Pediatric Hodgkin Lymphoma Treatment & Management

Hodgkin lymphoma is one of the most curable malignancies of childhood and adolescence. The treatment of pediatric Hodgkin lymphoma is based on the experience of adult Hodgkin lymphoma treatment regimens. In general, the treatment of Hodgkin lymphoma is tailored to the subtype, staging, and response to therapy, and, as such, an accurate histopathological diagnosis is required.

Hodgkin lymphoma can be cured with radiation therapy and/or chemotherapy. Combined-modality therapy, including radiation and chemotherapy, is the preferred approach for most pediatric patients. Because most pediatric patients with Hodgkin lymphoma are successfully treated, an important consideration in the treatment approach of children and adolescents is the selection of a treatment regimen, particularly in reference to the anticipated late toxicities associated with cancer-directed therapy. Late toxicities vary substantially according to the treatment modality used.

Most modern pediatric treatment strategies focus on reducing late effects of therapy while maintaining excellent cure rates with risk-adapted chemotherapy alone or response-adjusted combined-modality regimens. ^[10]

The optimum treatment for adolescents and young adults (18-25 y) is not well defined. Pediatric and adult regimens are used depending on center-specific policies and referral patterns. Adult regimens have been shown to be safe and effective; however, the cumulative doses of chemotherapy used on those regimens have a significant impact on the growing child or adolescent.

The authors believe that children and adolescents (≤18 y) with Hodgkin lymphoma should be treated at a pediatric oncology center where a multidisciplinary team of pediatric specialists is familiar with the treatment and the acute and long-term complications of pediatric malignancies. Whether patients older than 18 years should be treated with adult or pediatric approaches should be tested prospectively in future trials. Currently, retrospective reviews seem to suggest that pediatric approaches may be better for these patients.

Hospital admission is sometimes indicated for supportive medical care.

Goals of therapy

Although pediatric Hodgkin lymphoma is highly sensitive to the treatment regimens devised for adults, long-term toxicity is enhanced in the developing individual. As a result, there have been dual goals in the design of clinical trials for pediatric Hodgkin lymphoma: (1) to reduce long-term organ injury and (2) increase efficacy. Radiation doses and fields have been reduced by enhanced reliance on chemotherapy, thus limiting the risk of hypothyroidism, secondary cancers, and cardiac disease. Multiagent chemotherapeutic regimens have been developed to reduce the cumulative doses of alkylating agents and anthracyclines to avoid the risk of sterility, leukemia, and cardiopulmonary toxicity. Most pediatric approaches use the response to therapy to limit the number of chemotherapy cycles for patients with good responses to therapy.

Assessment of treatment response

Response-based protocols for low stage and advanced stage are the standard of care in pediatric patients. There is evidence that response to therapy after induction chemotherapy is a predictor of event-free survival. Early response to therapy is a measure of chemosensitivity and a reflexion of the complex interplay between tumor biology and host factors, and for that reason it is used to tailor individual treatment and can serve as a basis for reduction of therapy.

Overall response is measured by the presence of a significant reduction, in general (>50–70%) of measurable disease from diagnosis, as measured by a CT scan. Evaluation of response with functional images is becoming the standard of care. Evidence of a negative FGD-PET activity of the positive areas at the time of diagnosis early in the treatment is utilized to tailor intensity of subsequent therapy.

As the use of functional imaging to assess response to therapy has increased, the level of uptake is now more standardized. A scoring system of London-Deuville is now used.

Radiation Therapy

Sequential nodal spread of disease, usually from neck to pelvis, allows for cure with radiation therapy to the involved and contiguous nodal regions but requires accurate staging of the disease. Radiation therapy was the first curative modality used for Hodgkin lymphoma (HL) in the early 1960s. However, the doses and fields used for the treatment of adult Hodgkin lymphoma caused profound musculoskeletal retardation, cardiac toxicity, and increased incidence of secondary malignancies in the radiation field (eg, breast cancer in female survivors).

The use of mantle field (cervical, mediastinal, and axillary nodes) and the inverted-Y field (para-aortic, pelvic, and inguinal nodes) are only used in exceptional situations.

Radiation protocols are used as an adjuvant treatment after chemotherapy. To reduce complications, risk-adapted or response-based, low-dose, involved-field, or extended-field radiation is administered. In current pediatric trials, the use of nodal conformal radiation is being evaluated to further decrease the burden of radiation to other tissues. In addition, in some protocols the field for radiation has changed, from the involved areas at the time of diagnosis to the residual disease present at the time of response to therapy evaluation. For example, radiation is limited to the areas of bulky disease at the time of diagnosis and/or persistent positron-emission tomography (PET)–positive areas after induction therapy.

