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.

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

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
  • BEACOPP (Bleomycin, Etoposide, Doxorubicin, Cyclophosphamide, Vincristine, Procarbazine, & Prednisone) 
    • Developed by the German Hodgkin’s Lymphoma Study Groups (GHSG) as an alternative to Doxorubicin, Bleomycin, Vinblastine, & Dacarbazine (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
  • CHOP (Cyclophosphamide, Doxorubicin, Vincristine, Prednisone) 
    • Variant of Mechlorethamine, Vincristine, Procarbazine, & Prednisone (MOPP), replacing Mechlorethamine to avoid its toxic effects (severe nausea/vomiting, bone marrow depression)
  • CVP (Cyclophosphamide, Vincristine, Prednisone) 
    • Another hybrid of Mechlorethamine, Vincristine, Procarbazine, & Prednisone (MOPP) with reduced risk for infertility, secondary neoplasms, cardiac/lung toxicities used for patients with early stage or advanced disease
  • 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)
    • Standard combination from which other chemotherapeutic combinations were derived
    • Clinical response was reported at 80%, with cure rate of 50% in advanced-stage patients
  • 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 Mechlorethamine, Doxorubicin, Vinblastine, Vincristine, Bleomycin, Etoposide, & Prednisone (Stanford V) on overall response rate, overall survival, & 5-yr PFS is comparable to Doxorubicin, Bleomycin, Vinblastine, & Dacarbazine (ABVD)

Recommended Treatment Regimens

Favorable Stage IA/IIA Classic Hodgkin's Lymphoma (CHL)

  • Lower relapse rates & better results were seen with combined-modality therapies than in radiation therapy alone
  • Initial treatment with 2 cycles  Doxorubicin, Bleomycin, Vinblastine, & Dacarbazine (ABVD) is recommended for patients with no bulky disease, <3 disease sites, erythrocyte sedimentation rate (ESR) <50 & no E-lesions, followed by restaging with positron emission tomography (PET)
    • Patients with Deauville scores of 1-4 may subsequently be given a dose of involved-site radiation therapy (ISRT)
    • Involved-site radiation therapy (ISRT) is recommended for biopsy-negative Deauville 5 patients
  • Patients with no bulky disease, <4 disease sites, ESR <50 & with or without E-lesions may be given either 2 or 3 cycles of ABVD, or Stanford V, followed by restaging with positron emission tomography (PET)
    • Patients previously given 3 cycles of Doxorubicin, Bleomycin, Vinblastine, & Dacarbazine (ABVD) is further restaged with the following treatment recommendations:
      • Deauville 1-2: observation or 1 cycle of Doxorubicin, Bleomycin, Vinblastine, & Dacarbazine (ABVD); Deauvillle 3-4: 1 cycle of Doxorubicin, Bleomycin, Vinblastine, & Dacarbazine (ABVD) with involved-site radiation therapy (ISRT)
      • Deauville 5: biopsy is recommended, & 1 cycle of Doxorubicin, Bleomycin, Vinblastine, & Dacarbazine (ABVD) with involved-site radiation therapy (ISRT) if negative
    • Patients previously given 2 cycles of Doxorubicin, Bleomycin, Vinblastine, & Dacarbazine (ABVD) is further restaged with the following treatment recommendations:
      • Patients with Deauville 1-2 may be given 2 cycles of Doxorubicin, Bleomycin, Vinblastine, & Dacarbazine (ABVD) plus involved-site radiation therapy (ISRT); Deauvillle 3-4 may be given 2 cycles of dose-escalated BEACOPP with involved-site radiation therapy (ISRT) or 2 cycles of Doxorubicin, Bleomycin, Vinblastine, & Dacarbazine (ABVD) with involved-site radiation therapy (ISRT)
      • For patients with Deauville 5, biopsy is recommended, & 2 cycles of Doxorubicin, Bleomycin, Vinblastine, & Dacarbazine (ABVD) with involved-site radiation therapy (ISRT) if negative
    • Involved-site radiation therapy (ISRT) is recommended for Deauville 1-4 & biopsy-negative Deauville 5 patients previously given Stanford V
  • Mechlorethamine, Doxorubicin, Vinblastine, Vincristine, Bleomycin, Etoposide, & Prednisone (Stanford V) is an alternative to Doxorubicin, Bleomycin, Vinblastine, & Dacarbazine (ABVD) for the management of early-stage Hodgkin's lymphoma, with lesser chemotherapy-related adverse events such as infertility, cardiac toxicities, pulmonary diseases & growth of new tumors

Unfavorable Stage I/II Classic Hodgkin's Lymphoma (CHL)

