Successful allogeneic stem cell transplant in a patient with a left ventricular assist device: a novel case report

Abstract

Historically, severe heart failure has been considered a contraindication for hematopoietic stem cell transplant (HSCT). Despite the growing use of the left ventricular assist device (LVAD), clinicians have avoided HSCT in patients with hematologic malignancies and an LVAD due to a multitude of potential complicating factors, including the use of cardiotoxic conditioning regimens and severe post-transplant thrombocytopenia requiring anticoagulation interruption. Currently, there are no published reports of a successful allogeneic HSCT in a patient with an LVAD. The case herein documents a 36-year-old man with acute myeloid leukemia (AML) and post-induction systolic heart failure necessitating LVAD (HeartMate 3) placement, who later successfully underwent allogeneic HSCT and is now in remission. We highlight preparative regimen considerations, the need to account for the effects of irradiation on the LVAD and external controller, and the importance of a multidisciplinary care team to demonstrate that the presence of an LVAD does not necessarily preclude patients with AML from potentially curative HSCT, particularly when managed with careful coordination and individualized risk-adapted strategies.

Introduction

Hematopoietic stem cell transplant (HSCT) is the preferred consolidation strategy and is potentially curative in patients with intermediate or adverse risk acute myeloid leukemia (AML) [1, 2]. Despite its effectiveness, HSCT is associated with significant morbidity and mortality, with an estimated 25% non-relapse mortality at 5 years in patients with unfavorable cytogenetic risk factors [3]. Contributors to non-relapse mortality include advanced age, poor performance status, and high comorbidity burden, any of which may exclude patients from consideration for HSCT [4]. Pre-existing cardiac dysfunction, including heart failure, arrhythmias, or valvular disease is a major risk factor for non-relapse mortality, and may also preclude patients from receiving HSCT [5]. Given that standard anthracycline-based induction with cytarabine and daunorubicin, or “7 + 3,” has an incidence of grade 3–5 cardiac toxicities of 7–8%, it is not uncommon for patients to develop cardiac comorbidities in the pre-transplant period that may complicate HSCT planning [6]. In patients with severe heart failure, a left ventricular assist device (LVAD) may be used to augment cardiac output and maintain adequate tissue perfusion [7].

The feasibility of allogeneic HSCT in patients supported by a durable mechanical circulatory support has not been previously reported, and there are no published cases of a successful allogeneic HSCT in a patient with an LVAD. Because patients with LVADs are dependent on continuous anticoagulation, have impaired cardiac reserve, and are at increased risk for bleeding, thrombosis, and infection, the presence of an LVAD has generally been considered a contraindication to HSCT, which entails significant myelosuppression and immunosuppression [8, 9]. An added concern is that conditioning regimens which include total body irradiation (TBI) must consider the effect of irradiation on the functioning of both the LVAD and the external LVAD controller. The case herein documents a 36-year-old man diagnosed with AML who experienced post-induction heart failure requiring LVAD placement, yet later underwent successful allogeneic HSCT.

Case

A 36-year-old man without significant past medical history first noticed several weeks of gingival swelling and weight loss. He then had his wisdom teeth removed, which was complicated by poor wound healing and significant pain, prompting presentation to the emergency department. Initial laboratory work-up showed a white blood cell count of 116.7 × 10³/µL with 98% peripheral blasts concerning for acute leukemia. Peripheral blood flow cytometry and molecular testing were consistent with AML, with NPM1, FLT-3 ITD, and FLT-3 TKD mutations. He was started on hydroxyurea, and bone marrow biopsy showed 93% blasts with NPM1 (variable allele frequency (VAF) 42%), FLT3-ITD (VAF 6.4%), and FLT3-TKD (VAF 6.7%) mutations. Echocardiogram showed a left ventricular ejection fraction (LVEF) of 50%, and he was started on the “7 + 3” regimen with cytarabine and daunorubicin, followed by midostaurin. Repeat bone marrow biopsy on day 21 after the start of induction chemotherapy did not identify leukemia.

