Treatment modalities of non-Hodgkin lymphoma patients over 65 years of age: A two-center experience

Abstract

Objective

This study was conducted with the aim of making the contribution to a decision for treatment and determination of the modalities in patients diagnosed with non-Hodgkın lymphoma which increasingly become widespread in the geriatric population.

Materials and methods

Ninety-one patients aged over 65 years diagnosed with lymphoma and treated in Bezmialem Vakıf University Medical Faculty Hospital and Haseki Training and Research Hospital between 2008 and 2013 were retrospectively evaluated. Finally, 63 patients for whom data could be reached were included in the study.

Results

Examining the results, histological diagnoses of our patients were as follows: diffuse large B-cell lymphoma (50.8%), follicular lymphoma (23.8%), marginal zone lymphoma (12.7%), mantle cell lymphoma (4.8%), T-cell lymphoma (4.8%), lymphoplasmacytic lymphoma (1.6%) and small lymphocytic lymphoma (1.6%). Stages at the time of diagnosis were early stage by 33.3% and late stage by 66.7%. Of the patients, 36.5% had a low-intermediate and 63.5% a high-intermediate International Prognostic Index score. According to the Eastern Cooperative Oncology Group scoring, 34.9% of the patients have an Eastern Cooperative Oncology Group score of 2–4. Activities of daily living score of 33.3% patients was under 5. Looking at the responses to treatment, the complete response was found in 50.8%, partial response in 4.8%, stable disease in 1.6% and progressive disease in 9.5% of the patients. The mean follow-up duration of patients was found as 25.2 months and disease-free survival after remission as 20.2 months.

Conclusion

We found that we have achieved a complete remission in more than half of our patients (50.8%). Based on this, treatment should aim remission in elderly patients.

Keywords

Geriatric population non-Hodgkin lymphoma retrospective two-center experience

Introduction

Life expectancy is gradually increasing with the increase in the number of persons aged over 80 by 250% between 1960 and 2000.¹ As a result, among the increasing cases of non-Hodgkin lymphomas (NHL), more than 35% of newly diagnosed people are over 70 years of age.²

Although presentation and prognostic factors are similar between young and elderly patients, the prognosis of the disease is poorer in geriatric patients because of comorbidities, multiorgan failure, changes in drug metabolism and frequently encountered immunoblastic variant and EBV associated forms that are indicators or ABC genotype which is known as a poor prognostic factor.^3–5

Recently, several studies are performed because of the increasing incidence of NHL and lack of a gold standard treatment algorithm in this patient group.^6,7 For standardization of these studies, some scales have been used to determine performance status of patients. Karnofsky score and the Eastern Cooperative Oncology Group (ECOG) scale are the leading scales for this purpose. Today, because ECOG and Karnofsky scoring systems are not enough in determining the treatment protocols, comprehensive geriatric assessment (CGA) which is one of the new scoring systems has been introduced in geriatric patients.

This study was conducted with the aim of making a contribution to the decision for treatment and determination of the modalities in patients diagnosed with NHL which increasingly become widespread in the geriatric population. We assessed the decision of treatment according to our patients’ performance, chemotherapy doses, clinical outcomes and the prognostic value of clinical and biological parameters.

Materials and methods

In this study, 345 patients (251 NHL, 94 Hodgkin lymphoma) diagnosed with lymphoma and treated in Bezmialem Vakıf University Medical Faculty Hospital and Haseki Training and Research Hospital, the Department of Haematology, between 2008 and 2013 were retrospectively evaluated. Among these, 91 patients were found aged over 65 years. Finally, 63 patients (34 male, 29 female) whom data could be reached were included in the study. Patients’ age, gender, histologic type, ECOG performance score, activities of daily living (ADL) score, CGA score, Ann Arbor staging and IPI (International Prognostic Index) values were evaluated. Additionally, patients’ laboratory outcomes at admission (haemoglobin, neutrophil, platelet counts, sedimentation rate, albumin, creatinine, LDH, IgG, IgA, IgM, B2 microglobulin levels) were recorded. Radiological findings, the presence of splenomegaly, the presence of B symptom and clinical findings, left ventricular ejection fraction, the presence of bone marrow and extranodal involvement, treatment modalities and response to treatment and complications that have been developed during treatment were assessed. The study was conducted in accordance with the ethical principles of the 1975 Declaration of Helsinki, and a local approval from the committee on human investigation was obtained.

Results

Our patients aged between 65 and 89 years. The mean age was found as 73.9. Patients were classified according to The National Comprehensive Cancer Network (NCCN) as young old aged 65–74, old aged 75–84 and old–old aged 85 years and over.⁸ Accordingly, 35 of the patients were young old, 22 old and 6 old–old. Of these, 46% were female and 54% were male patients. Clinical and laboratory features of our patients are summarized in Table 1.

