hodgkin's%20lymphoma
HODGKIN'S LYMPHOMA

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 histological classification, anatomical stage & 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 & to see if additional treatment is needed

Pharmacotherapy

Standard Chemotherapeutic Regimens

  • ABVD (Doxorubicin, Bleomycin, Vinblastine, & Dacarbazine) 
    • Considered the gold standard for the treatment of limited & advanced Hodgkin's lymphoma
    • Developed as an alternative to Mechlorethamine, Vincristine, Procarbazine, & Prednisone (MOPP) regimen; with lesser adverse events
  • Brentuximab vedotin + AVD (Doxorubicin, Vinblastine, Dacarbazine)
  • BEACOPP (Bleomycin, Etoposide, Doxorubicin, Cyclophosphamide, Vincristine, Procarbazine, & 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, & 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, & 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, & 5-year progression-free survival is comparable to ABVD

Other Chemotherapeutic Regimens

  • MOPP (Mechlorethamine, Vincristine, Procarbazine, & 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 & better results were seen with combined-modality therapies than in radiation therapy alone

Combined Modality Therapy  

  • Initial treatment with 2 cycles ABVD is recommended for patients with no bulky disease, ≤2 nodal disease sites, erythrocyte sedimentation rate (ESR) <50 & no extralymphatic lesions, followed by restaging with PET-CT
    • Patients with Deauville scores of 1-3 may subsequently be given a dose of involved-site radiation therapy (ISRT) (20 Gy)
    • For patients with Deauville score of 4 consider additional 2 cycles of ABVD (total of 4) then have PET/CT prior to ISRT (30 Gy)
    • For Deauville 5 patients, biopsy is recommended; when negative additional 2 cycles of ABVD is considered followed by PET/CT then ISRT (30 Gy); if positive manage the patient as having refractory disease
  • For other patients with no bulky disease, 2 cycles of ABVD are given followed by restaging with PET-CT
    • Deauville 1-2: Additional 1 cycle of ABVD; Deauville 3: Additional 2 cycles of ABVD; Deauville 1-3 with ISRT (30 Gy)
    • Deauville 4: Either 2 additional ABVD cycles (total of 4) or 2 cycles of escalated-dose BEACOPP prior to PET/CT restaging
      • Deauville 1-3: Either ISRT alone or in combination with additional 2 ABVD cycles or additional 2 cycles of escalated-dose BEACOPP
      • Deauville 4-5: Biopsy is done; if negative manage as Deauville 1-3 & if positive manage the patient as having refractory disease
    • Deauville 5 managed as either
      • Biopsy: If negative, 2 cycles of dose-escalated BEACOPP or 2 cycles of ABVD; if positive, manage the patient as having refractory disease OR
      • Administer 2 cycles of dose-escalated BEACOPP then restage with PET/CT
        • For patients with Deauville 1-3, it is recommended to have either ISRT alone or additional 2 cycles of escalated-dose BEACOPP (total of 4) with or without ISRT
        • For Deauville 4-5, biopsy is done; if negative manage as Deauville 1-3 & 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
    • VEPEMB (Vinblastine, Cyclophosphamide, Prednisolone, Procarbazine, Etoposide, Mitoxantrone & Bleomycin) with or without 30 Gy ISRT

Chemotherapy Alone

  • Initial treatment is administration of 2 ABVD cycles followed by PET/CT restaging
    • Deauville 1 or 2 patients may have additional 1 to 2 cycles of ABVD (total of 3 or 4) or 4 cycles of AVD
    • For patients with Deauville 3, additional 2 cycles of ABVD (total of 4) may be given or 4 cycles of AVD
    • In Deauville 4 it is recommended to have 2 additional ABVD cycles or 2 cycles of dose-escalated BEACOPP then restage with PET/CT
      • Deauville 1-3: Additional 2 cycles of ABVD or additional 2 cycles of BEACOPP with or without ISRT or ISRT alone
      • Deauville 4-5: Biopsy is done; if negative should be manage as Deauville 1-3; if positive manage the patient as having refractory disease
    • Deauville 5 may undergo biopsy; if negative, administer 2 cycles of dose-escalated BEACOPP or 2 cycles of ABVD; if positive manage the patient as having refractory disease
      • Alternatively, may give 2 cycles of dose-escalated BEACOPP prior to restaging by PET/CT; Deauville 1-3 will have additional 2 cycles of escalated BEACOPP (total of 4) with or without ISRT or ISRT alone; Deauville 4-5 biopsy is done; if negative manage as described in Deauville 1-3 & if positive manage as refractory disease

