Acute Left Ventricular Dysfunction Following Gemtuzumab Ozogamicin in Two Pediatric AML Patients

Abstract

Gemtuzumab ozogamicin (GO) is an anti-CD33 antibody-tumor antibiotic conjugate with proven efficacy in pediatric and adult patients with CD33+ acute myeloid leukemia. Adverse effects commonly associated with GO include hyperbilirubinemia, elevated transaminases, and sinusoidal obstruction syndrome. Cardiotoxicity has not been a commonly described adverse event. We describe two pediatric patients with relapsed/refractory acute myeloid leukemia who received fractionated GO monotherapy and subsequently developed severe acute left ventricular dysfunction. Both patients achieved remission, recovered cardiac function with medical therapy, and tolerated subsequent stem cell transplantation.

INTRODUCTION

Gemtuzumab ozogamicin (GO) is an anti-CD33 antibody-tumor antibiotic conjugate used in the treatment of both de novo and relapsed/refractory (r/r) pediatric acute myeloid leukemia (AML) whose mechanism of action involves preferential binding to cells expressing CD33 and subsequent internalization of the tumor antibiotic (a calicheamicin derivative)¹. In newly diagnosed pediatric patients, GO has improved event-free survival, relapse risk, and disease-free-survival when incorporated as single 3 mg/m² doses in the induction I and intensification II cycles of therapy². In r/r pediatric AML, GO has been used both as monotherapy (2.5-10 mg/m^23-6 or as 9 mg/m² fractionated into three 3 mg/m² doses^7,8) and in combination with chemotherapy^6-9.

The main toxicities associated with GO include myelosuppression, hyperbilirubinemia, transaminitis, and sinusoidal obstruction syndrome (SOS). The incidence of SOS is directly associated with the absolute single dose of GO^{10, 11}. Phase 2 adult AML trials showed renewed CD33+ expression in ex vivo AML blasts following GO exposure, prompting the hypothesis that fractionated doses would enhance treatment efficiency while reducing toxicity^10,12. In clinical trials, fractionated GO was shown to have a lower incidence of SOS in adults¹² and no cases of SOS in two pediatric studies^7,8.

Cardiotoxicity related to GO is rare and only reported in pre-treated r/r AML patients receiving unfractionated dosing^3,6. One study that used two unfractionated 7.5mg/m² GO doses over two weeks in 30 patients with r/r pediatric AML found 4 patients (13%) had adverse effects in left ventricle shortening fraction (LVSF) with 2 of those 4 having grade 3 or 4 toxicity³. Another study using unfractionated GO in r/r pediatric AML had one patient die from worsening of pre-existing cardiomyopathy with SOS⁶. These reports did not provide detailed clinical context or longitudinal follow up of cardiac function^3,6.

We have used fractionated GO monotherapy in two pediatric patients with r/r AML that subsequently developed life-threatening acute left ventricular systolic dysfunction (LVSD). Herein, we present their vignettes along with echocardiography and laboratory findings to describe this rarely-described toxicity of an increasingly used immunotherapy.

MATERIALS AND METHODS:

Case descriptions were created using retrospective electronic medical record review including no identifiable patient information. Echocardiogram and laboratory data was graphed using Graphpad Prism software (GraphPad Inc).

RESULTS

Patient 1

A 23-month-old female with CD33+ AML was initially treated with AML-Berlin, Frankfurt, Münster (BFM) 2012 intermediate risk group protocol. At diagnosis, she was noted to have a mildly dilated LV with mitral regurgitation (MR) that preceded AML therapy, for which enalapril and furosemide were used during induction. Six months into maintenance therapy she developed an isolated medullary relapse and was re-induced (Table 1). A bone marrow biopsy and aspirate (BMBA) done on day 15 of re-induction chemotherapy showed an aplastic marrow with 88% blasts, prompting a decision to treat with GO for presumed chemorefractory disease.

TABLE 1: Characteristics of patient 1 and 2.

ADxE, cytarabine, liposomal daunorubicin, etoposide; haM, high-dose cytarabine/mitoxantrone; AI/2 CDA, cytarabine/ idarubicin/2-chloro-2-deoxyadenosine; HAE, high-dose cytarabine/etoposide; 6-TG, 6-thioguanine; AraC, cytarabine; FLAG-Ida, fludarabine, high-dose cytarabine, G-CSF, and idarubicin; ATG, anti-thymocyte globulin; ADE, cytarabine, daunorubicin, etoposide; AE, cytarabine, etoposide; AM, cytarabine, mitoxantrone.