Table 1.

Clinical and laboratory features.

Clinical and laboratory features	%
Mean age	73.9
Age groups
Young old (65–74)	35
Old (74–85)	22
Old–old (>85)	6
Gender (F/M)	29/34 (46%/54%)
Histological diagnosis
Diffuse large B-cell lymphoma	32 (50.8%)
Follicular lymphoma	15 (23.8%)
Marginal zone lymphoma	8 (12.7%)
Mantle cell lymphoma	3 (4.8%)
T-cell lymphoma	3 (4.8%)
Small lymphocytic lymphoma	1 (1.6%)
Lymphoplasmacytic lymphoma	1 (1.6%)
Ann Arbor staging
Early stage (1–2)	21 (33.3%)
Late stage (3–4)	42 (66.7%)
ECOG
0–1	41 (65.1%)
2–4	22 (34.9%)
IPI
Low intermediate	23 (36.5%)
High intermediate	40 (63.5%)
ADL
≥5	42 (66.7%)
<5	21 (33.3%)
CGA
Fit	23 (36.5%)
Unfit	25 (39.7%)
Frail	15 (23.8%)
Extranodal involvement
Yes	40 (63.5%)
No	23 (36.5%)
Bone marrow involvement^a
Yes	17 (44.7%)
No	21 (55.3%)
Splenomegaly
Yes	22 (34.9%)
No	41 (65.1%)
B symptom
Yes	16 (25.4%)
No	47 (74.6%)
Comorbidity
Yes	37 (58.7%)
No	26 (41.3%)
Cardiac performance
EF < 50%	5 (7.9%)
EF > 50%	58 (92.1%)
Neutrophil
>1.500/mm³	60 (95.2%)
<1.500/mm³	3 (4.8%)
Hemoglobin
>12–13.5 mg/dl^b	16 (25.4%)
<12–13.5 mg/dl	47 (74.6%)
Platelet
>100,000 mm³	57 (90.5%)
<100,000 mm³	6 (9.5%)
Albumin
>3.5 g/dl	41 (65.1%)
<3.5 g/dl	22 (34.9%)
Beta 2 microglobulin^c
<3 mg/dl	18 (47.3%)
>3 mg/dl	20 (52.7%)
LDH
<225 U/l	30 (47.6%)
>225 U/l	33 (52.4%)
GFR
<50 ml/min	6 (9.5%)
>50 ml/min	57 (90.5%)
Treatment
CHOP	10 (15.9%)
R-CHOP	36 (57.1%)
Splenectomy	2 (3.2%)
Chlorambucil	2 (3.2%)
Others^d	13 (20.6%)
Complication
Yes	14 (22.2%)
No	49 (77.8%)
R-CHOP complication
Fever	1 (2.7%)
Febrile neutropenia	5 (13.8%)
Tumor lysis syndrome	1 (2.7%)
Viral hepatitis	2 (5.5%)
Gastrointestinal bleeding	1 (2.7%)
Sweet syndrome	1 (2.7%)
Acute myocardial infarction	1 (2.7%)
CHOP complication
Acute renal failure	1 (10%)
Heart failure	1 (10%)
Treatment response^e
Complete response	32 (50.8%)
Partial response	3 (4.8%)
Stabile disease	1 (1.6%)
Progressive disease	6 (9.5%)

GFR: glomerular filtration rate; EF: ejection fraction; CGA: comprehensive geriatric assessment; ADL: activities of daily living; IPI: International Prognostic Index; ECOG: Eastern Cooperative Oncology Group; CHOP: cyclophosphamide+doxorubicin+vincristine+prednisone; R-CHOP: rituximab+cyclophosphamide+doxorubicin+vincristine+prednisone.

Bone marrow biopsy could not be performed in 25 patients due to various reasons. Staging was made according to PET\CT outcomes in these patients.

Hgb level was taken as 12 mg/dl for female and 13.5 mg/dl for male patients.

Beta 2 microglobulin levels could not be studied in 25 patients.

Unmedicated follow-up, cyclophosphamide + prednisone, radiotherapy, R+P,R-GEMOX, FC, FUFA.

Eight patients are currently under follow-up. 13 patients did not come to control and could not be reached.