His post-induction chemotherapy course was complicated by sepsis of unknown source followed by acute heart failure with respiratory distress. A repeat echocardiogram a few weeks after induction chemotherapy showed an EF of 18% and severe global hypokinesis. He was admitted to the cardiac intensive care unit and started on furosemide and milrinone infusions, but ultimately required transfer to our institution for advanced cardiac care and LVAD evaluation. After a multidisciplinary discussion between cardiology and hematology-oncology, LVAD placement was pursued with the intent of supporting the patient through consolidative chemotherapy and to bridge the gap to transplant candidacy. Following successful LVAD placement (HeartMate 3), he was discharged. Plans for consolidation chemotherapy were delayed to allow for adequate physical recovery. Repeat bone marrow biopsy was performed on day 121 after the start of induction chemotherapy and one day prior to planned consolidation chemotherapy, which revealed no evidence of leukemia; however, NPM1 minimal residual disease testing was positive. Additionally, a rash across the chest and thighs was noted on the day of admission, which was biopsied and indicative of leukemia cutis and therefore relapsed AML.

He then received salvage therapy with high-dose cytarabine and midostaurin, which was complicated by neutropenic fever without an identifiable source. He subsequently received one additional cycle of high-dose cytarabine with midostaurin for consolidation. Of note, this process was completed on a cardiology-specific unit due to nursing familiarity with LVAD management. However, the leukemia inpatient service was the primary team caring for the patient. The cardiology and leukemia attendings communicated daily to ensure the well-being of the patient, and overnight, cardiology advanced practice providers (APPs) were the primary coverage team but collaborated closely with the leukemia APPs to manage oncology-related issues. Due to the presence of leukemia cutis, cerebrospinal fluid was evaluated via flow cytometry, which was positive for leukemic cells. He was then treated with intrathecal methotrexate until documented cerebrospinal fluid clearance. After bone marrow biopsy showed absence of leukemia, he proceeded with reduced intensity conditioning with fludarabine and TBI, then underwent allogeneic HSCT using a matched unrelated donor.

Regarding TBI, the patient was treated using a traditional 16MV AP/PA anterior posterior/posterior anterior) technique at a source to surface distance of 515 cm for 400 cGy in two 200 cGy fractions. Based on imaging acquired at patient simulation, a 3 cm thick Cerrobend block was placed on the spoiler to reduce dose to the heart and LVAD to 150 cGy. The external controller was placed in a 1 cm thick plastic box to reduce neutron dose and positioned as far away as possible, just outside the treatment fields. In vivo measurements were made using optically stimulated luminescence dosimeters (OSLDs), placed inside the box at distances of 2 cm, 8.5 cm, and 14 cm from the field edge, and on the patient along the central axis and centered behind the LVAD block. Further ion chamber measurements were made using a solid water phantom to more accurately estimate the dose delivered to the LVAD. Based on the OSLD readings, the total estimated dose to the controller ranged from 135.3 cGy at 1 cm to 91.5 cGy at 14 cm from the field edge. The LVAD block reduced the surface dose to the patient to 271.6 cGy (68.1%). The block transmission factors of the 3 cm Cerrobend block measured in the phantom were 45% at 1 cm depth and decreased asymptotically to around 30% at 3 cm depth. Applying these transmission factors to the in vivo measurements yielded a dose of 120 cGy to the implanted device. No LVAD alarms, controller malfunction, or flow abnormalities occurred during or after TBI.

The patient’s immediate post-transplant course was complicated by clostridium difficile infection and febrile neutropenia, which resolved with antibiotics. On post-transplant day 30, he experienced gastrointestinal and dermatologic graft versus host disease (GVHD), which improved with budesonide and a prolonged prednisone taper. Unfortunately, on post-transplant day 100, blood work revealed peripheral blasts and flow cytometry confirmed relapsed AML. Bone marrow next generation sequencing showed NPM1 (VAF 40%), IDH1 (VAF 41%), FLT3 ITD (VAF 28%), and TP53 (VAF 62%) mutations. He then underwent salvage therapy with azacitidine, venetoclax, and ivosidenib, which was further complicated by differentiation syndrome and recurrent rash, with biopsy-confirmed GVHD. Fortunately, a repeat bone marrow biopsy 23 days after the start of salvage therapy showed complete response.