Unfavorable Stage I/II Classic Hodgkin Lymphoma (Non-bulky)

Combined Modality Therapy 

  • Initial treatment with 2 cycles of ABVD is recommended, followed by interim reassessment with PET/CT scan
    • Patients with Deauville scores of 1-2 may subsequently be given a dose of ISRT & additional 2 cycles of ABVD (total of 4)
    • Deauville 3-4 patients may be given 2 additional cycles of ABVD (preferred for Deauville 3) or 2 cycles of dose-escalated BEACOPP (preferred for Deauville 4), together with ISRT (30 Gy) after PET/CT
    • For Deauville 5 patients biopsy is recommended; if negative, see treatment for Deauville 3-4; if positive, treat as refractory disease
  • One of the treatment options is initial treatment with 2 cycles of dose-escalated BEACOPP & 2 cycles of ABVD, followed by assessment with PET/CT after completion of chemotherapy
    • Deauville 1-4 patients may subsequently have ISRT
    • For Deauville 5 patients biopsy is recommended & ISRT is given if negative; if positive, treat as refractory disease
  • Initial treatment with 2 cycles of dose-escalated BEACOPP, followed by ABVD & involved-field radiation therapy (IFRT) may improve tumor control & progression-free survival
    • Significant outcome improvements were seen in CHL patients with unfavorable prognosis that were given 2 cycles of dose-escalated BEACOPP
  • 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
    • 6 cycles of PVAG (Prednisone, Vinblastine, Doxorubicin & Gemcitabine) with or without 30 Gy ISRT
    • 6 cycles of VEPEMB with or without 30 Gy ISRT

Chemotherapy Alone 

  • Please see favorable stage IA/IIA CHL section

Unfavorable Stage I/II CHL (Bulky) 

  • Patients with bulky mediastinal disease or >10 cm adenopathy
  • Initial treatment with 2 cycles of ABVD is recommended, followed by interim reassessment with PET/CT
    • Patients with Deauville score 1-3 may subsequently be given additional 2 cycles of ABVD or 4 cycles of AVD with or without ISRT
    • Deauville 4 patients may have 2 cycles of ABVD or 2 cycles of dose-escalated BEACOPP with post PET-CT assessment & ISRT (30 Gy)
    • Deauville 4 patients may also have 3 cycles of dose-escalated BEACOPP with post PET-CT assessment then 1 cycle of dose-escalated BEACOPP
    • For Deauville 5 patients biopsy is recommended & when the result is negative will have the Deauville 4 treatment regimen; if positive treat as refractory disease
      • May also be given 2 cycles of dose-escalated BEACOPP with post PET-CT assessment then ISRT
  • A treatment option is initial treatment with Stanford V for 12 weeks, followed by ISRT then restaged with PET/CT after completion of chemotherapy
    • Deauville 1-4 patients may subsequently have ISRT to initial sites that are >5 cm (30-36 Gy starts optimally within 2-3 weeks)
    • For Deauville 5 patients biopsy is recommended, & ISRT is given if negative
  • Another treatment option is initial treatment with 2 cycles of dose-escalated BEACOPP & 2 cycles of ABVD followed by assessment by PET/CT after completion of chemotherapy
    • Deauville 1-4 patients may subsequently have ISRT
    • For Deauville 5 patients biopsy is recommended, & ISRT is given if negative