  • Combined-modality therapy is preferred
  • Initial treatment with 4 cycles of Doxorubicin, Bleomycin, Vinblastine, & Dacarbazine (ABVD) is recommended, followed by restaging with positron emission tomography (PET) scan
    • Patients with Deauville scores of 1-3 may subsequently be given a dose of involved-site radiation therapy (ISRT) &/or additional 2 cycles of Doxorubicin, Bleomycin, Vinblastine, & Dacarbazine (ABVD)
    • Deauville 4 patients may be given 2 additional cycles of Doxorubicin, Bleomycin, Vinblastine, & Dacarbazine (ABVD), together with involved-site radiation therapy (ISRT)
    • Additional 2 Doxorubicin, Bleomycin, Vinblastine, & Dacarbazine (ABVD) cycles may be administered in patients with Deauville 5 scores if follow-up biopsy was negative
  • Mechlorethamine, Doxorubicin, Vinblastine, Vincristine, Bleomycin, Etoposide, & Prednisone (Stanford V) or 2 cycles of dose-escalated Bleomycin, Etoposide, Doxorubicin, Cyclophosphamide, Vincristine, Procarbazine, & Prednisone (BEACOPP) plus involved-site radiation therapy (ISRT) for patients <60 yr of age are effective treatment options for patients unresponsive or intolerant to Doxorubicin, Bleomycin, Vinblastine, & Dacarbazine (ABVD) regimen
    • Studies have shown that Mechlorethamine, Doxorubicin, Vinblastine, Vincristine, Bleomycin, Etoposide, & Prednisone (Stanford V) regimen exhibited high efficacy against locally extensive & advanced Hodgkin's lymphoma when given concomitantly with involved-field radiation therapy (IFRT)
  • Three cycles of Mechlorethamine, Doxorubicin, Vinblastine, Vincristine, Bleomycin, Etoposide, & Prednisone (Stanford V) followed by involved-site radiation therapy (ISRT) is suggested for patients with bulky mediastinal disease or bulky disease >10 cm with B symptoms, & for patients with non-bulky disease
    • Restaging should be done after completion of Mechlorethamine, Doxorubicin, Vinblastine, Vincristine, Bleomycin, Etoposide, & Prednisone (Stanford V) cycles
  • Initial treatment with 2 cycles of Bleomycin, Etoposide, Doxorubicin, Cyclophosphamide, Vincristine, Procarbazine, & Prednisone (BEACOPP), followed by Doxorubicin, Bleomycin, Vinblastine, & Dacarbazine (ABVD) & involved-field radiation therapy (IFRT) may improve tumor control & progression-free survival
    • Significant outcome improvements were seen in classic Hodgkin's lymphoma (CHL) patients with unfavorable prognosis that were given 2 cycles of escalated Bleomycin, Etoposide, Doxorubicin, Cyclophosphamide, Vincristine, Procarbazine, & Prednisone (BEACOPP)

Stage III/IV Classic Hodgkin's Lymphoma (CHL)

  • Initial treatment with 2 cycles of Doxorubicin, Bleomycin, Vinblastine, & Dacarbazine (ABVD) is recommended, followed by restaging with positron emission tomography (PET) scan
    • Patients with Deauville scores of 1-3 may subsequently be given a dose of involved-site radiation therapy (ISRT) &/or additional 4 cycles of Doxorubicin, Bleomycin, Vinblastine, & Dacarbazine (ABVD)
    • For Deauville 4-5 patients, additional 4 cycles of Doxorubicin, Bleomycin, Vinblastine, & Dacarbazine (ABVD) is recommended
    • Addition of 4 cycles of escalated Bleomycin, Etoposide, Doxorubicin, Cyclophosphamide, Vincristine, Procarbazine, & Prednisone (BEACOPP) may help improve outcome in patients with Deauville score of 4-5
    • Studies have shown that patients given Doxorubicin, Bleomycin, Vinblastine, & Dacarbazine (ABVD) or Mechlorethamine, Vincristine, Procarbazine, & Prednisone (MOPP)/Doxorubicin, Bleomycin, Vinblastine, & Dacarbazine  (ABVD) therapies presented with 45-50% progression free survival rates & 65% overall survival rates
  • Dose-escalated Bleomycin, Etoposide, Doxorubicin, Cyclophosphamide, Vincristine, Procarbazine, & Prednisone (BEACOPP) & Mechlorethamine, Doxorubicin, Vinblastine, Vincristine, Bleomycin, Etoposide, & Prednisone (Stanford V) are effective alternative regimens
    • Three cycles of Mechlorethamine, Doxorubicin, Vinblastine, Vincristine, Bleomycin, Etoposide, & Prednisone (Stanford V) or 6 cycles of dose-escalated Bleomycin, Etoposide, Doxorubicin, Cyclophosphamide, Vincristine, Procarbazine, & Prednisone (BEACOPP) are recommended treatment alternatives, followed by restaging after completion of treatment regimen
    • Involved-site radiation therapy (ISRT) may be given to positron emission tomography (PET)-positive sites of patients with Deauville score of 1-3 with bulky disease, Deauville 4 with positron emission tomography (PET)-positive sites, & for Deauville 4-5 patients with negative biopsies & bulky disease
  • Use of Mechlorethamine, Vincristine, Procarbazine, & Prednisone (MOPP) regimen has been discouraged in the past years due to increasing cases of male infertility & myelodysplasia in patients

