Clinical Profile and Outcome of Adult Classical Hodgkin’s Lymphoma: Real World Single Centre Experience

Abstract

Hodgkin’s lymphoma treatment outcomes have been the true success story of modern medicine. Various data from western as well as Indian studies are available for classical Hodgkin’s lymphoma (cHL). Here we report treatment outcomes from a tertiary cancer care centre in Karnataka over a 5 year period. This was a retrospective review of cHL cases aged 15 years and above diagnosed between January 2015 and December 2019 at Kidwai Memorial Institute of Oncology, Bengaluru, Karnataka, India. The case files of the patients were retrieved and relevant data was collected. Two hundred patients of cHL were included in this study. Median age was 28 years with male to female ratio of 1.56:1. B symptoms were present in 58% cases. Mixed cellularity (46.5%) was the most common histological subtype. Majority patients had advanced stage at presentation (stage III/IV) (62.5%). Extranodal disease was present in 19.5% cases. GHSG early-favourable cases were 15.5%, early-unfavourable cases were 22.0%, while 62.5% were advanced cases. The most common chemotherapy regimen used was ABVD. Eighty-three (41.5%) patients received radiation therapy. Median follow-up was 34.2 months (range 4.1–67.8). The rates for complete response (CR), partial response (PR), stable disease (SD) and progressive disease (PD) were 84.5%, 8.5%, 5.0% and 2.0% respectively. PFS and OS rate at 6 years were 69.5% and 84.1% respectively. HL is one of the malignancies with high cure rate. The treatment outcome at our centre is comparable to western data and data from other tertiary centres from India.

Introduction

Hodgkin’s lymphoma (HL) is an uncommon malignancy of B cell origin. It has an incidence of 2–3 per 100,000 individuals per year; affecting most commonly young adults [1]. HL is classified into two major types: classical HL (cHL) and nodular lymphocyte-predominant HL, accounting for 95% and 5% of all HL cases, respectively [2]. Classical HL is further subdivided into four major histological subtypes: nodular sclerosis, lymphocyte-rich, lymphocyte-depleted, and mixed-cellularity [3].

Treatment of Hodgkin’s lymphoma largely depends on the histologic characteristics, the stage of the disease, and the presence or absence of prognostic factors. The goal of treatment for patients with Hodgkin lymphoma is to cure the disease with control of short and long-term complications. During the past few decades, the prognosis of patients with Hodgkin's lymphoma (HL) has improved drastically. This progress has been attributed to a better understanding of the biology of the disease, multi-disciplinary approach to treatment, newer biologic therapies and a risk adapted and PET guided tailoring of treatment as per individual needs [4–8, 31]. Currently, more than 80% of all newly diagnosed patients younger than 60 years of age are likely to be cured of their disease.

The outcome data for HL from developed countries is widely available [9–11]; but there is a paucity of similar data from India with only few studies with small numbers of patients being available, mostly from tertiary cancer centres from Delhi, Chennai, Mumbai and Hyderabad [12–20, 34]. This is the first study from the state of Karnataka, where we have analyzed cHL patients treated at our centre over a period of 5 years.

Material and Methods

This was a retrospective analysis of classical Hodgkin’s lymphoma (cHL) patients who presented to Kidwai Memorial Institute of Oncology, Bengaluru, Karnataka, India, between January 2015 and December 2019.

Case records of the patients were retrieved, reviewed and relevant data was captured including history, physical examination findings and reports of complete blood counts, renal and liver function tests, serum lactate dehydrogenase, erythrocyte sedimentation rate (ESR), viral markers, lymph node (LN) biopsy, immunohistochemistry, CT (Computed tomography)/PET CT(positron emission tomography/ computed tomography), bone marrow biopsy, two-dimensional echo, 12 lead electro-cardiogram, pulmonary function test and diffusing capacity of lung for carbon monoxide (DLCO).