Examining the results, histological diagnoses of our patients were as follows: diffuse large B-cell lymphoma (DBBHL) (50.8%), follicular lymphoma (FL) (23.8%), marginal zone lymphoma (12.7%), mantle cell lymphoma (4.8%), T-cell lymphoma (4.8%), lymphoplasmacytic lymphoma (1.6%) and small lymphocytic lymphoma (SLL) (1.6%). Stages at the time of diagnosis were early stage (stages 1–2) by 33.3% and late stage (stages 3–4) by 66.7%. The rate of patients presented with B symptom was found as 25.4%, bone marrow as 44.7% and extranodal involvement as 63.5%. Of the patients, 36.5% had a low-intermediate and 63.5% had a high-intermediate IPI scores. Of the patients, 58.7% had comorbidities (hypertension, ischemic heart disease, diabetes mellitus, chronic obstructive pulmonary disease, hepatic cirrhosis, epilepsy and cerebrovascular disease). Of the patients, 9.5% had a secondary malignancy (larynx ca, bladder ca, breast ca, prostate ca, the basal cell ca, lung ca). Cardiac performance of the patients was evaluated through left ventricular ejection fraction (EF) with 92.1% of the patients had an EF higher than 50%.

In order to determine performance status of the patients, we used ECOG, ADL and CGA scoring systems. According to the ECOG scoring, 34.9% of the patients had an ECOG score of 2–4. ADL score was under 5 in 33.3% of the patients. According to the CGA classification, 36.5% of the patients were classified as ‘fit’, 39.7% as ‘unfit’ and 23.8% as ‘frail’.

When laboratory outcomes were analysed, we found that neutrophil and platelet counts, albumin and glomerular filtration rate (GFR) were mostly (90%) within the normal range. Levels of LDH and Beta 2 globulin were increased in 52.4% and 52.7% of the patients, respectively. Haemoglobin values were under 12 mg/dl in women and 13.5 mg/dl in men in 74.6% of the patients.

Of the patients, 57.1% had received R-CHOP (rituximab+cyclophosphamide+doxorubicin+vincristine+prednisone), 15.9% CHOP (cyclophosphamide+doxorubicin+vincristine+prednisone) and 3.2% chlorambucil treatment protocols, while 4.8% had received no treatment and followed up. Of the patients, 15.9% had received cyclophosphamide+prednisolone, radiotherapy (RT), RP (radiotherapy+prednisolone), R-GEMOX (gemcitabine+oxaliplatin ± rituximab), FC (fludarabine + cyclophosphamide) and FUFA (5 fluorouracil/leucovorin) treatment protocols. Of the patients, 3.2% had undergone splenenctomy.

Fever, febrile neutropenia, tumor lysis syndrome, viral hepatitis, gastrointestinal bleeding, sweet syndrome and acute myocardial infarction were observed in 12 of 36 patients receiving R-CHOP. Acute renal failure and heart failure were observed in 2 of 10 patients receiving CHOP.

Thirteen of the 36 patients who had RCHOP had side effects such as esophagitis, diarrhea, neuropathy emesis and constipation. Neuropathy and emesis were observed in 2 of 10 patients receiving CHOP.

Looking at the responses to treatment, the complete response was found in 50.8%, partial response in 4.8%, stable disease in 1.6% and progressive disease in 9.5% of the patients.

The mean follow-up duration of patients was found as 25.2 months (2–75 months) and disease-free survival after remission as 20.2 months (1–73 months). Of the patients, 79.4% are currently followed up in our clinic, while 20.6% were lost during the follow-up.

Discussion

NHL is a malignant disease which essentially may also be originated from the B and T lymphocytes and extranodal organs.⁹ The incidence of NHL is gradually increasing. Although its aetiology is not fully understood; genetic, environmental and infectious factors have been associated with the development of lymphomas. The median age of patients with NHL has raised to 65. Its incidence increases with age and peaks in 80–84 age group.¹⁰ Non-Hodgkin lymphoma is more commonly seen in the male population and in our study also rate of male patients was higher than female patients at about 54%.¹¹

The median age of our patients was found as 73.9. The most common three types of NHL in the USA are in order of DBBHL (31%), FL (22%) and SLL/chronic lymphocytic leukaemia (CLL) (6%).¹²

Similarly, in our study DBBHL (50.8%) was at the first range followed by FL (23.8%). Marginal Zone Lymphoma was found in eight (12.7%) patients, mantle cell lymphoma in three (4.8%) patients, T-cell lymphoma in three (4.8%) patients, small lymphocytic lymphoma in one (1.6%) patient and lymphoplasmocytic lymphoma in one (1.6%) patient.

We used ECOG, ADL and CGA scoring systems to determine performance status for patients. In a retrospective analysis of DBBCL patients aged over 80, ADL score was found to be much more successful in demonstrating overall survival (OS) and progression-free survival (PFS) than ECOG and PFS,¹³ whereas CGA score is recently recommended as a more comprehensive and useful method compared to the other methods in classification of patients in order to determine tolerability in newly diagnosed NHL patients.¹⁴

CGA scale categorises patients into three classes: ‘fit’ group – having no grade 3 comorbidity (or having <3 grade 2 comorbidity), patients with ADL score 6, ‘unfit’ group – having no grade 3 comorbidity (or having 3–5 grade 2 comorbidity), patients with ADL score 5 or 6, ‘frail’ group – having one or more grade 3 comorbidity (or having >5 grade 2 comorbidity), patients with ADL score <5.¹⁵

According to the CGA classification, 36.5% of the patients were classified as ‘fit’, 39.7% as ‘unfit’ and 23.8% as ‘frail’. Based on CGA, 3 (15%) of 20 fit patients, 3 (14.3%) of unfit patients and 5 (38.5.%) of 13 frail patients were excluded in our study.

