Cardiac toxicity in Haplo-HSCT

Rémy DuléryClinical Hematology and Cellular Therapy Dpt.

Saint Antoine HospitalAP-HP6.Sorbonne University

Paris, France

Cardiac Toxicity in Haplo-HSCTRémy DULERY

Conflict of interest disclosures: Honoraria for lectures from Keocyt, Gilead, Novartis and Sanofi

Marseille, November 17, 2019

o Cardiotoxicity is a rare, but often lethal complication following HSCT.

o Cardiac events may occur early after HSCT or in the long term, mainly due to sepsis or chemotherapy toxicity

Shinya Ishida, et al. Ann Hematol 2016

Cardiovascular events after HSCT

o Cardiovascular diseases (CVD) after HSCT include cardiomyopathy, congestive heart failure, valvular dysfunction, arrhythmia, pericarditis, and coronary artery disease.

o CVD cumulative incidence is 5% to 10% at ten years after HSCT, accounting for 2% to 11% of mortality among long-term survivors.

Majhail NS, et al. Biol Blood Marrow Transplant 2012;18:348-371Tichelli A, et al. Blood 2007;110:3463-3471Tichelli A, et al. Haematologica 2008;93:1203-1210Chow EJ, et al. Ann Intern Med 2011;155:21-32Bhatia S, et al. Blood 2007;110:3784-3792

Cardiovascular diseases after HSCT

Cardiovascular diseases after HSCT

Chow EJ, et al. Ann Intern Med 2011;155:21-32

o Compared to the general population, HSCT recipients experience increased cardiovascular death.

o Incidence rate difference = 3.6 per 1000 person-years (95% CI:1.7-5.5)

Cardiovascular death

Cum

ulat

ive

inci

denc

e

Time (years)

Cyclophosphamide-induced cardiotoxicity

o Cyclophosphamide (Cy)-induced cardiotoxicity, in particular, develops within the first 2–10 days after its first administration.

o The minimum dose for cardiac toxicity is still not known, although there are few reports of Cy toxicity at less than 100 mg/kg.

o Cy-induced cardiac toxicity seems correlated with the Cy total dose

Gottdiener JS, et al. Arch Intern Med 1981;141:758–763Braverman AC, et al. J Clin Oncol 1991;9:1215–1223

Morandi P et al. Bone Marrow Transplant 2005;35:323–334

Mechanism of Cy-induced cardiotoxicity

Cy metabolites can cause oxidative stress and endothelial capillary damage, with extravasation of toxic metabolites that result in myocytedamage.

Haoyi Zheng, et al. Cardiac Effects of Cancer Therapy. Hematology, Oncology and Palliative Medicine. 2015.

EBMT activity survey

Passweg JR et al. Bone Marrow Transplant 2017

Haplo

Cy-induced cardiotoxicity in haplo ?

o High dose Cy in HSCT conditioning regimen: Cy-induced cardiomyopathy has been reported among 1.5–17% of patients by single center studies, depending on the regimen and the patient population.

o PT-Cy in the Haploidentical HSCT setting is now widely used but risk factors, clinical manifestations and incidence of early cardiac event (ECE) are still poorly assessed.

Cazin B et al. Cancer 1986; 57 (10): 2061-9 Gottdiener JS et al. Arch Intern Med 1981;141:758–763Braverman AC et al. J Clin Oncol 1991;9:1215–1223Shinya Ishida et al. Ann Hematol 2016;95:1145–1150

SFGM-TC study

Unpublished data

o 537 Haplo-SCT patientso 29 centerso Retrospective study (2010-2016)o Data from ProMISe + specific CRF

o No early cardiac event (3 months post-transplant) in 435 patients (81%)§ Last follow-up: 131 died (30%), 304 are alive (70%)

o Early cardiac event in 102 patients (19%)§ Last follow-up: 57 died (56%), 45 are alive (44%)§ 32 patients died with cardiac complications

SFGM-TC study

Unpublished data

o Early cardiac event occurred in 102 patients (19%)

§ Not related to PT-Cy (CRS, sepsis) = 14.5%§ Possibly or probably related to PT-Cy = 4.5% patients

§ Resolved in 2/3 patients (66%)

SFGM-TC study

Unpublished data

Saint Antoine Studyo We aimed to compare the clinical outcomes between patients who

received PT-Cy and patients who did not, focusing on early cardiac events (ECE).

o ECE = cardiac event occurring between days 0 to +100.

o All consecutive patients undergoing HSCT in Saint Antoine Hospital between January 2013 and June 2018 were included, except cord blood recipients.

o Transthoracic echocardiography and ECG were performed systematically in all patients before HSCT, at day + 90, in case of clinical manifestation of an ECE.

