Long-term effects after autologous stem cell transplantation for lymphoma – findings from a national multicenter study

Long-term effects after autologous stem cell transplantation for lymphoma

– findings from a national multicenter study

NORSMAN research seminar, January 2019

Knut Smeland

National Advisory Unit on Late Effects after Cancer Treatment, Department of Oncology, Oslo University Hospital,

= group of cancers that arise from lymphocytes (B-, T- or NK-cells)

• Hodgkin lymphoma (HL) – 139 new cases 2017

• Classical HL (95%)

• Nodular lymphocyte predominant HL (5%)

• Non-Hodgkin lymphoma (NHL) – 927 new cases 2017

• B-cell (85%):

• Diffuse large B-cell lymphoma (DLBCL)

• Follicular lymphoma

• Mantel cell lymphoma

• Burkitt lymphoma

• +++

• T- or NK-cell (15%)

• ++

Lymphoma

Incidence from “Cancer in Norway 2017”, Cancer Registry of Norway (2018)

5-year relative survival for lymphoma in Norway

0 10 20 30 40 50 60 70 80 90 100

HL males HL females NHL males NHL

fe- males

5-års relatv overlevelse (%)

Data from Cancer Registry of Norway (Cancer in Norway 2005, 2010, 2014 og 2017)

High dose chemotherapy with autologous stem cell transplantation (HDT-ASCT)

Stem cell harvest

High dose chemotherapy (BEAM¹)

Or (until 1996) total body irradiation (TBI)

High dose chemotherapy (BEAM¹)

Or (until 1996) total body irradiation (TBI)

Reinfusion of the patient’s own stem cells

Kill more/all malignant cells Prevent relapse

Permanent loss of bone marrow function

Stem cells frozen and stored

1BEAM = carmustine (BCNU), etoposide, cytarabine (Ara-C) og melphalan

Aims

• To assess prevalence and risk factors of long- term effects after HDT-ASCT for lymphoma

– Excess mortality and conditional survival – Second malignancies

– Cardiac disease and other somatic late effects – Chronic fatigue

– Psycho-social late effects – Life-style

– Total burden of late effects

HDT-ASCT follow-up study

• National multi-center study:

– Oslo, Bergen, Trondheim, Tromsø

• Inclusion criteria:

– HDT-ASCT for lymphoma in Norway 1987-2008 – Age ≥ 18 years at HDT-ASCT

– Resident in Norway at survey

– Not under active cancer treatment

National cross-sectional study (2012-2014)

• Mailed questionnaire

– Fatigue Questionnaire (FQ) – HADS (mental distress)

– Impact of event scale (PTSD) – Life-style

– Work ability

– Eysenck Personality Questionnaire (neuroticism) – SF-36 (HRQoL)

• Out-patient clinical examination (2012/2013)

– Clinical examination (co-morbidity and medications) – Fasting morning blood samples

– Bone mineral density examination – Echocardiography

– Lung function and cardio-respiratory fitness (incl VO_2max)

HDT-ASCT for lymphoma 1987-2008 (n=728)

Patients alive at survey (n=407)

Deceased (n=321)

Excluded

No address (n=3) Emigrated (n=1) Active disease (n=4)

Survivors invited to participate (n=399)

Declined/no response fatigue questionnaire (n=87)

Declined/did not attend clinical examination (n=40) Died prior to examination (n=1)

Completed questionnaire (n=312)

Completed questionnaire and clinical examination (n=271)

Results - 13 published papers (+ 2 subm++)

• Survival, excess mortality, second cancers

• Cardiac disease (heart failure, LVSD, RVSD and valvular dysfunction)

• Pulmonary function and cardiorespiratory fitness

• Bone mineral density

• Work ability

• Chronic fatigue

• Life-style

Patient characteristics entire cohort (n=728)

Hodgkin

(n=150) Non-Hodgkin (n=578) Age at diagnosis (years),

median (range) 31 (10-64) 47 (17-67)

Age at HDT-ASCT (years),

median (range) 33 (18-65) 51 (18-69)

Gender, n (%)

Males 58 % 65 %

Females 42 % 35 %

High-dose regimen

Total body irradiation (1987-1995) 11 % 15 % Chemotherpy (BEAM)¹ (1995-2008) 89 % 85 %

1BEAM = Carmustine, Etoposide, Cytarabine and Melphalan

Overall survival after HDT-ASCT (n=728)

1. Smeland, Haematologica 2015 2. Smeland, Br J Haematol 2016

Hodgkin lymphoma (n=150)¹

Non-Hodgkin lymphoma (n=578)²

0 1 2 3 4 5 6 7 8 9 10 0

2 4 6 8 10 12 14 16 18

Hodgkin lymphoma 1

Years survived after HDT-ASCT

Standariserd mortalitesratio (SMR)

0 1 2 3 4 5 6 7 8 9 10

0 5 10 15 20 25

Non-Hodgkin lymphoma 2

Years survived after HDT-ASCT

Standardisert mortalitetsratio (SMR)

Standardized mortality ratios (SMR)

(= observed mortality : expected mortality)

= 95% confidence interval

= point estimate SMR

16,9

12,3

1. Smeland, Haematologica 2015 2. Smeland, Br J Haematol 2016

Patient characteristics for patients attending clinical examination (n=274)

• Median age: 56 years (25-77)

• 62 % men

• Median time from diagnosis: 13 years (4-34)

• 273 of 274 had received anthracyclines

– Mean cumulative doxorubicin 311 mg/m² – 95 % ≤450 mg/m²

• 35 % cardiac radiotherapy

– Median 29,75 Gy (19-67)