Our patients’ prognostic factors were evaluated with IPI. In NHL patients, IPI is a worldwide recognized parameter in prediction of prognosis.¹⁶ In addition to clinical staging; IPI has been developed considering age, performance status, number of areas with extranodal involvement and LDL level. Studies about NHL show that prognostic factors other than IPI including histologic type, advanced clinical stage, low performance status, advanced age (>60), presence of more than two extranodal involvements, presence of B symptoms and bone marrow involvement, bulky mass, high LDL and elevated Beta 2 microglobulin are indicators of possibly poor prognosis.¹⁷

In addition to these factors, we also studied admission values of haemoglobin, neutrophil, platelet count, sedimentation rate, albumin, creatinine, IgG, IgA and IgM levels as well as the presence of splenomegaly and left ventricular ejection fraction. Based on the results, elevation of LDL was demonstrated to decrease survival of patients (p = 0.017).

Stages at the time of admission were found as early stage (stages 1–2) in 33.3% and late stage (stages 3–4) in 66.7% of the patients. Complete remission occurred in 61.9% of 21 patients with early stage and in 50% of patients with advanced stage. Although the advanced stage is a poor prognostic indicator, our results were not significant because of the limited number of our patients.

Looking at the treatment decisions made following this classification, the mean follow-up time was found as 25.2 months (2–75 months) and disease-free survival after remission as 20.2 months (1–73 months).

In the present study, 36 patients (57.1%) received R-CHOP, 10 patients (15.9%) CHOP, 3 patients (4.8%) RCHOP+RT, 2 patients (3.2%) splenectomy, 2 patients (3.2%) rituximab + prednol, 2 patients (3.2%) chlorambucil, 2 patients (3.2%) RT and the other patients received cyclophosphamide+ prednisolone, FUFA and FC treatment modalities.

Today, CHOP chemotherapy is widely used as the first treatment regimen in ‘high-grade’ NHL treatment. It has been demonstrated in some recent studies that CHOP regimen with reducing the number of cycles combined with RT prolongs the overall survival, especially in patients at early stage. With adding rituximab to the CHOP cycle which consists of nine cures, better results were achieved in elderly patients having DBBH aggressive lymphoma. Especially, R-CHOP regimen has been established as the gold standard treatment regimen by Groupe d’Etude des Lymphomes de l’Adulte (GELA) NHL trial (GELA LNH-98-5).¹⁸

Decreased hepatic and renal function and changed distribution ratio of water and fat in the body with ageing require a dose adjustment and if given at a normal dose, the incidence of side effects increases. Among these effects, mucositis, myelosuppression and cardiotoxicity are commonly encountered.¹⁹

Furthermore, these patients may be negatively affected by interactions of multi-drugs used because of frequently seen comorbidities. In the present study, we initiated the treatment with a full dose in 34.9%, 75% dose in 7.5% and half dose in 11.1% of the patients. As a result, no any side effect was seen in 68.3%, while emesis was found in 9.5% and neutropenia in 7.9% of the patients. The other rare adverse effects included neuropathy, esophagitis and constipation. Filgrastim injection was administered in 52 (82.5%) patients as neutropenia prophylaxis.

Remission was achieved in 50.8% of the patients. Although studies conducted on patients with DBBHL have proposed a direct correlation between age and several biological features that have negative prognostic significance, previously reported evidence and data confirm that clinical indicators, histological features and reactions to treatment in elderly patients having aggressive B-NHL are recorded as similar to that of young patients.^20,21

Conclusion

Treatment should aim remission in elderly patients (considering proper performance, comorbidities, dose adjustment). Data regarding NHL treatment in geriatric patients are limited. Therefore, we believe that further prospective studies are warranted about treatment options.

Footnotes

Declaration of Conflicting Interests

The author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

Ethical approval

All procedures performed in studies involving human participants were in accordance with the ethical standards of the institutional and/or national research committee and with the 1975 Helsinki Declaration and its later amendments or comparable ethical standards. This article does not contain any studies with animals performed by any of the authors.

Funding

The author(s) received no financial support for the research, authorship, and/or publication of this article.

Informed Consent

Informed consent was obtained from all individual participants included in the study.

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