Diagnosis of HL was based on morphological features on the LN biopsy with further confirmation by immunohistochemistry and sub-classification was as per the WHO criteria [21]. Patients were staged according to the modified Ann Arbor staging system and risk-stratified with German Hodgkin’s Study group (GHSG) score and International Prognostic Score (IPS) for early and advanced stage respectively [4, 22]. B symptoms were fever (temperature > 38 °C), drenching night sweats or unexplained loss of more than 10% of body weight within the previous 6 months. A mediastinal mass occupying more than one-third of the thoracic diameter or any LN mass > 10 cm was taken as a bulky disease. Patients with stage I, IIA, and IIB (non-bulky with no extranodal disease) were considered to have early-stage disease. Those with stage IIB (bulky or with extranodal disease), III, and IV disease were considered to have advanced-stage disease [4]. Treatment received, toxicities and responses achieved were captured and analyzed as well as data regarding relapsed/refractory cases.

Patients with early favourable cHL received 2 cycles of chemotherapy followed by involved field radiotherapy (IFRT 20 Gy).

Patients with early unfavourable disease received 4 cycles of chemotherapy followed by 30 Gy IFRT.

Patients with advanced cHL received 6–8 cycles of chemotherapy with radiotherapy (RT) for initial bulky sites and/or residual disease (≥ 2.5 cm). None of the patients received PET guided treatment during this time period.

Patients were assessed for response at the end of 2nd cycle of chemotherapy for early favourable disease, 2nd and 4th cycles for early unfavourable disease and 3rd and 6th cycles for advanced disease.

Response criteria and definitions were as per the 1998 International Workshop report by Cheson et al. [23].

Follow-up data every 3 months for the first 2 years, every 6 months for next 3 years and yearly thereafter of those in complete response (CR) was also captured for survival analysis.

Statistical Analysis

Progression-free survival (PFS) was defined as time from start of treatment until relapse or progressive disease (PD), no CR at the end of first-line treatment, death due to any cause or loss to follow-up with disease. Overall survival (OS) was defined as the time from the diagnosis to the death, loss to follow-up with the disease. Patient characteristics were analyzed using descriptive statistics. Inferential statistics was utilized for prognostic factors using log-rank test and the Kaplan–Meier curve estimated survival. Multivariate Cox regression analysis was done to identify independent predictors. P-values < 0.05 were considered statistically significant. The data has been censored on 31 December 2020. SPSS v.23 (IBM, USA) software is used for the survival curves and prognostic factors.

Results

Patient Characteristics

There were a total of 231 newly diagnosed cHL patients aged 15 years and above during the period January 2015 to December 2019. Of these, only 200 patients had undergone work-up and treatment and therefore were eligible for analysis with the last date of follow up being the 31st of December 2020.

The median age of presentation was 28 years (range: 16–76 years). One hundred and twenty-two patients (61%) were males and male to female ratio was 1.56:1. B symptoms were present in 116 (58.0%) patients. Fifty-five (27.5%) patients had bulky disease at initial presentation. Extranodal disease was present in 39 (19.5%) cases. Mixed cellularity (MC) was the most common histology seen in 93 (46.5%) patients, followed by nodular sclerosis (NS) in 86 (43.0%), lymphocyte rich (LR) in 17 (8.5%) and lymphocyte depleted (LD) in 4 (2.0%) patients. Fifteen (7.5%), 60 (30.0%), 91 (45.5%), and 34 (17.0%) cases were staged as stage I, II, III and IV respectively. Thirty-one (15.5%) patients had early favourable disease, 44 (22.0%) patients had early unfavourable disease, 125 (62.5%) patients had advanced disease. Patient characteristics are shown in Table 1.

Table 1.