Pt	Age and Sex	AML therapy prior to GO	Dose GO receiv ed	Bone marro w finding s after GO	Days following initiation of GO that diminish ed cardiac function was observed	Symptoms of heart failure	Bridging therapy prior to transpla nt	Conditioning for post-GO transplant	Outco me
1	23 months Female	Upfront therapy: AML-BFM 2012 IR group Induction 1: ADxE Induction 2: haM Consolidation 1: AI/2 CDA Consolidation 2: haM Intensification: HAE Maintenance: 6-TG and AraC Re-induction: FLAG-Ida Cumulative anthracycline dose: 400mg/m2	3mg/m2 on days 1, 4, 7, 15, 18, and 21; Total: 18mg/m2	MRD negative on day 14	82	Asymptomatic, initial recognition of abnormal systolic function on echocardiogram; subsequent development of pallor and fatigue	Azacytidine & venetoclax: 4 x 28 day cycles	Busulfan (4mg/kg/dose daily x 4 doses), fludarabine (40mg/m2/dose daily x 4 doses), ATG (3mg/kg/dose daily x 3 doses)	Alive in remission 18 months post-SCT LVEF 56% at last follow up
2	3 years Male	Upfront therapy: AAML1031 Arm B Induction I ADE+bortezomib Induction 2 ADE+bortezomib Intensification 1 AE+ bortezomib - Intensification 2 AM + bortezomib Re-induction: Fludarabine, cytarabine Idarubicin, cytarabine and topotecan Clorafabine, topotecan, thiotepa, and vinorelbine Conditioning: Fludarabine, thiotepa, and melphalan Stem cell transplant: Matched unrelated peripheral SCT Maintenance Azacytidine x 9 cycles Cumulative anthracycline dose: 600mg/m2	3 mg/m2 on days 1, 4, 8, 15, and 18; Total: 15mg/m2	No detectable leukemia on day 11*	22	Hypotensive shock, requiring vasopressors, respiratory distress, altered mental status	Decitabine	Busulfan (4mg/kg/dose daily x 4 doses), (cyclophosphamide 50mg/kg/dose daily x 4 doses), ATG (1.5mg/kg/dose daily x 3 doses)	Relapsed 21 months post 2nd BMT and died 24 months post BMT LVEF 66% at last follow up

^*MRD could not be run due to hypocellular marrow.

Her pre-GO cumulative anthracycline exposure was 400 mg/m² and an echocardiogram (ECHO) showed qualitatively low-normal left ventricular systolic function, with a left ventricular ejection fraction (LVEF) of 52%, an LVSF of 26%, and no mitral regurgitation (MR) (Figure 1). She received 3 mg/m² GO on days 1, 4, and 7, and then underwent repeat BMBA that was hypoplastic and minimal residual disease (MRD)-negative. She then received an additional three GO doses (3mg/m²/dose) on days 15, 18, and 21 and subsequently developed prolonged pancytopenia but exhibited no clinical symptoms of heart failure. At day 62 after GO, she initiated azacytidine and venetoclax as bridging therapy to planned bone marrow transplant (BMT).

FIGURE 1: Cardiac Function vs Time Post-GO for Patients 1 and 2.

Left ventricle ejection fraction (LVEF) as measured by Simpson biplane method and B-Natriuretic Peptide (BNP) in picograms (pg)/mL vs time in days from gemtuzumab ozogamicin (GO) with clinical highlights for Patient 1 (A) and Patient 2 (B).

At day 82 after GO, a routine ECHO revealed a decrease of LVEF to 40% and LVSF to 16%, a moderately dilated LV (4.4cm, from 3.5cm pre-GO), mild MR, and a brain natriuretic peptide (BNP) of 1592 pg/mL. As a result of these findings, she was restarted on furosemide and enalapril, followed by carvedilol. Two weeks later, she was admitted for decompensated heart failure with pallor and fatigue accompanied by hypotension. An ECHO showed a severely dilated LV, LV EF of 32%, and LVSF of 16%. Her carvedilol dose was decreased, digoxin was started, and she was prescribed spironolactone. She completed 4 cycles of azacytidine and venetoclax during which time her LVEF improved to 54% and LVSF improved to 30%.

Seven months post-GO, she remained in an MRD-negative remission and underwent unrelated donor BMT with a myeloablative regimen including busulfan, fludarabine, and anti-thymocyte globulin (ATG). She maintained stable cardiac function throughout her transplant course and did not develop SOS. She is considered to have New York Heart Association (NYHA) Class I and is maintained on a regimen of carvedilol, digoxin, spironolactone, and enalapril with close cardiology follow up. Her AML is in remission 18 months post-transplant, and cardiac function has been stable.

Patient 2

A 3-year-old male with CD33+ AML received upfront therapy on AAML1031 Arm B (bortezomib arm) and relapsed with a scalp chloroma seven months post-diagnosis. He was re-induced (Table 1), but following re-induction, a BMBA demonstrated 35% blasts. He then received clofarabine, topotecan, thiotepa, and vinorelbine, and his MRD decreased to 1%. He underwent unrelated donor peripheral stem cell transplant (PSCT) with myeloablative fludarabine, thiotepa, and melphalan conditioning followed by azacytidine for nine cycles before developing a maxillary sinus chloroma and 33% marrow involvement with CD33+ myeloid blasts. This second relapse prompted the decision to pursue GO. Prior to GO, he had received 600 mg/m2 of anthracycline without dexrazoxane.

