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 Table of Contents  
CLINICAL GUIDELINE
Year : 2019  |  Volume : 7  |  Issue : 3  |  Page : 195-201

Hodgkin's lymphoma: Saudi Lymphoma Group's clinical practice guidelines for diagnosis, management and follow-up


1 Adult Hematology and Stem Cell Transplantation Department, King Fahad Specialist Hospital, Dammam, Saudi Arabia
2 Oncology Department, Prince Sultan Military Medical City, Riyadh, Saudi Arabia; Clinical Oncology Department, Cairo University, Giza, Egypt
3 Department of Oncology, King Abdulaziz Medical City, Ministry of National Guard Health Affairs-Central Region, Riyadh, Saudi Arabia
4 Department of Adult Hematology and BMT, Comprehensive Cancer Center, King Fahad Medical City, Riyadh, Saudi Arabia
5 Oncology Institute, John Hopkins Aramco Healthcare, Dhahran, Saudi Arabia
6 Department of Medicine, College of Medicine, King Saud University, Riyadh, Saudi Arabia
7 Department of Oncology, King Faisal Specialist Hospital and Research Centre, Jeddah; College of Medicine, Alfaisal University, Riyadh, Saudi Arabia
8 College of Medicine, King Saud Bin Abdulaziz University for Health Sciences; Adult Medical Oncology, Princess Noorah Oncology Center, King Abdulaziz Medical City, Ministry of National Guard Health Affairs-Western Region, Jeddah, Saudi Arabia

Date of Submission24-Mar-2019
Date of Decision15-May-2019
Date of Acceptance24-Jul-2019
Date of Web Publication28-Aug-2019

Correspondence Address:
Dr. Mubarak Al-Mansour
College of Medicine, Adult Medical Oncology, Princess Noorah Oncology Center, King Abdulaziz Medical City, Ministry of National Guard Health Affairs-Western Region, PO Box 9515, Jeddah 21423
Saudi Arabia
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DOI: 10.4103/sjmms.sjmms_96_19

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How to cite this article:
Alhashmi H, Kandil M, Alhejazi A, Motabi I, Sagheir A, Alzahrani M, Dada R, Al-Mansour M. Hodgkin's lymphoma: Saudi Lymphoma Group's clinical practice guidelines for diagnosis, management and follow-up. Saudi J Med Med Sci 2019;7:195-201

How to cite this URL:
Alhashmi H, Kandil M, Alhejazi A, Motabi I, Sagheir A, Alzahrani M, Dada R, Al-Mansour M. Hodgkin's lymphoma: Saudi Lymphoma Group's clinical practice guidelines for diagnosis, management and follow-up. Saudi J Med Med Sci [serial online] 2019 [cited 2019 Sep 20];7:195-201. Available from: http://www.sjmms.net/text.asp?2019/7/3/195/265661




  Introduction Top


Hodgkin's lymphoma (HL) is a rare B-cell malignancy involving lymph nodes and the lymphatic system. It accounts for 3.6% of all cancers in Saudi Arabia, with 436 new cases in 2015. In HL, there is a slight male predominance, and it is the seventh and eight most common cancer among Saudi males and females, respectively. In 2015, the age-standardized rate was 2.6/100,000 for males and 1.7/100,000 for females. In addition, the median age at diagnosis was 26 years in both genders (range among males: 3–84 years; females: 4–89 years).[1]


  Methods Top


A committee comprising experts in hematology and medical oncology was established under the supervision of the Saudi Lymphoma Group and in collaboration with the Saudi Oncology Society. For collecting evidence, a literature search was carried out with relevant keywords using online database search engines such as PubMed/Medline, Web of Science and Scopus. In addition, expert opinion was considered when necessary. The levels of evidence used in developing this guideline were as follows:

  • Evidence level (EL)-1 (highest), evidence from Phase III randomized trials or meta-analyses
  • EL-2 (intermediate), evidence from well-designed Phase II trials or Phase III trials with limitations
  • EL-3 (low), evidence from retrospective or observational studies/reports and/or expert opinion.