Patient characteristics

Patient characteristics	n = 200 (%)
Male: Female	1.56:1
Median age (range)	28 years (range 16–76)
Comorbidities
Hypertension	16
Diabetes	10
Ischemic heart disease	5
Tuberculosis	3
HIV	7
Hepatitis B	3
Bronchial asthma	2
Stage at presentation (%)
Stage I	15/200 (7.5%)
Stage II	60/200 (30.0%)
Stage III	91/200 (45.5%)
Stage IV	34/200 (17.0%)
B-symptoms (%)	116 (58.0%)
HPE subtype (%)
NS	86/200 (43.0%)
MC	93/200 (46.5%)
LR	17/200 (8.5%)
LD	4/200 (2.0%)
Extra-nodal disease (%)	39 (19.5%)
Bone marrow involvement (%)	7 (3.5%)
Bulky disease (%)	55 (27.5%)
Extra-nodal sites (%)
Bone	17 (8.5%)
Lung	13 (6.5%)
Liver	6 (3.0%)
Others	8 (4.0%)
GHSG
Early favourable (%)	31 (15.5%)
Early unfavourable (%)	44 (22.0%)
Advanced (%)	125 (62.5%)

Treatment Characteristics and Response Assessment

All patients received chemotherapy. A total of 190 (95%) patients had received ABVD (adriamycin, bleomycin, vinblastine, and dacarbazine) regimen. Five patients (2.5%), 4 patients (2%), and one patient (0.5%) received AVD (adriamycin, vinblastine and dacarbazine), COPP (cyclophosphamide, vincristine, prednisone and procarbazine), and GVD (gemcitabine, vinorelbine, and doxorubicin) regimens respectively as they were not eligible for anthracycline or bleomycin-based chemotherapy. None of the patients received escalated BEACOPP (bleomycin, etoposide, doxorubicin, cyclophosphamide, vincristine, procarbazine and prednisolone) regimen. Among those treated with chemotherapy, 83 (41.5%) received IFRT subsequently. All patients with early favourable and early unfavourable disease received RT. Eight (4%) patients with advanced disease also received RT for localized residual disease (> 2.5 cm) post chemotherapy. The RT dose ranged from 20 to 45 Gy.

At the end of treatment, response evaluation showed that 169 (84.5%) patients had attained complete response (CR)/complete response unconfirmed (CRu). Seventeen (8.5%) patients had partial response (PR), while 10 (5.0%) had stable disease (SD) and 4 (2.0%) had progressive disease (PD) (Table 2).

Table 2.

Treatment outcome

Outcomes	n = 200 (%)
Treatment response (%)
CR/CRu	169/200 (84.5%)
PR	17/200 (8.5%)
SD	10/200 (5.0%)
PD	4/200 (2.0%)
Median follow-up	34.2 months (range 4.1–67.8 months)
Lost to follow up	13 (4 after 1st line & 9 after 2nd line chemotherapy)
Deaths (%)	33 (16.5%)
Disease progression	22
Acute Myocardial Infarction	2
RTA	1
TB Meningitis	1
HIV assoc. infectious complications	1
Therapy related deaths	6
Progression free survival at 6 years	69.5%
Overall survival at 6 years	84.1%

Forty-four patients received 2nd line chemotherapy post progression or relapse. 33 patients received GDP (gemcitabine, dexamethasone and cisplatin), 8 patients received ICE (ifosfamide, carboplatin and etoposide) and 3 patients received DHAP (dexamethasone, cytarabine and cisplatin) regimen. Among those receiving 2nd line chemotherapy 31 attained CR (70.4%). Only 2 patients underwent ASCT (autologous stem cell transplantation).

Survival Outcomes

The median follow up was 34.2 months (range 4.1–67.8 months). The estimated PFS and OS rate at 6 years were 69.5% and 84.1% respectively. The median PFS and OS were not reached. Thirteen patients were lost to follow up during these 6 years (4 after 1st line and 9 after 2nd line chemotherapy). Total 33 deaths were seen (22-disease progression, 2-AML (acute myeloid leukemia), 1-RTA (road traffic accident), 1-tuberculous meningitis, 1-HIV associated infectious complications, 6-therapy related deaths) (Table 2).

Prognostic Factors

Most important prognostic factor was risk group. The 6-year estimated PFS was significantly different in early favourable (87.1%), early unfavourable (81.8%) and advanced disease (59.2%) (p = 0.005). The 6-year estimated OS was also significantly different in early favourable (96.8%), early unfavourable (90.0%) and advanced disease (78.4%) [p = 0.042] (Figs. 1 and 2).