Anthracyclines (AC) and cardiac radiotherapy (RT) increase risk of LVSD in lymphoma survivors after HDT-ASCT¹

1. Murbræch, J Clin Oncol 2015

LVSD (EF <50%), n = 43 (15,7 %):

• 29 heart failure (10,6%)

• 14 asymptomatic (5,1%) Independent risk factors

(multivariate log regression) :

• Doxorubicin ≥300 mg/m² (OR=3.3)

• Cardiac RT >30 Gy (OR=4.3)

Cardiac disease in lymphoma survivors after HDT-ASCT (blue circle, n=274)

Left ventricular systolic dysfunction (LVSD): 31 % ¹ Heart failure (HF): 11 % ¹

Right ventricular systolic dysfunction (RVSD): 6 % ² Valvular disease (VD): 22 % ³ At least one: 42 %

56

Figure 9 Summary of pathological observations in the lymphoma survivors in papers I- III

The blue circle represents all the lymphoma survivorss, whereas the other circles (LVSD = red, 30.8 % - VD = yellow, 22.3 % - HF = purple, 10.6 % and RVSD = green, 6.2 %) are in proportion with the whole cohort as well as with each other in terms of overlapping pathological features.

(Illustraion by Øystein H. Horgmo, University in Oslo)

Illustration by Ø. Horgmo

1. Murbræch, J Clin Oncol 2015, 2. Murbræch, J Am Soc Echocardiogr 2016, 3. Murbræch, JACC Cardiovasc Imaging 2016

Chronic fatigue Chronic fatigue

Comorbidity

• Cardiovascular disease

• Pulmonary function

• Obesity

• Anemia

• Endocrine disturbances Comorbidity

• Cardiovascular disease

• Pulmonary function

• Obesity

• Anemia

• Endocrine disturbances Lymphoma related factors

• Lymphoma type

• Stage

• Treatment

Lymphoma related factors

• Lymphoma type

• Stage

• Treatment

Life style

• Physical activity

• Smoking Life style

• Physical activity

• Smoking Psychosocial factors

• Depression/mental distress

• Personality/neuroticism Psychosocial factors

• Depression/mental distress

• Personality/neuroticism Demographic factors

• Age

• Income

• Marital status Demographic factors

• Age

• Income

• Marital status

Pro-inflammatory cytokines

IL-6, IL-1β, IL1-RA, TNF-α ++

Pro-inflammatory cytokines

IL-6, IL-1β, IL1-RA, TNF-α ++

Fatgue in cancer survivors – a multfactorial phenomon

Detectable serum IL-6 in survivors with and without chronic fatigue (CF) and in controls

Survivors with CF Survivors without CF Controls 0

10 20 30 40 50 60 70 80

%

n = 79 n = 170 n = 100

*

**

* p = 0.003

** p <0.001

1. Smeland, Bone Marrow Transplant 2018

Chronic fatigue (31 %)

Chronic fatigue (31 %)

Comorbidity

• Cardiovascular disease

• Pulmonary function

• Obesity

• Anemia

• Endocrine disturbances Comorbidity

• Cardiovascular disease

• Pulmonary function

• Obesity

• Anemia

• Endocrine disturbances Lymphoma related factors

• Lymphoma type

• Stage

• Treatment

Lymphoma related factors

• Lymphoma type

• Stage

• Treatment

Life style

• Physical actvity

• Smoking Life style

• Physical actvity

• Smoking Psychosocial factors

• Depression/mental distress

• Personality/neurotcism Psychosocial factors

• Depression/mental distress

• Personality/neurotcism Demographic factors

• Age

• Income

• Marrital status Demographic factors

• Age

• Income

• Marrital status

Pro-inflammatory cytokines

IL-6, IL-1β, IL1-RA, TNF-α ++

Pro-inflammatory cytokines

IL-6, IL-1β, IL1-RA, TNF-α ++

Significant associatons in multvariate analysis ¹

1. Smeland, Bone Marrow Transplant 2018

Total burden of late effects after HDT- ASCT for lymphoma by CTCAE criteria

1. Mild; asymptomatic or mild symptoms; clinical or diagnostic observations only; intervention not

indicated

2. Moderate: minimal/noninvasive intervention

indicated; limiting age-appropriate instrumental ADL 3. Severe: or medically significant but not immediately

life-threatening; disabling; limiting self care ADL

4. Life-threatening consequences; urgent intervention indicated

5. Death

Lung function impairment

Hypertension

Peripharal neuropathy

Cardiac disease Thyroid dysfunction

Gonadal dysfunction

Osteoporosis

Second cancer

Renal impairment (eGFR) Hyperglycaemia/DM

Stroke

Increased BMI

Hypercholesterolaemia

Anaemia 0

10 20 30 40 50 60

Grade 2 or more severe somatc AEs

%

Majority of patients have multiple

moderate or more sever somatic AHOs

0 1 2 3 4 5 6 7 8

0 5 10 15 20 25 30

Number of grade 2 or more late effects (of 13)

%

Conclusions

• Many lymphoma patients with otherwise poor

prognosis are cured with HDT-ASCT and are today survivors

• Increased risk of several potentially serious late effects, most are mild or moderate

• No excess mortality after 10 years

• New and valuable knowledge for patient counseling and planning of follow-up care

– Identified high risk groups possibly in need of closer follow-up

• Insight into possible etiological and pathophysiological mechanisms

Acknowledgement!

• Participating survivors

• PI and supervisor Cecilie E Kiserud

• Co-supervisors, coauthors and collaborators

• Funding:

– Helse Sør-Øst – Kreftforeningen

– Radiumhospitalets legater