Hodgkin Lymphoma Treatment Protocols

Treatment protocols for classical Hodgkin lymphoma (HL) are provided below, including treatment for early-stage, advanced-stage, and relapsed/refractory disease.

General guidelines follow. Check specific guidelines for restaging and dosage adjustments for chemotherapy and/or radiation therapy depending on positron-emission tomography (PET) scanning throughout the various regimens.

Management of patients with early-stage favorable HL

Stages IA-IIA:

Regimens that combine chemotherapy and radiation therapy (RT) have replaced RT alone for treatment of early-stage, favorable disease. Involved-site radiation therapy (ISRT) is typically recommended, because high-dose, large-field radiation therapy (LFRT) increases risk for heart disease, pulmonary dysfunction, and secondary cancers.

Stage IA-IIA disease can be treated with the ABVD regimen for up to six cycles, or with the Stanford regimen for two cycles (ie, 8 weeks).

ABVD regimen

• The ABVD regimen includes doxorubicin [Adriamycin], bleomycin, vinblastine, and dacarbazine ^[1]

• Combined modality consisting of doxorubicin 25 mg/m² IV plus bleomycin 10 units/m² IV plus vinblastine 6 mg/m² IV plus dacarbazine 375 mg/m² IV on days 1 and 15; every 28 d generally for two to four cycles; followed by ISRT at a dose of 20-30 Gy (depending on German Hodgkin Study Group [GHSG] criteria)

• Patients with fewer than two disease sites can be safely treated with two cycles of ABVD followed by ISRT; other patients with early-stage favorable HL should receive four cycles ^[2]

• In selected patients with limited-stage, nonbulky HL with early response confirmed by functional imaging, ABVD for six cycles without RT has proved effective and safe. ^[3]

• Imaging studies demonstrating response should be performed before proceeding with radiation therapy

• Changes in therapy due to lack of efficacy must be supported by biopsy results documenting refractory/relapsed disease

Stanford V regimen

The Stanford V regimen includes doxorubicin, vinblastine, mechlorethamine, etoposide, vincristine, bleomycin, and prednisone given in a 28-day cycle, as follows:

• Day 1: mechlorethamine 6 mg/m² IV on day 1 plus

• Days 1 and 15: doxorubicin 25 mg/m² IV and vinblastine 6 mg/m² IV plus

• Days 8 and 22: bleomycin 5 units/m² IV and vincristine 1.4 mg/m² IV (not to exceed 2 mg/dose) plus

• Days 15 and 16: etoposide 60 mg/m² IV plus

• Prednisone 40 mg/m² PO every other day during weeks 1-6 (taper during weeks 7 and 8)

• Follow with ISRT 30 Gy within 3 weeks of chemotherapy completion

Management of patients with early-stage, unfavorable, nonbulky/bulky HL

Stages I-II unfavorable, bulky disease ^{[1, 4, 5, 6]} :

• ABVD regimen for four cycles followed by ISRT or
• Stanford V regimen for three cycles (12 weeks) plus ISRT or
• Escalated BEACOPP for two cycles then ABVD for two cycles plus ISRT

Stages I-II unfavorable, nonbulky disease ^{[1, 4, 6]} :

• ABVD regimen for two cycles (initially with staging and additional ABVD cycles as warranted) or
• Stanford V regimen for two cycles then ABVD for two cycles + ISRT or
• Escalated BEACOPP for two cycles then ABVD for two cycles + ISRT
• ^[4]

ABVD regimen:

• Combined modality consisting of doxorubicin 25 mg/m ² IV plus   bleomycin 10 IU/m ² IV plus   vinblastine 6 mg/m ² IV plus  dacarbazine 375 mg/m ² IV on days 1 and 15; every 28 d for two cycles (for nonbulky disease) or four cycles (bulky) +/- ISRT 30 Gy or systemic chemotherapy with ABVD for six cycles ^{[1, 4]}
• ISRT at 30 Gy should be strongly considered for patients with bulky disease or those exhibiting a slow response to therapy, as confirmed by functional imaging with PET (ie, patients with PET scan–avid disease after four cycles of ABVD)
• Changes in therapy due to lack of efficacy must be supported by biopsy results documenting proven refractory/relapsed disease          

Stanford V regimen:

The Stanford V regimen includes doxorubicin, vinblastine, mechlorethamine, etoposide, vincristine, bleomycin, and prednisone given in a 28-day cycle, as follows ^[5] :

• Day 1: mechlorethamine 6 mg/m² IV on day 1 plus

• Days 1 and 15: doxorubicin 25 mg/m² IV and vinblastine 6 mg/m² IV plus

• Days 8 and 22: bleomycin 5 units/m² IV and vincristine 1.4 mg/m² IV (not to exceed 2 mg/dose) plus

