hodgkin's%20lymphoma
HODGKIN'S LYMPHOMA
Treatment Guideline Chart

Hodgkin's lymphoma is a malignancy that arises from germinal center B cell.

Histologically, there is a presence of multinucleated giant cells in a mixed inflammatory background.

It is also known as Hodgkin's disease, Hodgkin lymphoma or Hodgkin disease.

It commonly affects individuals ages 15-30 years old and those 55 years old and above.

The key morphologic characteristics include presence of Reed-Sternberg cells and lymphocyte-predominant cells.

Hodgkin's%20lymphoma Treatment

Principles of Therapy

  • Management is based on the patient's age, gender, family and medical history, histological classification, anatomical stage and prognosis of the disease
  • Treatment should be started as soon as diagnosis has been established to prevent further disease progression
  • Chemotherapy or combined modality therapy is the recommended initial strategy followed by restaging at the completion of chemotherapy to assess treatment response and to see if additional treatment is needed

Pharmacotherapy

Standard Chemotherapeutic Regimens

  • ABVD (Doxorubicin, Bleomycin, Vinblastine, and Dacarbazine) 
    • Considered the gold standard for the treatment of limited and advanced Hodgkin's lymphoma
    • Developed as an alternative to Mechlorethamine, Vincristine, Procarbazine, and Prednisone (MOPP) regimen; with lesser adverse events
  • Brentuximab vedotin + AVD (Doxorubicin, Vinblastine, Dacarbazine)
  • BEACOPP (Bleomycin, Etoposide, Doxorubicin, Cyclophosphamide, Vincristine, Procarbazine, and Prednisone) 
    • Developed by the German Hodgkin Lymphoma Study Groups (GHSG) as an alternative to ABVD therapy, but was associated with more acute toxicities
    • Escalated doses provide lower disease progression rates as compared to the standard dose, and is therefore preferred
    • Doses are increased by increasing the dosage per cycle or by decreasing the intervals per cycle or per drug administration
  • Stanford V (Mechlorethamine, Doxorubicin, Vinblastine, Vincristine, Bleomycin, Etoposide, and Prednisone) 
    • Uses a short but intensive treatment course combined with radiation therapy, providing good outcomes with less toxicities
    • Some studies have shown that the efficacy of Stanford V on overall response rate, overall survival, and 5-year progression-free survival is comparable to ABVD

Other Chemotherapeutic Regimens

  • MOPP (Mechlorethamine, Vincristine, Procarbazine, and Prednisone)
    • The 1st combination therapy used for advanced-stage Hodgkin's lymphoma but use was eventually discouraged due to side effects (eg sterility, leukemia)
    • Clinical response was reported at 80%, with cure rate of 50% in advanced-stage patients
  • CHOP (Cyclophosphamide, Doxorubicin, Vincristine, Prednisone)
    • Variant of MOPP, replacing Mechlorethamine to avoid its toxic effects (severe nausea/vomiting, bone marrow depression)
  • CVP (Cyclophosphamide, Vincristine, Prednisolone)
    • Another hybrid of MOPP with reduced risk for infertility, secondary neoplasms, cardiac/lung toxicities used for patients with early-stage or advanced disease

Recommended Treatment Regimens

Favorable Stage IA/IIA Classic Hodgkin Lymphoma (CHL)

  • Lower relapse rates and better results were seen with combined-modality therapies than in radiation therapy alone
  • Recommended initial treatment for patients with no bulky disease, ≤2 nodal disease sites, ESR <50 and no extralymphatic lesions is administration of 2 ABVD cycles followed by restaging with PET-CT
  • Recommended additional therapy after restaging are as follows:
    • Deauville 1-2 may be given additional 1 cycle of ABVD; Deauville 3: Additional 2 cycles of ABVD; Deauville 1-3 with ISRT (30 Gy)
    • For patients with Deauville 3, additional 4 cycles of ABVD (total of 6) may be given
    • Combined modality therapy using a dose of involved-site radiation therapy (ISRT) at 20 Gy or additional 1 cycle of ABVD with 30 Gy ISRT may be given to patients with Deauville scores of 1-3
    • In Deauville 4, it is recommended to have 2 additional ABVD cycles then restage with PET/CT
      • Additional ISRT is recommended if Deauville 1-3 score is confirmed after restaging
      • For patients with Deauville 4-5 after restaging, biopsy is recommended; if negative should be managed as Deauville 1-3; if positive, manage the patient as having refractory disease
    • Patients with Deauville 5 disease may undergo biopsy; if negative, administer 2 cycles of ABVD; if positive manage the patient as having refractory disease
  • For patients >60 years old, regimens are:
    • 2 cycles of ABVD with or without AVD with 20-30 Gy ISRT (preferred)
    • 4 cycles of CHOP with 30 Gy ISRT