Clinical trials incorporating radiation-sparing therapy protocols for pediatric Hodgkin lymphoma have recently been implemented. Preliminary data suggest that a subset of patients with good response to therapy may have good outcomes without radiation therapy.

PET scanning is becoming an important modality to guide involved-field radiation therapy in adult Hodgkin lymphoma, ^[9] and its role in guiding involved-field radiation therapy in pediatrics is being explored.

New guidelines on treatment of pediatric lymphoma with radiation therapy by the International Lymphoma Radiation Oncology Group ^{[12, 13]} include the following:

• In children with Hodgkin lymphoma, treatment is more effective when 3-dimension imaging results are considered during the planning of radiation therapy (RT) and the calculation of the RT volume to be administered.

• CT and FDG-PET scans before chemotherapy are critical in the calculation of RT gross tumor volume because they indicate the extent of tissue involvement. Gross tumor volumes should be considered when defining the "volume we need to treat" or when planning the volume of RT to deliver in children.

• When planning RT volume, it is important to determine internal target volume, which takes into account variations in shape and motion in each patient, and the need for immobilization procedures.

• Postchemotherapy imaging provides information on sites that remain abnormal.

• A boost in radiation dose might be appropriate in cases of bulky residual disease or when responses are poor.

Several chemotherapeutic agents in various combinations are used to treat Hodgkin lymphoma. The combinations vary by the stage of disease and by the treating institution.

Combined-modality therapy is preferred to avoid the high cumulative doses of alkylating agents, bleomycin, and anthracyclines used in chemotherapy-only protocols.

Although the treatment of pediatric patients with Hodgkin lymphoma started with regimens devised for adults, over the past 30 years those approaches have evolved to yield produce pediatric-focused protocols, which although more dense and intense, tend to reduce the cumulative doses of chemotherapy, below the threshold for known long-term toxicities. Multi agent chemotherapeutic regimens for children have been developed to avoid or reduce the risk of sterility, leukemia, and cardiopulmonary toxicity.

Chemotherapy alone may be effective in low-stage disease with a good response to therapy or in patients with limited-stage nodular lymphocyte-predominant Hodgkin lymphoma. This approach is recommended, especially in centers where pediatric radiation therapy is not feasible but where chemotherapy can be reliably administered.

The most common pediatric regimens used for the treatment of Hodgkin lymphoma are:

Europeans Regimens:

• OPPA: Vincristine (Oncovin), procarbazine, prednisone, and doxorubicin (Adriamycin)

• OEPA: Vincristine (Oncovin), etoposide, prednisone, and doxorubicin (Adriamycin)

• COPP: Cyclophosphamide, vincristine, procarbazine, and prednisone

• COPDAC: Cyclophosphamide, vincristine, prednisone and dacarbazine

• VBVP: Vinblastine, bleomycin, etoposide, and prednisone

American Regimen (Children’s Oncology Group)

• ABVE: Doxorubicin, bleomycin, vincristine, and etoposide

• ABVE-PC: Doxorubicin (Adriamycin), bleomycin, vincristine, etoposide, prednisone, and cyclophosphamide

• BEACOPPesc: Bleomycin, etoposide, doxorubicin (Adriamycin), cyclophosphamide, vincristine, procarbazine, and prednisone

• COPP/ABV: Cyclophosphamide, vincristine, procarbazine, prednisone, doxorubicin (Adriamycin), bleomycin, and vinblastine

• VAMP/COP: Vincristine, doxorubicin (Adriamycin), methotrexate, and prednisone alternating with cyclophosphamide, vincristine, and prednisone

• Stanford V: Doxorubicin (Adriamycin), vinblastine, mechlorethamine, vincristine, bleomycin, etoposide, and prednisone

Other combinations of chemotherapeutic agents, as well as novel therapies, have been studied and found effective in front-line and salvage therapy for Hodgkin lymphoma. ^{[14, 15]}

Treatment for favorable-risk pediatric Hodgkin lymphoma

For early or favorable disease (stage IA or IIA with < 3 nodal sites, and some IIIA without bulky disease) standard treatment includes 2-4 chemotherapy cycles of ABVE, OEPA, or VAMP plus low-dose, involved-field radiation of 15-30 Gy or 6 chemotherapy cycles of COPP alternating with ABVD and no irradiation. 2-4 cycles of the adult regimen ABVD is also comparable in terms of survival and cumulative doses of chemotherapy. Other regimens are feasible, effective, and safe but expose patients to unnecessary doses of chemotherapy.