Initial characteristicsPT-Cy

(n=136)No PT-Cy(n=195) p

Disease, n (%)AMLALLLymphomaMyelomaMDSMPN

70 (51)17 (13)23 (17)4 (3)

13 (10)9 (7)

83 (43)32 (16)21 (11)4 (2)

22 (11)33 (17)

ND

Disease risk index, n (%)lowintermediatehighvery high

0 (0)87 (64)41 (30)8 (6)

4 (2)147 (75)35 (18)9 (5)

0.0188

Initial characteristicsPT-Cy (n=136)

No PT-Cy(n=195) p

Donor, n (%)HLA-identical siblingMUDHaploidentical

6 (4)13 (10)117 (86)

83 (42.5)111 (57)1 (0.5)

<0.001

Conditioning regimen, n (%)MACRICSequential

32 (23.5)46 (34)

58 (42.5)

99 (51)39 (20)57 (29)

<0.001

Graft source, n (%)PBSCBone marrow

118 (82)25 (18)

192 (98)3 (2) <0.001

ATG, n (%) 118 (87) 194 (99.5) NSPT-Cy, n (%)

1 day 33 (24) 0 (0) ND

Initial characteristicsPT-Cy (n=136)

No PT-Cy(n=195) p

Donor, n (%)HLA-identical siblingMUDHaploidentical

6 (4)13 (10)117 (86)

83 (42.5)111 (57)1 (0.5)

<0.001

Conditioning regimen, n (%)MACRICSequential

32 (23.5)46 (34)

58 (42.5)

99 (51)39 (20)57 (29)

<0.001

Graft source, n (%)PBSCBone marrow

118 (87)18 (13)

192 (98)3 (2) <0.001

ATG, n (%) 118 (87) 194 (99.5) NSPT-Cy, n (%)

1 day 35 (26) 0 (0) ND

Initial characteristicsPT-Cy

(n=136)No PT-Cy(n=195)

p

Age (years), median (range) 53 (15-76) 56 (16-76) 0.1069Previous cardiac event, n (%) 27 (20) 45 (23) 0.4843Left ventricular systolic dysfunction, n (%) 10 (7) 21 (11) 0.2939

Antracycline beforetransplant, n (%) 108 (79) 133 (68) 0.0242

% of anthracyline maximumtolerated dose (IQR) 39 (23-65) 39 (0-64) 0.0285

HCT-CI Sorror ≥ 3, n (%) 27 (20) 54 (28) 0.2533

Karnofsky index ≤ 80 25 (18) 27 (14) 0.2645

Cardiovascular risk factorsCardiovascularrisk factors, n (%)

PT-Cy (n=136)

No PT-Cy(n=195) p

No CVD risk factor 24 (18) 31 (16) 0.6739Age >50y (Male) or 60y (Female) 62 (46) 110 (56) 0.0525

Obesity 12 (9) 32 (16) 0.0455Male/Female, n (%) 86 (63)/ 50 (37) 110 (56)/ 85 (44) 0.3822High blood pressure 22 (16) 30 (15) 0.7642Diabetes 8 (6) 17 (9) 0.1724Dyslipidaemia 7 (5) 23 (12) 0.0382Smoking 37 (27) 55 (28) 0.8418

Cardiovascular risk factorsCardiovascularrisk factors, n (%)

PT-Cy (n=136)

No PT-Cy(n=195) p

No CVD risk factor 24 (18) 31 (16) 0.6739Age >50y (Male) or 60y (Female) 62 (46) 110 (56) 0.0525

Obesity 12 (9) 32 (16) 0.0455Male/Female, n (%) 86 (63)/ 50 (37) 110 (56)/ 85 (44) 0.3822High blood pressure 22 (16) 30 (15) 0.7642Diabetes 8 (6) 17 (9) 0.1724Dyslipidaemia 7 (5) 23 (12) 0.0382Smoking 37 (27) 55 (28) 0.8418

OutcomesPT-Cy

(n=136)No PT-Cy(n=195) p

Acute GVHD II-IV 20.4% 29.3% 0.0415Chronic GHD 25.2% 33.6% 0.0897GRFS 41.4% 46.1% 0.44897OS 56.3% 62.8% 0.1497PFS 48.7% 59.4% 0.05503Relapse 23.2% 18.9% 0.5359NRM 28.1% 21.6% 0.1343