Nodular Lymphocyte-Predominant Hodgkin Lymphoma (NLPHL) 

  • Chemotherapy [ie Doxorubicin, Bleomycin, Vinblastine, & Dacarbazine (ABVD), Cyclophosphamide, Doxorubicin, Vincristine, Prednisone (CHOP), Cyclophosphamide, Vincristine, Prednisone (CVP)] plus radiation therapy, with or without Rituximab is recommended for patients with stage IB/IIB & stage IA/IIA bulky disease
  • Chemotherapy [ie Doxorubicin, Bleomycin, Vinblastine, & Dacarbazine (ABVD), Cyclophosphamide, Doxorubicin, Vincristine, Prednisone (CHOP), Cyclophosphamide, Vincristine, Prednisone (CVP)] with or without radiation therapy, with or without Rituximab is recommended for all patients with stage III-IV nodular lymphocyte-predominant Hodgkin's lymphoma (NLPHL)
  • Initial treatment with 2 cycles of Doxorubicin, Bleomycin, Vinblastine, & Dacarbazine (ABVD) is recommended, followed by restaging with positron emission tomography (PET) scan
    • Patients with Deauville scores of 1-3 may subsequently be given a dose of involved-site radiation therapy (ISRT) &/or additional 4 cycles of Doxorubicin, Bleomycin, Vinblastine, & Dacarbazine (ABVD)
    • For Deauville 4-5 patients, additional 4 cycles of Doxorubicin, Bleomycin, Vinblastine, & Dacarbazine (ABVD) is recommended
    • Addition of 4 cycles of escalated Bleomycin, Etoposide, Doxorubicin, Cyclophosphamide, Vincristine, Procarbazine, & Prednisone (BEACOPP) may help improve outcome in patients with Deauville score of 4-5
  • Dose-escalated Bleomycin, Etoposide, Doxorubicin, Cyclophosphamide, Vincristine, Procarbazine, & Prednisone (BEACOPP) & Mechlorethamine, Doxorubicin, Vinblastine, Vincristine, Bleomycin, Etoposide, & Prednisone (Stanford V) (Stanford V) are effective alternative regimens
  • Rituximab with or without chemotherapeutic regimens has been considered in various clinical studies as an alternative treatment, since nodular lymphocyte-predominant Hodgkin's lymphoma (NLPHL) cells express CD20 antigens
    • Some patients can be given Rituximab monotherapy as maintenance if proven responsive to this regimen

Refractory/Relapsed Disease

  • Confirmatory biopsy should be obtained prior to initiation of therapy
  • Positron emission tomography-computed tomography (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 month

Treatment

  • High-dose chemotherapy with autologous stem cell transplantation (ASCT) is recommended for both refractory & relapsed classic Hodgkin's lymphoma
  • Conventional chemotherapy is recommended for patients previously treated with radiotherapy for early-stage Hodgkin's lymphoma
  • 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)
  • For patients who achieved complete remission with completed chemotherapy but later on experienced recurrence, high-dose chemotherapy plus autologous stem cell transplantation (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 autologous stem cell transplantation (ASCT)

Refractory Classic Hodgkin's Lymphoma (CHL) Disease

  • Second-line chemotherapeutic agents (eg Everolimus, Brentuximab vedotin) may be considered prior to initiation of high-dose chemotherapy with autologous stem cell transplantation (ASCT)
  • Involved site radiation therapy may be given if areas with relapse that have no history of irradiation
  • A Deauville score of 1-3 may prompt treatment with high-dose chemotherapeutic agents with autologous stem cell transplantation (ASCT) with or without involved site radiation therapy
  • Patients with Deauville scores of 4-5 may be given additional 2nd-line therapy
  • Re-evaluation of Deauville score should be done to assess response to 2nd-line treatment
  • Third-line agents used for relapsed/refractory classic Hodgkin's lymphoma include Bendamustine & Lenalidomide

Relapsed Classic Hodgkin's Lymphoma (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 involved-site radiation therapy (ISRT) or high-dose chemotherapeutic agents with autologous stem cell transplantation (ASCT) is preferred for stage IA/IIA classic Hodgkin's lymphoma 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
  • Involved site radiation therapy (ISRT) alone may also be considered

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

  • Observation is advised for patients with negative biopsies & asymptomatic patients
  • Second-line therapy includes Rituximab with or without chemotherapy or involved site radiation therapy 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) 

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 autologous stem cell transplantation (ASCT) &/or 2 chemotherapeutic regimens

Regimens for Relapsed or Refractory Hodgkin's lymphoma

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