Fig. 1.

Estimated Progression free survival at 6 years stratifying for GHSG risk groups (p = 0.005)

Fig. 2.

Estimated Overall survival at 6 years stratifying for GHSG risk groups (p = 0.042)

For the other prognostic groups, a significant impact on PFS was seen with age (p = 0.04), extranodal disease (p = 0.01), stage (p = 0.002), histology (p = 0.048) and bulky disease (p = 0.001). The impact on OS was significant with age (p = 0.037), histological subtype (p = 0.039), extranodal disease (p = 0.008), stage (p = 0.013) and bulky disease (p = 0.003). Other factors like gender, B-symptoms, hemoglobin, total leukocyte count and serum albumin had no influence on the PFS (Table 3).

Table 3.

Prognostic factors

Prognostic factors	PFS (log rank test)	OS (log rank test)
Age group (< / ≥ 45 years)	0.04	0.037
Sex (M/F)	0.82	0.98
Stage	0.002	0.013
Histology	0.048	0.039
B-symptoms	0.71	0.62
Extra-nodal disease	0.01	0.008
Bulky disease	0.001	0.003
Hemoglobin (< / ≥ 10.5 g%)	0.71	0.82
Total Leucocyte count (< / ≥ 15,000/cmm)	0.07	0.09
Serum Albumin (< / ≥ 4 g/dl)	0.96	0.83

Statisticlly significant values were written in bold letters

Toxicities and Complications

Grades 3–4 myelosuppression was the most common hematological toxicity (16%) with or without febrile neutropenia in 19 (9.5%). Other toxicities were anaemia (13.5%), thrombocytopenia (14.5%), CINV (chemotherapy induced nausea and vomiting) (18%), and pulmonary toxicity (3.5%). Six (3%) treatment related deaths were seen (4 due to febrile neutropenia and sepsis, and 2 due to bleomycin induced pulmonary fibrosis.

Discussion

This study is a retrospective review of classical Hodgkin’s Lymphoma patients treated at a tertiary cancer care centre in Karnataka. We found that 13% of patients who register in our institute don’t end up undergoing workup and treatment. Varying reasons could be attributed to it, like low literacy rate, low socioeconomic status, lack of awareness, distance from the treatment centre, over-dependence on handful of government medical centres, over-centralization of cancer treatment or delay in diagnostic workup due to resources being over-burdened. At least 6.5% patients were lost to follow-up at different time points after the 1st line of treatment. The loss to follow up could be due to varying reasons like relapse, financial burden, and prolonged unemployment among others.

In the present study, we found that patients had relatively young age at diagnosis, higher frequency of B symptoms, advanced stage at presentation and mixed cellularity as the predominant histologic subtype.

The median age of presentation was lower as compared to western countries, and there was absence of 2nd peak after 50 years, which was also seen in other Indian studies [18, 19]. Higher male to female ratio was seen in our study, which has also been reported in earlier studies from India [17–20].

In the present study, clinical presentation was found to be more or less similar to other studies from India. About 58% of patients had B symptoms at presentation which was similar to an Indian study by Ganesan et al. [19] but higher than that reported from developed countries (≤ 20%) [9, 24]. Bulky disease was present in 27.5% patients and 19.5% patients had extranodal disease which is similar to the study reported by Ganesan et al. [19]. In our study, 46.5% of the patients had mixed cellularity histology, a figure lower than that reported from other developing countries [25, 26] and other studies from India [19, 20]; but higher than Western countries where nodular sclerosis histology predominates (55–60%) [24]. Higher frequency of mixed cellularity subtype has been attributed to higher frequency of Epstein–Barr virus infection [27, 28], even though its prevalence was not assessed in our patients.

Similarly, higher proportion of patients (62.5%) had stage III and IV disease, a figure higher than that reported from US (35%) [SEER data 2001–2005] [9].