His GVHD was initially managed with prednisone, however he then developed recurring fevers and was found to have both vancomycin-resistant enterococcus bacteremia as well as an invasive pulmonary fungal infection. As a result, prednisone was rapidly tapered and his GVHD was treated with tacrolimus. He was also treated with daptomycin and isavuconazole under the guidance of the infectious disease team. He eventually stabilized and was discharged, yet over the coming months had several episodes of gastrointestinal and dermatologic GVHD, as well as additional infectious complications such as streptococcus pneumonia and E. coli bacteremia requiring hospitalization for septic shock. This hospitalization occurred about one year after salvage therapy, during which he experienced severe thrombocytopenia that did not initially recover after resolution of sepsis, requiring cessation of anticoagulation. Fortunately, a repeat bone marrow biopsy showed no evidence of leukemia. He has since recovered and is now on mycophenolate mofetil for chronic GVHD as well as a suppressive antibiotic and antifungal regimen, with one and two-year post-transplant peripheral blood chimerism showing full donor chimerism. He has now been without hospitalization for the past 16 months. A succinct timeline of major events in the patient’s clinical course is available in Fig. 1.

Fig. 1.

Timeline of clinical course

Discussion

Pursuing HSCT in a patient with an LVAD is feasible, yet requires careful planning and understanding of potential complications. Cardiac risk stratification is essential when planning induction therapy in patients with AML and pre-existing cardiac dysfunction, and typically involves obtaining a transthoracic echocardiogram to assess for LVEF, diastolic function, and valvular disease as well as detailed history to assess for the presence of cardiac symptoms or prior cardiotoxic therapies [10]. In those with cumulative doxorubicin-equivalent doses exceeding 250 mg/m², age of 65 or greater, or with pre-existing cardiovascular risk factors, intensive chemotherapy with anthracyclines is often deferred in favor of hypomethylating agents (such as azacitidine) and venetoclax [11, 12]. In this case, the patient’s initial LVEF was 50% and he did not have any cardiac symptoms, thus he underwent intensive chemotherapy with cytarabine and daunorubicin. He later developed systolic heart failure refractory to medical therapy, requiring LVAD placement. Had this patient’s heart failure or LVAD preceded induction therapy, a lower intensity regimen such as azacitidine and venetoclax would have been pursued.

Based on his cytogenetic profile, this patient was initially stratified as having intermediate risk AML, which often requires HSCT to achieve prolonged remission or cure [1, 2]. HSCT is more successful in patients who have achieved complete remission following induction therapy compared to those with minimal residual disease [13]. Therefore, salvage chemotherapy was initiated when the patient experienced relapse in the form of leukemia cutis. Leukemia cutis represents extramedullary infiltration by leukemic cells, is a recognized risk factor for central nervous system involvement in patients with AML, and is associated with worse survival [14]. As a result, he was treated with intrathecal methotrexate and once in complete remission, he received reduced-intensity conditioning with fludarabine, TBI given the presence of extra-medullary disease, and then allogeneic HSCT. Reduced-intensity conditioning regimens, including those containing fludarabine, treosulfan, and busulfan, have demonstrated similar survival rates compared to more intensive regimens in AML and have reduced toxicity, making them suitable for patients with pre-existing cardiac risk factors [15, 16].

When pursuing TBI, the presence of an LVAD requires careful planning and understanding of risk factors with radiation. Multiple case studies have reported patients with LVADs receiving radiation, although these involved external beam radiation and not TBI [17, 18]. Typically, TBI as part of reduced intensity conditioning involves 2 to 8 Gy (Gy) delivered in 1 to 4 fractions, with higher doses (12 to 15 Gy) reserved for myeloablative conditioning regimens [19]. Myeloablative TBI has been shown to carry the risk of long-term cardiotoxicity in up to 14% of patients [20] and reduced intensity TBI is typically reserved for patients with pre-existing comorbidities that preclude myeloablative dosing [21]. In the BMT Survivor Study, which assessed 1,369 survivors who underwent BMT for AML, the most common causes of death at 15- and 20-years post BMT included cardiovascular disease, which was responsible 16.5% and 16.7% of deaths at these time periods, respectively [22]. Given these results and data suggesting the risk of cardiac injury is rare at doses below 10 Gy [23], the patient was treated with 4 Gy in 2 fractions with the addition of a heart block to further reduce radiation delivery to the heart. This process required coordination with LVAD coordinators and nursing staff, who were present during radiation in the event of LVAD malfunction, helped to keep the LVAD backpack out of the radiation field, and kept the LVAD controller within a plastic container to minimize neutron exposure. Additional information regarding TBI in this patient, including visual recreation of the treatment set up, is detailed by Webster et al. [24]. Ultimately, the patient tolerated TBI well without appreciable toxicity or effect on the LVAD and was able to proceed with HSCT.