A pre-GO ECHO showed normal left ventricular systolic function, with an LVEF of 60% and LVSF of 31% (Figure 1). He received GO (3 mg/m²/dose) on days 1, 4, and 8 and concurrent radiotherapy to his maxillary sinus. BMBA on day 11 showed hypocellularity without leukemic blasts. He received two additional doses of GO on days 15 and 18 for 15mg/m² total. On day 21, he developed respiratory distress, hypotension, altered mental status, and a distended abdomen requiring transfer to the intensive care unit (ICU) while afebrile with negative blood cultures. An ECHO showed a severely diminished LVEF of 21%, LVSF of 12%, and mild LV dilation. An abdominal ultrasound (AUS) showed hepatomegaly but normal portal venous flow. Labwork showed a BNP of 6373 pg/mL and a bilirubin that peaked at 2.9 mg/dL. He was started on dobutamine, milrinone, and epinephrine for cardiogenic shock, and stabilized within 12 hours. His epinephrine and dobutamine were stopped after 2 days, milrinone was stopped after 14 days, and he initiated enalapril and spironolactone. His systolic function improved to an LVEF of 58% and LVSF of 29% within 12 days of the ICU transfer. A BMBA 2 months post-GO remained MRD negative, and an ECHO three months post-GO showed stable LV function. As a bridge to a second SCT, he received a cycle of decitabine.

Four months following GO, he underwent a second unrelated donor BMT with myeloablative busulfan, cyclophosphamide, and ATG in addition to defibrotide prophylaxis. On day +16 he developed hepatomegaly and a new cardiac gallop. An ECHO showed a decrease in LVEF to 45% and LVSF to 25%, with a BNP of 8167pg/ml. AUS showed hepatomegaly with normal flow in the portal vein. He was transferred to the ICU where his congestion improved with diuretics and milrinone. Five days later, milrinone was stopped, BNP trended down to 396 pg/mL and LVEF and LVSF normalized. 50 days post-BMT an ECHO and BNP were repeated and remained normal. Unfortunately, 21 months post-BMT, he had a bone marrow/extramedullary relapse and passed away 3 months later.

DISCUSSION

We present vignettes of two pediatric patients with r/r AML who developed acute LV dysfunction following 15-18mg/m² of fractioned GO monotherapy, suggesting a potential relationship between GO and cardiotoxicity in heavily pre-treated AML patients. Both patients had significant prior anthracycline exposure but low-normal to normal cardiac function before GO administration. Their cardiac dysfunction was characterized by decreased systolic function (LVSF and LVEF), elevated natriuretic peptide levels, LV dilation, and improvement with medical therapy.

Patient 1 had received azacytidine and venetoclax in the interval between her GO and her first ECHO, however, her ECHO showed severely diminished LV function that improved while she was on azacyditine/venetoclax subsequently, suggesting these were not the cause of the dysfunction. She was initially asymptomatic, suggesting the utility of routine ECHO monitoring in patients with AML receiving GO-monotherapy at these doses. Patient 2 was critically ill without alternative clinical explanation when LV systolic dysfunction was identified. Both patients achieved remission following three 3 mg/m² doses of GO, tolerated full-intensity SCT, did not develop SOS, and maintained post-SCT remissions for 18 months and counting for Patient 1, and 21 months for Patient 2.

Understanding potential GO-associated cardiotoxicity risks is important for guiding and improving cardiac surveillance in AML patients receiving GO monotherapy. While cardiotoxicity is not commonly described with GO, these cases and previous reports of worsening LVSF following GO^3,6 suggest the need for cardiac surveillance before and following GO administration, particularly in patients with AML and those treated with anthracyclines. As seen here, heart failure-directed interventions may be prompted by surveillance echocardiography. Our protocol for GO includes obtaining a baseline ECHO. Due to the observed change in cardiac function in these patients, echocardiography will also be performed following the first three 3mg/m² doses of GO in future patients to receive fractionated gemtuzumab monotherapy. While fractionation was hypothesized to reduce toxicity from GO, it did not prevent cardiac toxicity at doses of 15-18 mg/m² in these heavily pre-treated patients, although SOS did not occur. Importantly, these outcomes suggest that GO-associated cardiotoxicity can be managed and not preclude SCT with curative intent. Future studies evaluating cardiotoxicity following single-agent GO may deepen our understanding of this clinically important toxicity and guide optimal monitoring strategies for these patients who routinely receive anthracycline-exposure early in therapy.