This easy-to-follow grading system is convenient for readers to understand and allows an accurate assessment of the guideline's applicability in individual patients.[2]

1. DIAGNOSIS AND WORK-UP

1.1. The diagnostic work up for HL patients has evolved since the introduction of positron emission tomography-computed tomography (PET/CT) scanning. In patients undergoing PET/CT evaluation, a bone marrow biopsy is not indicated. However, if PET/CT is not available, bone marrow biopsy should be carried out in patients with advanced stage disease, B-symptoms and/or abnormal complete blood count (CBC) (EL-1)[3],[4],[5]

1.2. A diagnostic assessment based solely on fine needle aspiration is insufficient (EL-3)[6],[7],[8]

1.3. Before initiating treatment, cardiac and pulmonary function tests should be carried out to identify patients at increased risk of acute or chronic complications. In addition, young patients should be offered reproductive counseling before the treatment is initiated, as chemo-and radiotherapy can permanently impair fertility

1.4. Summary of the diagnostic work-up (EL-1).[3],[4],[5],[9],[10]

1.4.1. Evaluations should include complete history and physical examination

1.4.2. Excisional biopsy is the optimal method for diagnosis

1.4.3. Laboratory evaluations of all patients should comprise CBC, renal and liver profile, albumin, as well as routine blood chemistry including lactate dehydrogenase and erythrocyte sedimentation rate

1.4.4. Bone marrow biopsy is recommended if PET is not available for patients with advanced stage disease, B-symptoms and/or abnormal CBC

1.4.5. Pregnancy test should be done for women of childbearing age

1.4.6. Patients should be screened for hepatitis B, hepatitis C and human immunodeficiency viruses

1.4.7. Thyroid-stimulating hormone (TSH) test should be carried out if radiation is planned.

1.4.8. PET/CT is the preferred imaging modality

1.4.9. CT scan of neck, chest, abdomen and pelvis (CAP) should be performed in all cases

1.4.10 Cardiac function should be assessed by multigated acquisition scan or 2D echocardiography

1.4.11. Pulmonary function test should be done in all cases.

1.5. Several prognostication models have been developed in the past decades. One of these is the International Prognostic Score (IPS), which is defined as the number of adverse prognostic factors present at diagnosis, with the score ranging from 0 to 7 IPS helps determine the clinical management and predict prognosis for Stages III and IV patients (EL-1).[11] Patients with a score of 0 and ≥5 have a median 5-year survival of 89% and 56%, respectively.

1.5.1. International Prognostic Score for Hodgkin Lymphoma (Stages III and IV)

1.5.1.1Serum albumin <40 g/L

1.5.1.2Hemoglobin <105 g/L

1.5.1.3.Male gender

1.5.1.4.Stage IV disease

1.5.1.5.Age >45 years

1.5.1.6White blood cell count ≥15,000/mm 3

1.5.1.7 Lymphocyte count <600/mm 3 or <8% of white cell count.

2. PATHOLOGICAL DIAGNOSIS

2.1. Excisional biopsy is the preferred method for diagnosis, provided adequate material is obtainable for fresh frozen and formalin-fixed samples. Diagnosis should be in accordance with the World Health Organization classification

2.2. For confirming the diagnosis of classic HL, it is recommended that the immunohistochemistry panel should include CD3, CD15, CD20, CD30, CD45, CD79a and PAX5

2.3. Classic HL and nodular lymphocyte predominant Hodgkin lymphoma (NLPHL) have significantly different malignant cell phenotypes

2.4. In classic HL, malignant cells are positive for CD30 and CD15, occasionally positive for CD20 and negative for CD45, whereas in NLPHL, malignant cells are positive for CD20 and CD45, but negative for CD15 and CD30 (EL-1).[12]

3. STAGING

3.1. There are two practical approaches for staging HL: The North American (United States and Canada) and European (European Organisation for Research and Treatment of Cancer, Germany) approach. We recommend the North American approach, where patients can be classified to limited or advanced disease based on stage, presence/absence of B-symptoms and presence/absence of bulky disease (EL-3)[9],[10],[11]

3.2. Stage: Stages I and II versus Stage III and IV according to the Ann Arbor staging system

3.3. B-symptoms is defined as recurrent unexplained fever of >38°C, recurrent night sweats or unexplained weight loss of ≥10% in the past 6 months

3.4. Bulky disease is defined as having a tumor of diameter ≥10 cm on CT scan.

4. MANAGEMENT OF CLASSICAL HODGKIN'S LYMPHOMA

4.1. Limited Stage I and II (non-bulky and no B-symptoms)

4.1.1. The preferred treatment is a combined therapy of two cycles of doxorubicin, bleomycin, vinblastine and dacarbazine (ABVD) plus 30 Gy of involved-field radiation therapy (ISRT) (EL-1)[13],[14],[15],[16],[17],[18]

