Hodgkin's%20lymphoma Treatment

• 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
• Interim PET scans are prognostic and are now being used to assess need for treatment adaptation (eg use of chemotherapy alone), including treatment escalation and de-escalation

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
    • For patients <60 years old, dose-escalated BEACOPP is the only option
    • 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

• 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