoring bias of recent anecdotal experience and outcomes.

The study by Ramu et al. (2) in this issue of JACC: CardioOncology is a valuable addition to the limited published experience on the clinical characteristics and outcomes of patients who receive transplants for adriamycin-associated cardiomyopathy. Ramu et al. (2) chose the patient population and era carefully; they excluded patients with previous heart transplant, congenital heart disease, and restrictive cardiomyopathy who would be less likely to be candidates for a left ventricular assist device (LVAD) and focused on the decade 2008 to 2018 to encompass the era of continuous-flow LVADs. In an analysis of 18,270 adult patients undergoing de novo single-organ heart transplantation, the 257 heart transplant recipients with adriamycin-associated cardiomyopathy were less likely to have an LVAD as bridge to transplantation than those with nonischemic and ischemic cardiomyopathy but had comparable post-transplant survival, with no difference in death from malignancy up to 5 years.

How do these results compare with those of other studies on the impact of chemotherapy-associated cardiomyopathy? Considering this study in the context of the 2 other large registry analyses on the topic, several themes emerge (Table 1). First, chemotherapy-associated cardiomyopathy comprises a small fraction of the entire heart transplant population, and thus, registry studies are essential to gather an adequate sample from which to draw conclusions. Second, the current study by Ramu et al. (2) offers experience in the current era, nearly a decade past the span of other published analyses, with an older median age (51 years vs. 44 to 45 years) and a higher proportion of female transplant recipients (76% vs. 64% to 66%). Although eras overlap, the use of LVAD support as a bridge to transplant is higher in successive eras: 13% in 1987 to 2011, 20% in 2000 to 2008, and 35% in 2008 to 2020. Although patients in the current era were older with more LVAD use, the 5-year survival was higher: 81% versus 71% to 72%. What are the lessons here? That, on a registry level, we are making the right predictions. Patients in the current era may be at higher risk for post-transplant mortality based on older age and LVAD use (3), but they have better outcomes than in prior eras—a nod to the importance of careful selection.

Table 1.

Summary of Studies of Chemotherapy-Associated Cardiomyopathy and Heart Transplantation

First Author (Ref. #)	Registry	Years	N	Age, yrs	Women, %	Type of Cancer, %	MCS, % LVAD	5-Year Post-Transplant Survival, %
Lennemen et al. (5)	UNOS	1987–2011	453 ACM	44	66	Breast: 24 Hematologic: 17	13	72
Oliveira et al. (6)	ISHLT	2000–2008	232 CCM	45	64	Hematologic: 33 Breast: 31	20	71
Ramu et al. (2)	UNOS	2008–2018	357 ACM	51	76	Breast: 44 Hematologic: 25	35	81

ACM = adriamycin-associated cardiomyopathy; CCM = chemotherapy-associated cardiomyopathy; ISHLT = International Society of Heart and Lung Transplantation; LVAD = left ventricular assist device; MCS = mechanical circulatory support; UNOS = United Network of Organ Sharing.

Will these findings move the needle on the role of heart transplantation in patients with adriamycin-associated cardiomyopathy and advanced heart failure? As the aphorism goes, the plural of anecdote is not data—but it may be registries. This registry experience offers the best evidence to date that transplantation is a feasible option for patients with adriamycin-associated cardiomyopathy and, by extension, pre-existing malignancy. Certainly, the findings should offer confidence to heart transplant selection committees as they incorporate more than just single-center anchoring bias but rather the valuable experience of other centers, encapsulated by registries, into their decision-making process.

However, although the current study by Ramu et al. (2) is a necessary step toward greater confidence in the role of heart transplantation in patients with adriamycin-associated cardiomyopathy and advanced heart failure, there is much we still need to learn. Do these findings apply to patients with other forms of cancer therapy– or radiation-associated cardiomyopathy? Do they apply to patients with prior malignancies regardless of whether their cardiomyopathy is related to cancer therapy? Do outcomes differ based on the type of cancer, time from cancer diagnosis, and time from remission or control of disease? Although survival might be comparable, are these patients at risk for morbidity, including worsening functional status, cancer recurrence, or infections over time? Is there a risk of later-term mortality not captured in existing studies?

Additions to the UNOS dataset to better capture the details of cancer-associated cardiomyopathy and pre-existing malignancies in transplant candidates would be one way to address these questions. However, although the strength of the UNOS dataset is the comprehensive inclusion of transplant centers, this detailed granularity may not be feasible and may be best derived from focused multicenter collaborations, such as the Cardiac Transplant Research Database (4). The Cardiac Transplant Research Database collected data from 42 institutions across the United States and Canada from 1990 to 2008, and the detailed prospective information from this collaboration resulted in scores of publications spanning decades, offering insight into the prognostic value of donor, recipient, and early post-transplant factors on post-transplant outcomes. Perhaps the time has come for another multicenter, prospective, focused collaboration with the power to address together the questions we cannot answer on our own.

We may hope for a future where refinement in the administration of chemotherapy and radiation therapy and effective preventive measures have reduced cancer-associated cardiomyopathy to a historical curiosity. Until then, heart transplantation remains a viable option for select patients with advanced heart failure who have survived cancer. As we forge ahead, trying to predict the best course for our patients, future multicenter collaborations may offer the detailed information necessary to effectively harness the power of experience and best navigate the right path for our patients.

Funding Support and Author Disclosures

The author has reported that she has no relationships relevant to the contents of this paper to disclose.