jueves, 6 de junio de 2019

Childhood Hodgkin Lymphoma Treatment (PDQ®) 5/6 —Health Professional Version - National Cancer Institute

Childhood Hodgkin Lymphoma Treatment (PDQ®)—Health Professional Version - National Cancer Institute

National Cancer Institute



Childhood Hodgkin Lymphoma Treatment (PDQ®)–Health Professional Version



Treatment of Primary Refractory or Recurrent Hodgkin Lymphoma in Children and Adolescents

The excellent response to frontline therapy among children and adolescents with Hodgkin lymphoma limits opportunities to evaluate second-line (salvage) therapy. Because of the small number of patients that fail primary therapy, no uniform second-line treatment strategy exists for this patient population.
Adverse prognostic factors after relapse include the following:[1][Level of evidence: 3iiA]
  • The presence of B symptoms (fever, weight loss, and night sweats) and extranodal disease.[2]
  • Early relapse (occurring 3–12 months from the end of therapy).[3,4]
  • Inadequate response to initial second-line therapy.[4]
Children with localized favorable (relapse ≥12 months after completing therapy) disease recurrences whose original therapy involved reduced cycles of risk-adapted therapy or with chemotherapy alone and/or low-dose involved-field radiation therapy (LD-IRFT) consolidation have a high likelihood of achieving long-term survival after treatment with more intensive conventional chemotherapy.[5,6]
Treatment options for children and adolescents with refractory or recurrent Hodgkin lymphoma include the following:

Chemotherapy and Targeted Therapy

Chemotherapy is the recommended second-line therapy, with the choice of specific agents, dose-intensity, and number of cycles determined by the initial therapy, disease characteristics at progression/relapse, and response to second-line therapy.
Agents used alone or in combination regimens in the treatment of refractory or recurrent pediatric Hodgkin lymphoma include the following:
  • ICE (ifosfamide, carboplatin, and etoposide).[7]
  • Ifosfamide and vinorelbine with or without bortezomib.[8][Level of evidence: 2Div]; [9][Level of evidence: 3iiiDiv]
  • Vinorelbine and gemcitabine.[10]
  • IEP/ABVD/COPP (ifosfamide, etoposide, prednisone/doxorubicin, bleomycin, vinblastine, dacarbazine/cyclophosphamide, vincristine, procarbazine, prednisone).[3]
  • EPIC (etoposide, prednisolone, ifosfamide, and cisplatin).[11]
  • APE (cytosine arabinoside, cisplatin, and etoposide).[12]
  • MIED (high-dose methotrexate, ifosfamide, etoposide, and dexamethasone).[13]
  • Rituximab (for patients with CD20-positive disease) alone or in combination with second-line chemotherapy.[14]
  • Brentuximab vedotin. Brentuximab vedotin has been evaluated in adults with Hodgkin lymphoma. (Refer to the Recurrent Adult Classic HL Treatment section in the PDQ summary on Adult Hodgkin Lymphoma Treatment for more information.) The U.S. Food and Drug Administration (FDA) indications for brentuximab vedotin in adult patients are as follows: (1) classical Hodgkin lymphoma after failure of autologous HCT or after failure of at least two previous multiagent chemotherapy regimens in patients who are not autologous HCT candidates, and (2) classical Hodgkin lymphoma at high risk of relapse or progression, as postautologous HCT consolidation therapy.
    1. A phase I study in adults with CD30-positive lymphomas identified a recommended phase II dose of 1.8 mg/kg on an every 3-week schedule and showed an objective response rate of 50% (6 of 12 patients) at the recommended phase II dose.[15][Level of evidence: 2Div]
    2. A phase II trial in adults with Hodgkin lymphoma (N = 102) who relapsed after autologous HCT showed the following:[16-19]
      • A complete remission rate of 34% and a partial remission rate of 40% was observed.[16-18]
      • Patients who achieved a complete remission (n = 34) had a 3-year progression-free survival (PFS) rate of 58% and a 3-year overall survival (OS) rate of 73%, with only 6 of 34 patients proceeding to allogeneic HCT while in remission.
      • Further follow-up demonstrated a 5-year OS rate of 41% and a PFS rate of 22%. However, patients who achieved a complete remission (38%) had a 5-year OS rate of 64% and a PFS rate of 52%.[19][Level of evidence: 2A]
    3. The number of pediatric patients treated with brentuximab vedotin is not sufficient to determine whether they respond differently than do adult patients. Clearance and volume of brentuximab vedotin significantly correlates with weight (P < .001), and its area under the curve and C max are lower in children than those reported in adult studies with weekly dosing.[20]
    4. The Children’s Oncology Group phase I/II study AHOD1221 (NCT01780662)investigated treatment with brentuximab vedotin and gemcitabine in 46 children and young adults with primary refractory Hodgkin Lymphoma or early relapse.[21]
      • The recommended phase II dose of brentuximab vedotin was 1.8 mg/kg.
      • Twenty-four of 42 patients (57%; 95% CI, 41%–72%) treated at this dose level experienced a complete response within the first four cycles. Four of 13 patients (31%) with partial response or stable disease had all target lesions with Deauville scores of 3 or less after cycle four. By modern response criteria, these are also complete responses, increasing the complete response rate to 28 of 42 patients (67%; 95% confidence interval [CI], 51%–80%).
      • Compared with alternate second-line regimens, brentuximab vedotin with gemcitabine offers the advantage of avoiding agents associated with late treatment-related sequelae, such as anthracyclines, alkylators, or epipodophyllotoxins.
    There are ongoing trials to determine the toxicity and efficacy of combining brentuximab vedotin with chemotherapy.