In this study, 31(15.5%) patients had early favourable disease, 44 (22.0%) patients had early unfavourable disease, 125 (62.5%) patients had advanced disease which is similar to a multicentric review from India in which 46.65% patients had early stage and 53.35% patients had advanced stage disease [29].

PET–CT is an integral part of evaluation and tailoring of management in Hodgkins’s lymphoma but non availability at our center and more importantly affordability issues have limited its use in this study. We had performed bone marrow biopsy to assess bone marrow involvement which was present in 7 (3.5%) patients. But as we know PET CT has higher sensitivity and accuracy than bone marrow examination for assessing marrow involvement, it is worth mentioning that the numbers would have been different with the use of PET–CT scan.

Higher frequency of B symptoms with a more advanced stage at initial presentation in our study possibly reflects delay in diagnosis, lack of awareness among the primary care physicians, high incidence of tuberculosis (leading to the initial management in many cases of lymphadenopathy with anti-tubercular treatment) and inaccessibility to quality medical care.

ABVD was the most commonly used chemotherapeutic regimen in our centre. Majority (95%) of the patients had received ABVD; 2.5% patients received AVD, 2% patients received COPP and 0.5% of patients received GVD. In a study by Ganesan et al. 84% patients received ABVD, 4.2% received COPP and COPP/AVB and 5% received EVAP (etoposide, vinblastine, doxorubicin and prednisolone) [19].

In this study, 84.5% patients had attained CR/CRu, 17 (8.5%) patients had PR, 10 (5.0%) had SD and 4 (2.0%) had PD. In the study by Ganesan et al. 92% patients attained CR, 4% patients had PR, and 4% had PD [19]. In another study by Maddi et al. CR, PR, SD and PD was documented in 88.7%, 8.9%, 1.3% and 0.9% patients [20].

On analysis, risk group was the most important prognostic factor. The 6-year PFS was significantly different in early favourable (87.1%), early unfavourable (81.8%) and advanced disease (59.2%) [p = 0.005]. The 6-year OS was also significantly different in early favourable (96.8%), early unfavourable (90.0%) and advanced disease (78.4%) [p = 0.042]. In a similar study done by Yadav BS et al. [32], five year disease-free survival (DFS) in patients with early favorable stage, early unfavorable stage, and advanced stage was 91%, 82%, and 73%, respectively.

(P = 0.026) and five year overall survival (OS) was 93%, 92%, and 84%, respectively (P = 0.139). Similar type of results was also reported by Ganesan et al. and Maddi et al. [19, 20].

For the other prognostic groups, the significant influence on PFS and OS was seen with factors such as age, extranodal disease, stage, histology and bulky disease. Factors such as gender, B-symptoms, hemoglobin, total leukocyte count, and serum albumin had no influence on the PFS or OS which could be due to small patient numbers, selection bias, shorter follow-up period, and inclusion of loss to follow up as event. In a study by Nayak et al. [33], stage at presentation, bone marrow involvement, partial response at interim positron emission tomography and international prognosis score (IPS) > 3 were predictors of poor EFS. Comparison of our study with some of the other studies are given in Table 4.

Table 4.

Comparison with previous studies

Parameters	Present study	Maddi et al. [20]	Laskar et al. [17]	US SEER data1 [10]
Study period	2015–2019	1991–2010	1993–1996	2000–2007
N	200	301	179	16,710
Age	28 years (range 16–76)	36 years (range 19–75)	< 15 years- 49%  > 15 years- 50%	42 years (white) 38 years(blacks)
M:F	1.56:1	2.9:1	4:1	1.27:1
Histology	MC-46.5% NS-43%	MC-74.4% NS-13.9%	MC-71% NS-15%	MC-13% NS-59.4%
B-symptoms	58%	75.7%	55%	36%
Stage
I	7.5%	12.3%	31%	19.3%
II	30.0%	22.9%	24%	39.4%
III	45.5%	38.8%	38%	18.7%
IV	17.0%	25.9%	7%	16.8% (unknown 5.8%)
Outcomes	PFS: 69.5%-6 years OS: 84.1%-6 years	PFS: 66.3%-5 years OS: 79.7%-5 years	EFS: 76–88%- 8 years OS: 89–100%-8 years	RSR: 87%-2 years 80%—5 years