Median follow-up = 36 months (19-50)

Results

PT-Cy (n=135)

No PT-Cy(n=220)

p

Early cardiac event, n (%) 29 (21) 16 (8) <0.0001Left ventricular systolic dysfunction, n (%)

20 (15) 6 (3) <0.0001

APO, n (%) 9 (7) 4 (2) 0.0354Arrhythmia, n (%) 5 (4) 7 (4) NSPericarditis, n (%) 5 (4) 2 (1) NDCoronary artery disease, n (%) 2 (1.5) 1 (0.5) ND

Risk factors for early cardiac eventmultivariate analysis

HR 95% CI pPT-Cy 2.5 1.3-4.8 0.004Age (per 10 years) 1.2 0.99-1.6 0.0595DRI (high vs. Low-intermediate) 1 0.49-2 0.991Karnofsky (80% or less) 0.8 0.38-1.7 0.553RIC (reference) 1MAC 0.6 0.25-1.6 0.309Sequential conditioning 1.99 0.9-4.4 0.091History of pre-transplant cardiac event 1.7 0.9-3.3 0.099

o History of pre-transplant cardiac event was significantly associated with higher NRM and lower OS, PFS and GRFS in multivariate analysis.

o Cardiovascular risk factors and the cumulative doses of anthracycline were not significantly associated with the incidence of ECE.

Ove

rall

Surv

ival

Time (years)

No cardiac event

Cardiac event

72%

44%

p=0.0154

Figure 1

Number patients at risk No cardiac event - 274 196 138

Cardiac event - 33 20 6

o ECE resolved in 38/49 patients (78%) o 11 patients (22%) died without recovering from ECE within 4 months after transplanto ECE was associated with decreased OS (landmark analysis on day+100)

Outcomes

p=0.0154

o Early cardiac events (ECE) occurred more frequently (21% of patients)after HSCT with PT-Cy than after HSCT without PT-Cy (8% of patients)

o ECE may resolve in the majority of patients (78%)

o Patients who developed a cardiac event after transplantation have decreased OS (71% without ECE vs. 44% after ECE)

oThese results may help better selecting patients who are eligible to receive HSCT with PT-Cy, especially elderly ones, and those with a history of cardiac events.

Conclusions

o Better select patients who are eligible to receive HSCT with PT-Cy ?

o Patients without cardiovascular disease risk factors may develop cardiac events: close cardiac monitoring is warranted for all patients

o To prevent oxydative stress ?? (N-Acetylcysteine, Selenium)

o To reduce PT-Cy dose ? (GVHD?)

Future directions to reduce cardiac toxicity

Kurauchi et al. BMC Res Notes, 2017Gunes et al. Biol Trace Elem Res, 2017

Impact of PT-Cy doses ? ALWPStudy designRetrospective, EBMT database and survey

Purpose of the studyTo assess the impact on outcomes of PT-Cy at 100 mg/kg compared to lower doses after haploidentical stem cell transplantation in patients with AML in CR.

Primary endpointGRFS at 1 year (PT-Cy at 100 mg/kg versus lower doses of PT-Cy)

Secondary endpoints§ Cumulative incidence of acute GVHD at 6 months § Cumulative incidence of chronic GVHD at 12 months§ Cumulative incidence of NRM at 12 months§ Disease-free and overall survival at 12 months

Inclusion criteria§ Acute myeloid leukemia in complete

remission§ Age ³ 18 years. § T-cell-replete haploidentical stem cell

transplantation with PT-Cy§ Bone marrow or peripheral blood stem cell

grafts§ MAC, RIC or sequential conditioning regimen

Exclusion criteria§ Previous allogeneic stem cell transplantation§ T-cell depleted graft

Hematology Department§ Anne Banet§ Giorgia Battipaglia§ Ramdane Belhocine§ Eolia Brissot§ Anke Delie§ N-C Gorin§ Françoise Isnard§ Myriam Labopin§ Tounes Ledraa§ Ollivier Legrand§ Florent Malard§ Clémence Médiavilla§ Mohamad Mohty§ Annalisa Paviglianiti§ Simona Sestili§ Zoé Van de Wyngaert§ Anne Vekhoff

AcknowledgmentsCardiology Department

§ Stéphane Ederhy§ Ariel Cohen

INSERM§ Béatrice Gaugler§ Florent Malard§ Mohamad Mohty§ Nicolas Stocker

Nursing staff

Data managers

Thank you!Any questions? @RemyDuleryremy.dulery@aphp.fr