Unfavorable Stage I/IIB CHL (Bulky)

  • Recommended initial treatment for patients with B-symptoms, bulky disease and >10 cm adenopathy is administration of 2 ABVD cycles followed by PET/CT restaging
  • Recommended additional therapy after restaging are as follows:
    • Deauville 1-3 patients may be given additional 4 cycles of AVD or may use combined modality therapy composed of 4 cycles of AVD plus 30 Gy ISRT
    • In Deauville 4-5 patients, it is recommended to give 2 additional cycles of dose-escalated BEACOPP then restage with PET/CT
      • Additional 2 cycles of BEACOPP are recommended if patient is confirmed for Deauville 1-3 after restaging or may use combined modality therapy with 30 Gy ISRT
      • For patients with Deauville 4-5 after restaging, biopsy is recommended; if negative should be managed as Deauville 1-3; if positive, manage the patient as having refractory disease
  • For patients >60 years old, regimens are:
    • 2 cycles of ABVD followed by 4 cycles of AVD if PET scan is negative after 2 cycles of ABVD 
    • Brentuximab vedotin with Dacarbazine
    • Brentuximab vedotin followed by ABVD, conditionally followed by Brentuximab vedotin in responding patients with CR or PR
    • 6 cycles of CHOP with or without 30 Gy ISRT

Stage III/IV CHL

  • Initial treatment with 2 cycles of ABVD is recommended, followed by restaging with PET/CT
    • Patients with Deauville scores of 1-3 may subsequently be given 4 cycles of AVD then observe or give ISRT to initially bulky or selected PET-positive sites
    • For Deauville 4-5 patients, 3 cycles of dose-escalated BEACOPP are given then restaged with PET/CT
      • Patients with Deauville 1-3 score after restaging should continue therapy with additional 1 cycle of dose-escalated BEACOPP with or without ISRT to initially bulky or selected PET-positive sites
      • Patients with Deauville 4-5 score after restaging, biopsy is recommended, and therapy for Deauville 1-3 is given if negative, while if positive, treat as refractory disease
  • In selected patients with IPS ≥4 and age <60 years old, initial 2 cycles of dose-escalated BEACOPP is given followed by restaging assessment with PET/CT
    • For patients with Deauville scores of 1-3, add 2 cycles of dose-escalated BEACOPP (total of 4) or 4 cycles of ABVD
    • Additional 2 cycles of dose-escalated BEACOPP (total of 4) are recommended for patients with Deauville score 4-5 then restage assessment with PET/CT
      • For patients with Deauville 1-3 or 4-5 with negative biopsy, add 2 cycles of dose-escalated BEACOPP (total of 6) with ISRT to initially bulky or PET-positive sites
      • For positive biopsy of patients with  Deauville 4-5, manage it as a refractory disease
  • For select patients in category 2B or category 2A with no known neuropathy, IPS ≥4 or Bleomycin is contraindicated, Brentuximab vedotin with 6 cycles of AVD is recommended, followed by restaging assessment with PET/CT
    • For patients with Deauville scores of 1-5, additional 4 cycles of Brentuximab vedotin with AVD are given but for patients with Deauville score of 5, may consider alternative therapy (eg dose-escalated BEACOPP or any therapy for refractory disease)
    • After the above Brentuximab vedotin with AVD cycle regimens, restaging assessment with PET/CT is done and for patients that scored Deauville 3-4, observation or ISRT to PET-positive sites is given; Deauville 1-2 patients are followed up and Deauville 5 patients are managed as refractory disease
    • For patients with Deauville 1-3, ISRT may be considered to initially bulky or PET-positive sites and strict follow-up should be advised
    • For patients with Deauville 4-5 score after restaging, biopsy is recommended, and therapy for Deauville 1-3 is given if negative, while if positive, treat as refractory disease
  • Use of MOPP regimen has been discouraged in the past years due to increasing cases of male infertility and myelodysplasia in patients
  • For patients >60 years old, regimens are:
    • 2 cycles of ABVD followed by 4 cycles of AVD; additional 2 cycles of ABVD in patients with negative results in PET/CT after 2 cycles
    • Brentuximab vedotin with Dacarbazine
    • Brentuximab vedotin followed by AVD, conditionally followed by Brentuximab vedotin in patients with positive treatment response (partial/complete response)
    • 6 cycles of CHOP with or without 30 Gy ISRT