Checkpoint Inhibitor Therapy

Treatments that block the interaction between programmed death-1 (PD-1) and its ligands have shown high levels of activity in adults with Hodgkin lymphoma. The anti–PD-1 antibody nivolumab induced objective responses in 20 of 23 adult patients (87%) with relapsed Hodgkin lymphoma.[22] Another anti–PD-1 antibody, pembrolizumab, produced an objective response rate of 65% in 31 heavily pretreated adult patients with Hodgkin lymphoma who relapsed after receiving brentuximab vedotin.[23] (Refer to the Recurrent Adult Classic HL Treatment section in the PDQ summary on Adult Hodgkin Lymphoma Treatment for more information.)
Evidence (pembrolizumab):
  1. Studies that used pembrolizumab to treat patients with relapsed Hodgkin lymphoma have reported the following:[23]; [24][Level of evidence: 3iiiDiv]
    • An overall response rate of 64% to 74%, with a complete response rate of 22.4% (95% CI, 6.9%–28.6%).
    • Pembrolizumab is well tolerated by patients and can be used to achieve a clinical complete remission before autologous or allogeneic HCT.
    • Pembrolizumab is FDA approved for use in cases of refractory disease or relapse after three or more lines of therapy.
Nivolumab is FDA approved in adult patients with classical Hodgkin lymphoma who have relapsed or progressed after autologous HCT and brentuximab vedotin or three or more lines of systemic therapy that included autologous HCT.[22,25]
There are ongoing trials to determine the toxicity and efficacy of combining brentuximab vedotin and nivolumab with chemotherapy in pediatric patients with Hodgkin lymphoma.

Chemotherapy Followed by Autologous Hematopoietic Cell Transplantation (HCT)

Myeloablative chemotherapy with autologous HCT is the recommended approach for patients who develop refractory disease during therapy or relapsed disease within 1 year after completing therapy.[7,26-33]; [34][Level of evidence: 3iiA]; [35][Level of evidence: 3iiiA] In addition, this approach is also recommended for those who recur with extensive disease after the first year of completing therapy or for those who recur after initial therapy that included intensive (alkylating agents and anthracyclines) multiagent chemotherapy and radiation therapy.
  • Autologous HCT has been preferred for patients with relapsed Hodgkin lymphoma because of the historically high transplant-related mortality (TRM) associated with allogeneic transplantation.[36] After autologous HCT, the projected survival rate is 45% to 70% and PFS is 30% to 89%.[18,34,37,38]; [39][Level of evidence: 3iiiA]
  • Brentuximab vedotin as maintenance therapy given for 1 year after autologous HCT in adult patients with high risk of relapse or progression was demonstrated to improve PFS in a randomized, placebo-controlled, phase III trial.[40]
  • A multicenter, open-label, dose-escalation, phase I/II study evaluated the safety, maximum tolerated dose, and pharmacokinetics of brentuximab vedotin and identified a recommended phase II dose in 36 pediatric patients with relapsed or refractory classical Hodgkin lymphoma (n = 19) and anaplastic large cell lymphoma (n = 17). Toxicity was manageable (33% of patients had transient, limited-severity peripheral neuropathy), the maximum tolerated dose was not reached, and pediatric pharmacokinetics were similar to that of adults. The recommended phase II dose of brentuximab vedotin was 1.8 mg/m2 and it was administered for up to 16 cycles (median, 10 cycles) on the phase II arm. Among Hodgkin lymphoma participants on the phase II arm, 47% of patients achieved an overall response (33% complete response, 13% partial response), which provided a bridge to HCT for some patients.[41][Level of evidence: 3iii]
  • The most commonly utilized preparative regimen for peripheral blood stem cell transplant is the BEAM regimen (carmustine [BCNU], etoposide, cytarabine, melphalan) or CBV regimen (cyclophosphamide, carmustine, etoposide).[32,37-39]; [34][Level of evidence: 3iiA]; [35][Level of evidence:3iiiA] Carmustine may produce significant pulmonary toxicity.[39]
  • Other noncarmustine-containing preparative regimens have been utilized, including high-dose busulfan, etoposide, and cyclophosphamide [42] and lomustine, cytarabine, cyclophosphamide, and etoposide (LACE).[43][Level of evidence: 3iii]
Adverse prognostic features for outcome after autologous HCT include extranodal disease at relapse, bulky mediastinal mass at time of transplant, advanced stage at relapse, primary refractory disease, poor response to chemotherapy, and a positive positron emission tomography scan before autologous HCT.[1,37-39,44,45]
(Refer to the Autologous HCT section in the PDQ summary on Childhood Hematopoietic Cell Transplantation for more information about transplantation.)