SEER Surveillance Epidemiology and End Results, PFS Progression free survival; OS Overall survival, EFS Event free survival, RSR Relative survival risk

In this study, 16% patients developed grade 3–4 myelosuppression, 9.5% patients had febrile neutropenia, 3.5% patients had bleomycin induced pulmonary toxicity and 3% patients died due to treatment related toxicity. Granulocyte colony stimulating factors (GCSF) were administered in 18.5% patients. In a similar study by Maddi et al. grade 3–4 neutropenia occurred in 12.2% patients and 3.9% patients had bleomycin induced pulmonary toxicity [20]. In another study by Yang Liang Boo et al. 5.4% patients developed febrile neutropenia and 3.2% patients had bleomycin induced pulmonary toxicity [30].

In our study, out of 31 patients only 2 patients underwent high dose chemotherapy and autologous HSCT. majority of the patients could not bear the cost of the procedure (21 patients), 5 deemed unfit due to advanced age and comorbidities and 3 patients refused to undergo the procedure.

Limitations of the Study

The present study being a retrospective analysis inherently would have had selection bias. There was only limited use of FDG PET–CT during initial staging work-up and response assessment, which is now a standard of care (only 7.5% of our patients underwent FDG PET–CT scans). In our study, out of 63 patients, only 44 patients received salvage therapy after primary treatment failure and only 2 patients underwent autologous stem cell transplantation which is the standard of care for relapsed/ refractory HL patients. Due to the Covid pandemic, subsequent follow up of these patients could not be documented. So despite such favorable survival outcomes without HSCT it will be difficult to justify to suggest that autologous HSCT can be replaced by conventional chemotherapy.

Conclusions

Hodgkin’s lymphoma is one of the highly curable malignancies. Age > 45 years, histology, advanced stage, extranodal disease and bulky disease were proven to be significant adverse prognostic factors for PFS and OS at 6 years. Response rates, PFS and OS were comparable to available literature. Faster workup and early initiation of treatment, use of PET–CT for staging and for response assessment, reducing treatment delays, more rigorous follow up and patient counseling might further improve outcome.

Abbreviations

cHL

Classical Hodgkin’s lymphoma

CR

Complete response

CRu

Complete response unconfirmed

PR

Partial response

SD

Stable disease

PD

Progressive disease

GHSG

German Hodgkin’s Study group

IPS

International Prognostic Score

ESR

Erythrocyte sedimentation rate

CT

Computed Tomography

FDG

Fluorodeoxyglucose

PET–CT

Positron emission tomography–computed tomography

DLCO

Diffusing capacity of lung for carbon monoxide

IFRT

Involved field radiotherapy

PFS

Progression free survival

OS

Overall survival

MC

Mixed cellularity

NS

Nodular sclerosis

LR

Lymphocyte rich

LD

Lymphocyte depleted

ABVD

Adriamycin, bleomycin, vinblastine, and dacarbazine

AVD

Adriamycin, vinblastine and dacarbazine

COPP

Cyclophosphamide, vincristine, prednisone and procarbazine

GVD

Gemcitabine, vinorelbine and doxorubicin

BEACOPP

Bleomycin, etoposide, doxorubicin, cyclophosphamide, vincristine, procarbazine and prednisolone

GDP

Gemcitabine, dexamethasone and cisplatin

ICE

Ifosfamide, carboplatin and etoposide

DHAP

Dexamethasone, cytarabine and cisplatin

EVAP

Etoposide, vinblastine, doxorubicin and prednisolone

ASCT

Autologous stem cell transplantation

RTA

Road traffic accident

AML

Acute myeloid leukemia

CINV

Chemotherapy induced nausea and vomiting

GCSF

Granulocyte colony stimulating factors

Declarations

Conflict of interest

The authors have no relevant financial or non-financial interests to disclose.