Nodular Lymphocyte-Predominant Hodgkin Lymphoma (NLPHL) 

  • A separate treatment guideline is presented for NLPHL patients as they have a different disease history and response to therapy than CHL, especially in stages I-II patients
  • For patients with stage IA or IIA contiguous stage non-bulky disease, ISRT (30-36 Gy) is recommended; observation is done in highly selected stage 1A patients with completely excised solitary node
  • Chemotherapy (ie ABVD, CHOP, CVP) plus ISRT with Rituximab are recommended for patients with stage IB/IIB and stage IA/IIA bulky or non-contiguous disease
  • Chemotherapy (ie ABVD, CHOP, CVP) and Rituxumab with or without ISRT or Rituximab alone or local radiation therapy are recommended for all patients with stage III-IV disease
  • After the above primary treatments for the different stages of NLPHL, restaging with PET-CT is done
    • For patients with good response, observe if symptomatic or give ISRT if there is no prior radiation therapy given
    • For patients with stable or progressive disease, biopsy is recommended and if negative continue to observe if asymptomatic; if positive, treat as refractory disease or suspected relapse

Refractory/Relapsed Disease

  • Confirmatory biopsy should be obtained prior to initiation of 2nd-line systemic therapy
  • PET-CT, fluorodeoxyglucose-positron emission tomography (FDG-PET) and gallium-60 may also be used to determine the prognosis of relapsed Hodgkin's lymphoma
  • Relapse rate for patients given radiation therapy for Hodgkin's lymphoma accounts to 30-35%, with occurrence within 3 year after completion of treatment
  • For patients who completed chemotherapy, about 10% develops disease progression or relapse within 3 month after, 15% presents with disease relapse within 12 month of complete remission, and about 15% develops late relapses after complete remission of >12 months

Treatment

  • Indicated for patients who achieved initial complete remission
  • Includes radiotherapy for non-irradiated localized disease, conventional salvage chemotherapy, and high-dose chemotherapy then autologous stem cell transplantation (ASCT) 
  • High-dose chemotherapy with ASCT is recommended for both refractory and relapsed classic Hodgkin lymphoma (CHL)
  • Conventional chemotherapy is recommended for patients previously treated with radiotherapy for early-stage Hodgkin's lymphoma
  • For patients who achieved complete remission with completed chemotherapy but later on experienced recurrence, high-dose chemotherapy plus ASCT is recommended, with 30-65% long-term disease-free survival rates recorded
  • Salvage regimens are recommended to reduce tumor burden and mobilize stem cells prior to high-dose chemotherapy with ASCT

Refractory CHL Disease

  • Second-line chemotherapeutic agents (eg Brentuximab vedotin, Etoposide) may be considered prior to initiation of high-dose chemotherapy with ASCT
  • Involved site radiation therapy (ISRT) may be given to areas with relapse that have no history of irradiation
  • A Deauville score of 1-3 may prompt treatment with high-dose chemotherapeutic agents with ASCT with or without radiotherapy or observation with or without radiotherapy
    • Followed by observation or a year of Brentuximab vedotin maintenance therapy for patients with a high risk for relapse
  • Patients with Deauville scores of 4-5 may be given additional 2nd-line therapy with or without radiotherapy or radiotherapy alone
    • Alternatively for Deauville 4 patients, they may be given high-dose chemotherapy with ASCT with or without radiotherapy followed by a year of Brentuximab vedotin maintenance therapy for patients with a high risk for relapse
  • Re-evaluation of Deauville score should be done to assess response to 2nd-line treatment
  • Third-line agents used for relapsed/refractory CHL include Bendamustine, Everolimus and Lenalidomide