4.1.2. ABVD alone is also an effective treatment modality, especially among younger patients (i.e., <60 years old) who achieve complete remission after two cycles, according to the interim PET/CT (Deauville score of 1–3). In these patients, there should only be subsequent one or two cycles of ABVD (i.e., a total of three to four cycles of ABVD) to avoid the long-term risks of radiotherapy (EL-1)[15],[19],[20],[21],[22],[23],[24]

4.1.3. However, if interim PET/CT is positive for residual disease (Deauville score of 4 or 5), it is recommended to complete the planned two cycles of ABVD plus ISRT. If end-of-therapy PET/CT is positive for residual disease, it is recommended to re-biopsy, and if positive, proceed to salvage therapy (EL-1).[15],[19],[25],[26],[27]

4.2. Advanced stage (Stages III or IV, bulky and/or B symptoms)

4.2.1. ABVD is recommended as the preferred first-line therapy. Another option is brentuximab plus adriamycin, vinblastine and dacarbazine (AVD) in selected patients if IPS >4, bleomycin contraindicated, no known neuropathy (EL-1).[13],[26],[27],[28],[29],[30],[31],[32],[33],[34],[35],[36]

4.2.1.1. Two cycles of ABVD should be followed by an interim PET/CT (EL-1)[13]

4.2.1.2. Patients with a negative interim PET/CT (Deauville score of 1–3) should be treated with an additional four cycles of AVD (i.e. a total of six cycles) followed by observation (EL-1)[26]

4.2.1.3. In patients with a positive interim PET/CT (Deauville score of 4–5):

4.1.2.1.3.1. Treat with an additional four cycles of ABVD (i.e. a total of 6 cycles)[26]

4.1.2.1.3.2. An alternative approach is treating with four cycles of escalated BEACOPP with or without ISRT (EL-1).[28],[30],[31]

4.2.1.4. An end-of-therapy PET/CT should be carried out 6–8 weeks after completion of chemotherapy and 8–12 weeks after completion of radiotherapy. For single-site residual disease, the following is recommended (EL-1):[26]

4.2.1.4.1.If PET/CT is negative, observe.

4.2.1.4.2. If PET/CT is positive, a biopsy is recommended if accessible, otherwise ISRT is indicated.

4.2.1.4.3. If the biopsy is negative, observe with or without ISRT

4.2.1.4.4. Patients with a positive biopsy can be managed either with ISRT or as a refractory disease (described in Section 4.3 below).

4.2.1.5. If PET/CT is not available, then a CT scan can be utilized to assess response after three to four cycles. In clinically responding patients, proceed to completing the six cycles of ABVD. However, if there is evidence of disease progression, then consider it as a refractory disease, and proceed with salvage chemotherapy and autologous stem cell transplantation (ASCT)(EL-3).

4.3. Refractory/Relapsed disease

Most patients with HL achieve complete remission and long-term disease control with standard management approach. However, relapse may occur in about 10% of patients with limited HL and in 15%–30% of patients with advanced HL. Approximately 10%–15% of patients may have refractory disease that either does not respond to standard therapy or progresses after an initial partial response (EL-1).[13],[18],[20],[23],[35]

4.3.1. A case of suspected relapse must be confirmed with a new biopsy, and obtaining a new biopsy should be considered in refractory disease

4.3.2. In some patients with a localized late relapse, salvage radiotherapy alone is likely to be sufficient (EL-3)[37]

4.3.3. In most patients with relapsed or refractory HL, the preferred treatment modality comprises platinum-based or brentuximab vedotin-containing regimen followed by high-dose chemotherapy and ASCT (EL-2).[38],[39],[40],[41],[42],[43],[44],[45],[46],[47],[48]

4.3.3.1 Salvage regimens such as GDP (gemcitabine, dexamethasone, and cisplatin);[49] DICEP (dose-intensive cyclophosphamide, etoposide, cisplatin);[42],[43] ESHAP (etoposide, methylprednisolone (solumedrol), high-dose cytarabine (ara-C) and cisplatin (platinum chemotherapy);[50] DHAP (dexamethasone, cytarabine, cisplatin);[40] IGEV (ifosfamide, gemcitabine, and vinorelbine);[41] ICE (ifosamide, carboplatin, and etoposide);[51] B-ICE (brentuximab vedotin plus ifosamide, carboplatin, and etoposide;[52] B-ESHAP (brentuximab vedotin plus etoposide, methylprednisolone (solumedrol), high-dose cytarabine (ara-C) and cisplatin (platinum chemotherapy);[53] BeGEV (bendamustine, gemcitabine and vinorelbine) or BvB (Brentuximab vedotin and bendamustine)[54],[55] have been shown to reduce the disease burden and mobilize stem cells before high-dose chemotherapy and ASCT. However, no comparative trails have shown any salvage approach to be superior than the others (EL-2).