Chemotherapy Followed by Allogeneic HCT

For patients who fail after autologous HCT or for patients with chemoresistant disease, allogeneic HCT has been used with encouraging results.[11,36,46-48] Investigations of reduced-intensity allogeneic transplantation that typically use fludarabine or low-dose total body irradiation to provide a nontoxic immunosuppression have demonstrated acceptable rates of TRM.[49-53]
(Refer to the Allogeneic HCT section in the PDQ summary on Childhood Hematopoietic Cell Transplantation for more information about transplantation.)

Involved-site Radiation Therapy (ISRT)

ISRT to sites of recurrent disease may enhance local control if these sites have not been previously irradiated. ISRT is generally administered after high-dose chemotherapy and stem cell rescue.[54] For patients who are not responsive to salvage therapy, ISRT may be an appropriate consideration before HCT.[55]

Response Rates for Primary Refractory Hodgkin Lymphoma

Salvage rates for patients with primary refractory Hodgkin lymphoma are poor even with autologous HCT and radiation. However, intensification of therapy followed by HCT consolidation has been reported to achieve long-term survival in some studies.
Evidence (response to treatment of primary refractory Hodgkin lymphoma):
  1. In one large series, 5-year OS after primary refractory Hodgkin lymphoma was attained with aggressive second-line therapy (high-dose chemoradiation therapy) and autologous HCT in 49% of patients.[56]
  2. In a Gesellschaft für Pädiatrische Onkologie und Hämatologie (GPOH) study, patients with primary refractory Hodgkin lymphoma (progressive disease on therapy or relapse within 3 months from the end of therapy) had 10-year event-free survival (EFS) and OS rates of 41% and 51%, respectively.[3]
  3. A study of 53 adolescent patients of the same types as those who participated in the GPOH study had similar results for EFS and OS.[57] Chemosensitivity to standard-dose second-line chemotherapy predicted a better survival (66% OS), and tumors that remained refractory to chemotherapy did poorly (17% OS).[58]
  4. Another group has reported the PFS post-HCT for chemosensitive patients as 80%, compared with 0% for those with chemoresistant disease.[34]

Second Relapse After Initial Treatment With Autologous HCT

In a phase II study, patients (median age, 26.5 years) who had relapsed or refractory disease after autologous HCT received brentuximab vedotin, with an objective response rate of 73% and a complete remission rate of 34%. Patients who achieved a complete remission (n = 34) had a 3-year PFS rate of 58% and a 3-year OS rate of 73%, with only 6 of 34 patients proceeding to allogeneic SCT while in remission.[18][Level of evidence: 2A]

Treatment Options Under Clinical Evaluation

Information about National Cancer Institute (NCI)–supported clinical trials can be found on the NCI website. For information about clinical trials sponsored by other organizations, refer to the ClinicalTrials.gov website.
The following is an example of a national and/or institutional clinical trial that is currently being conducted:
  1. Anti–PD-1 antibodies being studied in children with Hodgkin lymphoma include nivolumab (ADVL1412 [NCT02304458]) and pembrolizumab (NCT02332668). The anti–PD-L1 antibody atezolizumab is also being studied in children with Hodgkin lymphoma (NCT02541604). Nivolumab in combination with brentuximab vedotin is being studied in an international phase II trial in children with Hodgkin lymphoma (CheckMate 755 [NCT02927769]).

Current Clinical Trials

Use our advanced clinical trial search to find NCI-supported cancer clinical trials that are now enrolling patients. The search can be narrowed by location of the trial, type of treatment, name of the drug, and other criteria. General information about clinical trials is also available.
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