Stage III/IV Classic Hodgkin Lymphoma (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 patients, 2 cycles of dose-escalated BEACOPP or 2 cycles of ABVD are given then restaged with PET/CT; for Deauville 5 patients, 2 cycles of dose-escalated BEACOPP are given then restaged with PET/CT; if biopsy is performed, treat using Deauville 4 therapy if negative & treat as refractory disease if positive
      • Deauville 1-3 to continue therapy with additional 2 cycles of ABVD or dose-escalated BEACOPP with or without ISRT to initially bulky or selected PET-positive sites
      • Deauville 4-5 biopsy is recommended, & therapy for Deauville 1-3 is given if negative, while if positive treat as refractory disease
  • In selected patients with IPS ≥4 & 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 or 2 cycles of ABVD or AVD with ISRT to initially bulky or PET-positive sites
    • Additional 2 cycles of dose-escalated BEACOPP are recommended for patients with Deauville score 4 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 with ISRT to initially bulky or PET-positive sites
      • For positive biopsy of patients with  Deauville 4-5, manage it as a refractory disease
    • Biopsy is done in patients with Deauville score 5, if negative 4 cycles of dose-escalated BEACOPP with or without ISRT to initially bulky or PET-positive sites is recommended, while if positive, treat 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 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 & for patients that scored Deauville 3-4, observation or ISRT to PET-positive sites is given; Deauville 1-2 patients are followed up & Deauville 5 patients are managed as refractory disease
  • Use of MOPP regimen has been discouraged in the past years due to increasing cases of male infertility & myelodysplasia in patients
  • For patients >60 years old, regimens are:
    • 2 cycles of ABVD followed by 4 cycles of AVD. Then PET/CT is done & if it is negative additional 2 cycles of ABVD
    • Brentuximab vedotin with Dacarbazine
    • 6 cycles of CHOP with or without 30 Gy ISRT
    • 6 cycles of PVAG (Prednisone, Vinblastine, Doxorubicin & Gemcitabine) with or without 30 Gy ISRT
    • 6 cycles of VEPEMB 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 & 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 & stage IA/IIA bulky or non-contiguous disease
  • Chemotherapy (ie ABVD, CHOP, CVP) & 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 & 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) & 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, & 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, & high-dose chemotherapy then autologous stem cell transplantation (ASCT) 
  • High-dose chemotherapy with ASCT is recommended for both refractory & 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 & mobilize stem cells prior to high-dose chemotherapy with ASCT

Refractory CHL Disease

  • Second-line chemotherapeutic agents (eg Everolimus, Brentuximab vedotin) may be considered prior to initiation of high-dose chemotherapy with ASCT
  • Involved site radiation therapy 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 involved site radiation therapy or observation with or without ISRT
    • 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 ISRT or ISRT alone
    • Alternatively for Deauville 4 patients, they may be given high-dose chemotherapy with ASCT with or without ISRT 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 & Lenalidomide

Relapsed CHL Disease

  • Observation is advised for patients with negative biopsies
  • Restaging is recommended for patients with a positive biopsy
  • 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
  • ISRT alone may also be considered

Palliative Therapy for 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 & other immunologic complications

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

  • Observation is advised for patients with negative biopsies & asymptomatic patients
  • Second-line therapy including Rituximab or 2nd-line systemic therapy &/or ISRT is recommended for symptomatic patients
  • Rituximab may be given for 2 years as maintenance treatment if previously responsive to this regimen
  • Reevaluation & follow-up biopsy is recommended after treatment & 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 & microtubule disrupting agent
  • Indicated for Hodgkin's lymphoma patients who were unresponsive or with contraindications to ASCT &/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 & 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 & were previously treated with Brentuximab vedotin therapy

Combination Regimens for Refractory or Relapsed Hodgkin's Lymphoma

CHL 

  • 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, & Prednisone) 
  • GCD (Gemcitabine, Carboplatin, Dexamethasone)
  • GEMOX (Gemcitabine, Oxaliplatin)
  • MINE (Etoposide, Ifosfamide, Mesna, Mitoxantrone)
  • Mini-BEAM (Carmustine, Cytarabine, Etoposide, Melphalan)

NLPHL

  • Rituximab + DHAP
  • Rituximab + ESHAP
  • Rituximab + ICE
  • Rituximab + IGEV
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