• Days 15 and 16: etoposide 60 mg/m² IV plus

• Prednisone 40 mg/m² PO every other day during weeks 1-10 (taper during weeks 11 and 12)

• Follow within 3 weeks with ISRT 36 Gy in patients with stage 1-2 bulky mediastinal disease or bulky disease >10 cm; for nonbulky disease, use ISRT 30-36 Gy based upon presence of B symptoms

Escalated BEACOPP:

Escalated BEACOPP comprises bleomycin, etoposide, doxorubicin, cyclophosphamide, vincristine [Oncovin], procarbazine, and prednisone in a combined-modality 21-day cycle consisting of the following:

• Day 1: Cyclophosphamide 1,200 mg/m² PO plus doxorubicin 35 mg/m² IV plus

• Days 1-3: etoposide 200 mg/m² IV plus

• Days 1-7: procarbazine 100 mg/m² PO plus

• Days 1-14: prednisone 40 mg PO plus

• Day 8: vincristine 1.4 mg/m² IV (not to exceed 2 mg/dose) plus bleomycin 10 mg/m² IV, follow by

• Two 28-day cycles of ABVD and then ISRT

Management of patients with advanced-stage HL

Stages III-IV:

• ABVD for up to six cycles +/- ISRT ^[7]  or

• Stanford V for three cycles (12 weeks) if International Prognostic Score (IPS) < 3, +/- ISRT

• Patients with advanced HL and IPS ≥4 should be treated with dose-escalated BEACOPP (bleomycin, etoposide, doxorubicin, cyclophosphamide, vincristine, procarbazine, and prednisone) for four cycles, followed by either four standard doses of BEACOPP (bleomycin 10 units/m² IV on day 8 plus  etoposide 100 mg/m² IV on days 1-3 plus  doxorubicin 25 mg/m² IV on day 1 plus cyclophosphamide 650 mg/m² IV on day 1 plus  vincristine 1.4 mg/m² IV [not to exceed 2 mg/dose] on day 8 plus procarbazine 100 mg/m² PO on days 1-7 plus  prednisone 40 mg/m² PO on days 1-14; every 21 d) if early responders ^[8] OR

• For slow responders, administer four additional dose-escalated BEACOPP (bleomycin 10 units/m² IV on day 8 plus  etoposide 200 mg/m² IV on days 1-3 plus  doxorubicin 35 mg/m² IV on day 1 plus  cyclophosphamide 1200 mg/m² IV on day 1 plus  vincristine 1.4 mg/m² IV [not to exceed 2 mg/dose] on day 8 plus  procarbazine 100 mg/m² PO on days 1-7 plus  prednisone 40 mg/m² PO on days 1-14; every 21d) ^[8]

• ISRT should be strongly considered following any of the above chemotherapy regimens for patients with bulky disease or those exhibiting a slow response to therapy by functional imaging (PET scan)

• Changes in therapy due to lack of efficacy must be supported by biopsy results documenting refractory/relapsed disease

Previously untreated stage III-IV classical HL:

• Brentuximab vedotin plus AVD is indicated as first-line therapy for previously untreated stage III-IV classical HL ^[9]
• Brentuximab 1.2 mg/kg IV (not to exceed 120 mg/dose) plus doxorubicin 25 mg/m ² IV plus vinblastine 6 mg/m ² IV plus dacarbazine 375 mg/m ² IV on days 1 and 15 of each 28-day cycle for up to 6 cycles

Treatment recommendations for relapsed/refractory HL

See the list below:

• It has been estimated that approximately 20-30% of patients with HL do not achieve a long-term remission with front-line chemotherapy

• Salvage therapy followed by high-dose chemotherapy and autologous stem cell transplantation (HDC-ASCT) can cure approximately 50% of patients (see below) ^[10]

• Based on the British Columbia data, the best timing for HDC-ASCT is after the first relapse ^[11]

Regimens for patients eligible for HDC-ASCT (treatment goal = cure):

• Many regimens are used in the treatment of patients with relapsed/refractory diffuse large B-cell lymphoma (DLBCL); these are primarily based on chemotherapy agents non–cross-resistant to those used in the front-line setting, with or without rituximab

• The goal of salvage regimens is to achieve maximum tumor burden cytoreduction in preparation for HDC-ASCT ^[12]

• ICE regimen (ifosfamide, carboplatin, and etoposide) ^[13] : Ifosfamide 5 g/m² IV on day 2 plus carboplatin area under the curve (AUC) 5 (not to exceed 800 mg/dose) on day 1 plus  etoposide 100 mg/m² IV daily on days 1-3; every 14 d for two cycles (see the Carboplatin AUC Dose Calculation [Calvert formula] calculator)