Relapsed CHL Disease

  • Observation is advised for patients with negative biopsies
  • Restaging is recommended for patients with confirmed disease relapse defined by a positive biopsy result
  • Second-line therapy with or without ISRT or high-dose chemotherapeutic agents with ASCT with or without ISRT is preferred for stage IA/IIA CHL patients previously treated with chemotherapy but unresponsive
  • Second-line therapy is recommended for all other stages who were previously treated with monotherapy or combined modality therapy

Palliative Therapy for Refractory/Relapsed CHL Patients >60 Years Old  

  • Treatment is individualized, though clinical trials or monotherapy with a palliative approach is advised  
  • Agents may include Bendamustine, Brentuximab vedotin, Nivolumab, Pembrolizumab or ISRT

Checkpoint Inhibitors (CPI) for Refractory or Relapsed CHL  

  • Recommended for any patients with CHL that have relapsed or progressed after autologous hematopoietic stem cell transplant (HSCT) with or without Brentuximab vedotin
  • Also a treatment option for patients with refractory/relapsed CHL who are not transplant candidates based on comorbidity or failure of 2nd-line chemotherapy
  • Use with caution prior to allogeneic transplantation due to increased risk of graft-versus-host disease and other immunologic complications

Refractory or Relapsed Nodular Lymphocyte-Predominant Hodgkin Lymphoma (NLPHL)

  • Observation is advised for patients with confirmed disease relapse and asymptomatic patients
  • Second-line therapy including Rituximab or 2nd-line systemic therapy and/or ISRT is recommended for symptomatic patients
  • Rituximab may be given for 2 years as maintenance treatment if previously responsive to this regimen
  • Reevaluation and follow-up biopsy is recommended after treatment and if with disease progression despite all treatments
  • Patients with progressive disease should be assessed for disease transformation to diffuse large B-cell lymphoma (DLBCL) 

Monotherapy for Refractory or Relapsed CHL

  • Includes Brentuximab, Bendamustine, Everolimus, Lenalidomide, Nivolumab, Pembrolizumab

Brentuximab vedotin

  • A antibody-drug combination consisting of a CD30 antibody and microtubule disrupting agent
  • Indicated for Hodgkin's lymphoma patients who were unresponsive or with contraindications to ASCT and/or 2 chemotherapeutic regimens

Nivolumab 

  • A human immunoglobulin G4 monoclonal antibody that binds to PD1 receptor to inhibit immune response
  • Treatment option for patients whose disease relapsed or progressed after high-dose chemotherapy/ASCT and Brentuximab vedotin therapy

Pembrolizumab 

  • A human monoclonal PD-1 directed antibody
  • Treatment option for patients with refractory HL, or those who have relapsed after 3 or more prior lines of therapy and were previously treated with Brentuximab vedotin therapy

Combination Regimens for Refractory or Relapsed Hodgkin's Lymphoma

CHL 

  • Bendamustine/Carboplatin/Etoposide 
  • Brentuximab/Bendamustine
  • Brentuximab/Nivolumab 
  • DHAP (Dexamethasone, Cisplatin, high-dose Cytarabine)
  • ESHAP (Etoposide, Methylprednisolone, high-dose Cytarabine, Cisplatin)
  • Gemcitabine/Bendamustine/Vinorelbine
  • GVD (Gemcitabine, Vinorelbine, liposomal Doxorubicin)
  • ICE (Ifosfamide, Carboplatin, Etoposide)
  • IGEV (Ifosfamide, Gemcitabine, Vinorelbine)
  • C-MOPP (Cyclophosphamide, Vincristine, Procarbazine, and Prednisone) 
  • GCD (Gemcitabine, Carboplatin, Dexamethasone)
  • GEMOX (Gemcitabine, Oxaliplatin)
  • MINE (Etoposide, Ifosfamide, Mesna, Mitoxantrone)
  • Mini-BEAM (Carmustine, Cytarabine, Etoposide, Melphalan)

NLPHL

  • Rituximab + Bendamustine 
  • Rituximab + DHAP
  • Rituximab + ESHAP
  • Rituximab + ICE
  • Rituximab + IGEV
  • Other combinations (if not previously used): Rituximab + CHOP, Rituximab + ABVD, Rituximab + CVP
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