4.3.3.2. Several conditioning regimes such as BEAM (carmustine, etoposide, cytarabine, melphalan) or single agent high-dose melphalan have also been used (EL-3).[39],[45],[46],[47]

4.3.3.3. The use of brentuximab vedotin as maintenance therapy for 1 year after ASCT is highly recommended for high-risk patients (primary refractory, patients who relapsed within 12 months, relapse with extra-nodal disease or pre-transplant positive PET/CT) (EL-2).[44],[48]

4.3.4. Following ASCT, in responding patients found to have localized residual disease on PET, a consolidative radiotherapy to the active site is recommended (EL-3).

4.3.5. Patients who experience a relapse following ASCT have been shown to respond to the following treatment options (EL-2):

3.2.5.1.Brentuximab vedotin [55],[56]

3.2.5.2.Nivolumab [57],[58]

3.2.5.3.Pembrolizumab [59]

3.2.5.4. Allogeneic stem cell transplantation (in young patients with good general condition).[60]

5. MANAGEMENT OF NODULAR LYMPHOCYTE PREDOMINANT HODGKIN LYMPHOMA

NLPHL has a similar natural history to indolent lymphomas. As NLPHL cells consistently express CD20, addition of an anti-CD20 therapy improves treatment efficacy; currently, data provides support for the use of rituximab.[61]

5.1. Limited stage:

5.1.1. Observation is a reasonable option for completely excised lymph node

5.1.2. 30 Gy of ISRT (EL-3)[62]

5.1.3. Two to three cycles of combination chemotherapy (rituximab plus ABVD [R-ABVD], rituximab plus cyclophosphamide, doxorubicin, vincristine and prednisone [R-CHOP] or ABVD) with or without ISRT (EL-3).[62]

5.2. Advance stage:

5.2.1. The preferred option is combination chemotherapy (R-ABVD, R-CHOP or ABVD) for six cycles with or without ISRT (EL-3)[62]

5.2.2. Single-agent rituximab is recommended for patients who are unfit for cytotoxic chemotherapy.[63]

5.3. Relapsed (EL-3):[63],[64],[65]

5.3.1. A case of NLPHL relapse must be confirmed by a new biopsy before initiating salvage therapy to exclude transformation to aggressive non-HL

5.3.2. Individualized treatment should be considered because the natural history of the disease is variable

5.3.3. Localized NLPHL relapses can effectively be treated with rituximab with or without ISRT

5.3.4. Advanced disease at relapse often requires a more aggressive salvage therapy including high-dose chemotherapy and ASCT

5.3.5. Observation is a reasonable option for select asymptomatic patients.

6. TREATMENT RESPONSE EVALUATION AND LONG-TERM FOLLOW UP (EL-3)

6.1. The preferred imaging modality for assessing the response to therapy is PET/CT. This is typically first (“interim”) done after the initial two cycles of chemotherapy and 6–8 weeks after completing chemotherapy/ASCT or 8–12 weeks after completing radiotherapy. After completion of treatment, follow-up assessments are mainly focused on monitoring for recurrence and late side effects. In long-term survivors, the most serious late side effects are secondary cancers, hypothyroidism, cardiovascular diseases and fertility issues. The incidence of these late side effects is directly proportional to the duration of follow-up; nonetheless, the current treatment protocols are likely to have lesser side effects compared with those used >10 years ago. However, it is recommended that patients are encouraged to seek counseling regarding survivorship, long-term treatment effects, health habits and psychosocial issues.

6.1.1. The follow-up schedule after achieving remission:

6.1.1.1.1 Every 3 months for 2 years, then every 6 months for 3 years, and then annually

6.1.1.1.2. History and physical examination should be documented in every visit

6.1.1.1.3. CBC with differential count, erythrocyte sedimentation rate and LFT should be requested in every visit

6.1.1.1.4. TSH test should be carried out at least once annually if the patient received radiotherapy to the neck

6.1.1.1.5. Annual influenza immunization is recommended

6.1.1.1.6. Chest X-ray should be performed at each visit in the first 2 years, and then at every other visit, especially for patients who previously had intrathoracic disease

6.1.1.1.7. Mammogram or MRI of breast is required for women who received chest radiotherapy, beginning 10 years after diagnosis of lymphoma or when aged 40 years, whichever comes first

6.1.1.1.8.  Pap smear More Details is recommended.

Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflicts of interest.



 
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