• DHAP regimen (high-dose cytarabine [Ara-C], cisplatin, and dexamethasone) ^[14] : Dexamethasone 40 mg on days 1-4 plus cytarabine at 2 g/m² IV every 12 h for two doses on day 2, plus cisplatin 100 mg/m² IV on day 1; every 21 days for two cycles

• ESHAP regimen (etoposide, methylprednisolone, Ara-C, and cisplatin) ^[15] : Etoposide 40 mg/m²/day IV plus methylprednisolone 500 mg/day IV plus  cisplatin at 25 mg/m²/day continuous IV infusion for 4 d plus  cytarabine 2 g/m² on day 5; every 21-28 d for three cycles (transplant candidate)

Regimens for patients who are not eligible for HDC-ASCT or patients who have relapsed/refractory disease after HDC-ASCT

Unfortunately, patients who are not eligible for HDC-ASCT or in whom HDC-ASCT has failed remain a challenge for the treating oncologist, pointing to the need for novel therapeutic strategies. Second-line therapies include the following ^[16] :

• Brentuximab vedotin ^{[17, 18]} : 1.8 mg/kg IV infused over 30 min q3wk; continue treatment, not to exceed 16 cycles, or until disease progression or unacceptable toxicity

• Nivolumab is indicated for classical HL that has relapsed or progressed after ASCT and post-transplantation brentuximab vedotin ^{[19, 20]}

• Nivolumab dosage is 240 mg IV q2wk or 480 mg q4wk over 30 min until disease progression or unacceptable toxicity

• Pembrolizumab is indicated for adult and pediatric patients with refractory classical HL or who have relapsed after 3 or more prior lines of therapy ^[21]

• Pembrolizumab dosage is 200 mg IV q3wk or 400 mg IV q6wk until disease progression or unacceptable toxicity (for up to 24 months) ^[23]

• Everolimus 10 mg PO once daily

• C-MOPP (cyclophosphamide, vincristine, procarbazine, prednisone): cyclophosphamide 650 mg/m² plus vincristine 1.4 mg/m² (not to exceed 2 mg/dose) on day 1 plus procarbazine 100 mg/m²/day PO on days 1-7 plus prednisone 40 mg/m²/day PO on days 1-14; every 28 d

• ESHAP (etoposide, methylprednisolone, Ara-C, and cisplatin) ^[15] : Etoposide 40 mg/m²/day IV plus methylprednisolone 500 mg/day IV plus cisplatin 25 mg/m²/day continuous IV infusion on days 1-4 plus cytarabine 2 g/m² on day 5; every 21-28 d for six cycles (nontransplant candidate)

• GCD (gemcitabine, carboplatin, dexamethasone): gemcitabine 1000 mg/m² IV on days 1 and 8 plus carboplatin AUC 5 IV on day 1 plus dexamethasone 40 mg/day PO on days 1-4

• GVD (gemcitabine, vinorelbine, liposomal doxorubicin): vinorelbine 20 mg/m² IV plus gemcitabine 1000 mg/m² IV plus doxorubicin liposomal 15 mg/m² IV on days 1 and 8; every 21d for 2-6 cycles

• IGEV (ifosfamide, gemcitabine, vinorelbine): 2000 mg/m² IV plus mesna 2600 mg/m² IV plus gemcitabine 800 mg/m² on days 1-4 plus vinorelbine 20 mg/m² on day 1

• Mini-BEAM (carmustine, cytarabine, etoposide, melphalan): carmustine 60 mg/m² on day 1 plus etoposide 75 mg/m²/day IV plus cytarabine 100 mg/m² q12h on days 2-5 plus melphalan 30 mg/m² IV on day 6; every 4-6 weeks

• MINE (etoposide, ifosfamide, mesna, mitoxantrone): ifosfamide 1.33 g/m²/day IV plus mesna 1.33 g/m²/day IV (with ifosfamide), then mesna 500 mg PO 4 hr after each ifosfamide dose plus etoposide 65 mg/m²/day IV on days 1-3 plus mitoxantrone 8 mg/m² IV on day 1

• Histone deacetylase inhibitors, ^[22] immunomodulatory drugs, and adoptive cell transfer are therapeutic strategies with promising antitumor activity in heavily pretreated patients with HL

• Referral of patients with relapsed/refractory HL is mandatory to further improve the clinical outcome of such patients.

Third-line therapies ^[16]

• Bendamustine in patients who have failed HDT/ASCR or at least 2 prior multiagent chemotherapy regimens: 120 mg/m2 on days 1-2; every 28d for up to 6 cycles

• Lenalidomide: 25 mg PO once daily on days 1-21; every 28d