Table 2. Survival Rates Associated With Chemotherapy and Radiation Therapy (Open Table in a new window)

Treatment of advanced or unfavorable pediatric Hodgkin lymphoma

For intermediate-risk disease (stage IIA bulky disease with extension or 3 nodal sites, stage IIB, stage III, stage IV), standard treatment includes 3-5 cycles (depending on response to induction treatment) with ABVE-PC plus 21 Gy of involved-field radiation. The regimen delivers effective chemotherapy with a dose-dense regimen while reducing cumulative chemotherapy exposure for all patients.

For advanced or unfavorable disease (stages IIB, IIIB, or IV), one of the following 3 approaches is used:

• The OEPA regimen spares the use of procarbazine by replacing it with etoposide and therefore reduces gonado-toxicity. It is also combined with COPP or COPDAC and is well tolerated and effective in the pediatric population.

• The BEACOPP regimen is highly effective, but the cumulative doses of chemotherapy are problematic. The most benefit with this regimen is seen in patients with stage IVB disease.

• Eliminating radiation therapy from the treatment of patients in this category has reduced event-free survival. ^[16]

Table 3. Survival Rates Associated With Chemotherapy and Radiation Therapy in Advanced or Unfavorable-Risk Disease (Open Table in a new window)

 

The treatment of Hodgkin lymphoma is a moving target. All cooperative groups are aiming to find the best strategy that will produce the best results with minimal toxicity. In this effort, the introduction of novel therapies such as Brentuximab-Vedotin, an anti-CD30 antibody conjugated and antitubulin agent, is being introduced in combination of standard chemotherapy agents, within the context of clinical trials.

Retrieval therapies for relapsed Hodgkin lymphoma

In patients with relapsing or unresponsive disease, autologous stem cell transplantation significantly prolongs disease-free survival. Various drug combinations have been used with stem cell rescue.

In the United States, (ICE) is the most widely used reinduction treatment option in children with Hodgkin lymphoma. Although, the use of ICE can put patients in second remission, it is not optimal, since it is associated with myelosuppression and increased risk of treatment-related secondary malignant neoplasms associated with the use of alkylating agents and epipodophyllotoxins.

Other retrieval regimens, such as the combination of ifosfamide with vinorelbine (IV), or Gemcitabine in combination with Vinorelbine (GV) have shown to be safe and effective as a reinduction regimen for relapsed pediatric Hodgkin lymphoma. ^[17] They have the advantage of eliminating the use of etoposide and reducing the increased incidence of treatment-related secondary myelodysplasia and acute myelocytic leukemia associated with this medication.

Other novel approaches for relapsed Hodgkin lymphoma in children include the combination of bortezomib, a proteasome inhibitor, to ifosfamide/vinorelbine (IV). Methotrexate, ifosfamide, etoposide, and dexamethasone has also been studied. ^[18]

In March 2017, pembrolizumab, a monoclonal antibody to programmed cell death-1 protein (PD-1) gained accelerated approval from the FDA for cHL. It is indicated in adults and pediatrics patients with refractory cHL or who have relapsed after 3 or more prior lines of therapy. Approval was based on data from the KEYNOTE-087 trial (n=210), which demonstrated an ORR with pembrolizumab averaging ~67% (95% CI: 62, 75), a CRR of 22%, and a PRR of 47%. The median follow-up time was 9.4 months. Among the 145 responding patients, the median duration of response was 11.1 months. ^[19] Efficacy for pediatric patients is extrapolated from the results in the adult cHL population.

Although all of the salvage regimens produce remission rates in the range of 50–65% for relapsed Hodgkin lymphoma, when used alone, they are not curative and the disease-free survival (DFS) remains low. Addition of more intensive chemotherapy regimens followed by stem cell rescue has been shown to improve DFS compared with salvage chemotherapy alone. ^{[20, 21]}

High-dose therapy followed by autologous stem cell transplantation, after reinduction or salvage chemotherapy, is the current standard treatment for relapse disease. The most commonly used regimen is called BEAM (carmustine, etoposide, cytarabine and melphalan), which is given in the same fashion as given for adult patients.