With LVADs and other mechanical circulatory support devices, contact between blood and the artificial materials of the LVAD stimulates the coagulation cascade with potential development of thrombosis that could lead to LVAD failure, stroke, or other organ damage [25]. As a result, the profound and prolonged thrombocytopenia following chemotherapy and HSCT presented a significant challenge. In the initial period after LVAD placement, the patient was anticoagulated with aspirin and warfarin with a goal INR of 2–3, which was then changed to heparin for ease of reversal once the patient was admitted for planned re-induction chemotherapy. Once his platelet count decreased to less than 50 × 10³/µL, aspirin and heparin were discontinued, however aspirin and warfarin were eventually resumed on an outpatient basis once his platelet count recovered. This process was repeated when the patient was re-admitted for reduced-intensity conditioning chemotherapy and HSCT. During his hospitalization for post-HSCT relapse, the patient required salvage chemotherapy, again leading to thrombocytopenia and anticoagulation cessation. He continued to have low platelets over the subsequent months, the etiology of which was multifactorial and included infection and medication-induced thrombocytopenia, which limited anticoagulation. He then experienced hemoptysis secondary to aspergillus pneumonia, again prompting anticoagulation cessation, which has not yet been restarted. Compared to the HeartMate 2, the HeartMate 3 has an improved hemocompatibility profile with reduced rates of pump thrombosis, stroke, and major bleeding events, however anticoagulation is still the standard of care [26].

Febrile neutropenia and bacteremia are commonplace during the immunosuppressive phase after HSCT, which become more complicated to manage in the context of an LVAD. This patient’s treatment and post-transplant course consisted of febrile neutropenia, vancomycin-resistant enterococcus bacteremia, and aspergillosis, all of which required repeated, prolonged courses of antibiotics and antifungals in consultation with infectious disease specialists and pharmacists to account for potential drug interactions. Once sepsis has resolved with intravenous antibiotics, it is advisable to continue long-term antibiotic suppression given the potential for bacterial seeding of the device [27, 28]. Device exchange may be performed due to infection, although this has not been demonstrated to improve mortality or lower infection recurrence rates [29].

Now over three years since LVAD placement and HSCT, the patient’s native cardiac function has improved to an estimated LVEF of 35%. The Interagency Registry for Mechanically Assisted Circulatory Support (INTERMACS) demonstrated that in patients with anthracycline-induced cardiomyopathy necessitating LVAD placement, 22.1% experienced partial cardiac recovery, although rarely to the extent allowing for LVAD explant, with only a 4.1% removal rate at 3 years [30]. However, Topkara et al. [30] note there are multiple single-center studies showing higher rates of complete myocardial recovery via the use of guideline-directed medical therapy (GDMT), individualized device weaning strategies, and prospective assessment of native cardiac function, highlighting the importance and proactive role of LVAD programs. Additionally, the left ventricular muscle core excised during LVAD placement in this patient exhibited focal interstitial fibrosis, which is a common histologic finding at the time of LVAD placement [31], however this has not yet demonstrated to be a validated marker for predicting myocardial recovery. LVAD explant may be challenging for several reasons, including the possible presence of fibrous adhesions surrounding the device, potential for cardiac injury during removal, or recurrent heat failure after removal [32, 33]. On the other hand, heart transplant is generally deferred in patients with malignancy until 5 years after remission, when there is a lower chance of cancer recurrence after transplant and better outcomes [34]. As such, the patient was started on GDMT, and his cardiac function will continue to be monitored closely over the coming years with consideration for either LVAD removal or transplant.

Conclusion

This case demonstrates that through multidisciplinary coordination and individualized treatment planning, allogeneic HSCT can be successfully performed in a patient with an LVAD, achieving acceptable short- and intermediate-term outcomes. This experience highlights that LVAD presence should not be viewed as an absolute contraindication to HSCT in select, well-optimized patients.

Author contributions

**Kevin G Zablonski: ** Writing – Original Draft, Writing – Review and Editing. **Umar Sabir: ** Writing – Original Draft. **Jason H. Mendler: ** Writing – Review and Editing. **Jeffrey D. Alexis: ** Writing – Review and Editing. **Matthew Webster: ** Writing – Review and Editing. **Louis S. Constine: ** Writing – Review and Editing. **Omar Aljitawi: ** Writing – Review and Editing, Supervision.

Funding

The authors received no specific funding for this work.

Data availability

Data sharing is not applicable to this article as no datasets were generated or analyzed during the current study.

Declarations

Patient consent

The patient granted informed consent for the publication of this case.

Competing interests

The authors declare no competing interests.