One of the defining features of HL is CD30 expression by Reed-Sternberg cells. The use of an anti-CD30 molecule has been an attractive target in the treatment for HL. ^[8] Several anti CD30 antibodies have been engineered: MDX-060 (Medarex) a fully humanized antibody to CD30 (SGN-30), an ad chimeric monoclonal anti-CD30 antibody, both have shown to inhibit cell proliferation and to induce cell death in CD30 positive lymphomas. However, when used alone they were not effective as single agents, showing response rates much lower than traditional cytotoxic chemotherapy.

Newer generations of anti-CD30 antibodies with enhanced Fc receptor-antibody activity (Medarex, MDX-1401) and with antibody-drug conjugates are currently under study. The recent introduction of a conjugated anti-CD30 antibody conjugated to the antitubulin agent (brentuximab vedotin) has shown excellent results in CD30 positive lymphomas.

In a phase I, open label, multicenter dose-escalation study, 42 evaluable patients with refractory CD30 lymphomas demonstrated tumor regression of 86%. ^[22] An additional phase II clinical trial used Brentuximab Vedotin intravenously, at a dose of 1.8 mg/kg every 3 weeks with a response of 75% (76 out of 102) in patient with Hodgkin lymphoma, with complete remission in 34% of them. The average duration of response was 6.7 months. The excellent results of these studies resulted in the recent FDA approval of brentuximab vedotin for the treatment of patients with Hodgkin lymphoma whose disease has progressed after autologous stem cell transplant, or after 2 prior multiagent chemotherapy treatments among patients ineligible to receive a transplant. Prospective studies in the pediatric population are warranted.

Other novel pharmacological approaches include inhibition of NF-kB pathway. NF-kB is a transcription factor that is constitutively activated in Hodgkin lymphoma, and that is thought to be responsible for cell proliferation and antiapoptosis in Hodgkin lymphoma. ^[23]

Bortezomib (Velcade) is a proteasome inhibitor that also inhibits NF-kB pathway. Bortezomib has shown some limited efficacy when used as a single agent or in combination with dexamethasone. ^[24] Inhibition of the antiapoptotic molecule XIAP has shown some encouraging results in preclinical studies. ^[25] M-TOR inhibitors, particularly everolimus, have also shown some promising results, with as much as a 42% overall response rate in patients with RR-Hodgkin lymphoma. ^[26]

A variety of medications may be used to counter the toxicities of treatment, such as the following:

• Antiemetics (eg, ondansetron, diphenhydramine [Benadryl])

• Pain relievers (eg, codeine, gabapentin) for neuropathic pain secondary to vinca alkaloids

• H2 blockers or proton pump inhibitors to protect the gastric mucosa in patients receiving steroids

• Pneumocystis prophylaxis and granulocyte colony-stimulating factor are also considered.

The effects of therapy in the developing child/adolescent is significant. Most acute and late complications are due to treatment-related toxicities. Hypothyroidism after neck and chest irradiation is prevalent and affects as many as 50% of patients who survive pediatric Hodgkin lymphoma (HL) 10 years after treatment. In particular, white female patients are at greater risk than male patients and black patients.

Cardiac and pulmonary complications after radiotherapy depend on the cumulative doses of anthracyclines (cardiac effects) and bleomycin (pulmonary effects) and on the radiation dose.

Girls, and especially boys, are at high risk for infertility after they receive regimens containing high doses of alkylating agents. Therefore, male patients should receive counseling about storing their sperm in a sperm bank, when appropriate, before such a regimen is started.

As many as 30% of patients who survive pediatric Hodgkin lymphoma develop a secondary malignancy up to 30 years after their Hodgkin lymphoma is diagnosed. The most common secondary malignancies are thyroid cancer, breast cancer, no melanoma skin cancer, non-Hodgkin lymphoma, and acute leukemia.

Long-term survivors of Hodgkin lymphoma are more likely to die from treatment-related complications 30 years after diagnosis than from Hodgkin lymphoma. ^[27]

Patients require regular monitoring to assess their response to therapy and to check for adverse effects of treatment. During periods of decreased blood cell counts due to bone marrow suppressive effects of treatment, neutropenic and thrombocytopenic precautions should be observed.

In patients who achieve remission, follow-up visits are recommended every 2-4 months for the first 1-2 years and every 3-6 months for the next 3-5 years. Most relapses occur in the first 3 years after therapy.