eMedicine Specialties > Pediatrics: General Medicine > Oncology

Non-Hodgkin Lymphoma: Treatment & Medication

Author: J Martin Johnston, MD, Associate Professor of Pediatrics, Mercer University School of Medicine; Director of Pediatric Hematology/Oncology, Backus Children's Hospital; Consulting Oncologist/Hematologist, St Damien's Pediatric Hospital
Contributor Information and Disclosures

Updated: Dec 5, 2008

Treatment

Medical Care

Proper care of non-Hodgkin lymphoma (NHL) requires a referral to a comprehensive tertiary care center. The current intense treatment regimens, particularly those for advanced stages of disease, necessitate inpatient administration of chemotherapy, as well as aggressive support by a team experienced in the care of children with immunosuppression.

Before and during the initial induction phase of chemotherapy, patients may develop tumor lysis syndrome. This term describes metabolic derangements caused by a highly proliferative and/or bulky malignancy. Renal involvement by lymphoma is an additional risk factor.

Hyperuricemia or tubular obstruction may lead to acute renal failure, requiring dialysis. In general, this is not a contraindication to continuing chemotherapy. However, some protocols now include a preliminary phase of relatively gentle cytoreductive chemotherapy designed to avoid these metabolic complications.

With all patients, administer intravenous fluids at twice the maintenance rates, usually without potassium. Add sodium bicarbonate to the intravenous fluid to achieve moderate alkalinization of the urine (pH of approximately 7). This measure enhances the excretion of tumor metabolites. For example, the solubility of uric acid is 10-12 times higher at a pH of about 7 than it is at pH 5, whereas the solubility of xanthine is doubled. Avoid a urine pH higher than this to prevent crystallization of hypoxanthine or calcium phosphate. Administer allopurinol to prevent or correct hyperuricemia. In high-risk situations (extreme elevations of lactate dehydrogenase [LDH] and/or uric acid or evidence of impaired renal function at presentation), consider administration of recombinant urate oxidase (rasburicase [Elitek]).³¹

Follow up the patient's laboratory values to monitor tumor lysis syndrome throughout initial therapy. Testing may be needed as often as 2-4 times per day. This follow-up is especially important during the first 48-72 hours of therapy in a patient with bulky disease.

If present, fever simply may reflect the underlying malignancy. However, consider beginning empiric broad-spectrum antibiotic coverage until sepsis or focal infection (eg, due to bowel perforation) is excluded.

Current treatment regimens are primarily based on the immunophenotype of the particular lymphoma (B cell vs T cell). In broad terms, T-cell therapies are longer and less intensive (particularly with respect to the use of alkylating agents) than B-cell therapies. Treatments for B-cell lymphomas involve relatively high doses of alkylators and antimetabolites.

Current survival rates for patients with advanced disease are 65-75% for T-cell (lymphoblastic) lymphomas and 80-90% for those with B-cell lymphomas.

Lymphoblastic Lymphoma

The most successful treatment protocols for advanced-stage lymphoblastic lymphoma feature chemotherapy combinations designed to treat ALL.

LSA₂ L₂ protocol

The LSA₂ L₂ protocol evolved from ALL protocols used at the Memorial Sloan-Kettering Cancer Center in the early 1960s. The LSA₂ L₂ protocol features 3 phases of therapy—namely, induction, consolidation, and repeated cycles of maintenance—given over a total of 2-3 years.³² Methotrexate is administered intrathecally for CNS prophylaxis throughout treatment. When this protocol was first described, it included irradiation of sites of bulky disease; however, radiation is no longer routinely applied.

Children's Cancer Group protocol 552

Between 1986 and 1989, 143 subjects with lymphoblastic lymphoma (10% with localized disease) received treatment with a modified LSA₂ L₂ regimen in a Children's Cancer Group trial (see Table 1). Their 5-year event-free survival was 74%.³³

Table 1. Modified LSA₂ L₂ Therapy in Children's Cancer Group Protocol 552

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Source.—Children's Cancer Group.
Ara-C = cytarabine; BCNU = 1,3-bis(2-chloroethyl)-1-nitrosourea, or carmustine; IM = intramuscular; IT = intrathecal; IV = intravenous; PO = oral; SC = subcutaneous.
^* A minimum of 5 repeated courses (total duration of therapy >18 mo) are noted. Each course of intrathecal methotrexate (day 0 of each course) consists of 4 cycles of rotating drug pairs that are administered every 2 weeks after blood counts have recovered.

German Berlin, Frankfurt, Muenster treatment protocol

The German Berlin, Frankfurt, Muenster (BFM) protocols demonstrated excellent results in patients with ALL or lymphoblastic lymphoma. As reported in 1995, 71 subjects with stage III or IV non–B-cell non-Hodgkin lymphoma (see the Children's Oncology Group protocols below) received treatment, as shown in Table 2.³⁴

Compared with the LSA₂ L₂ protocol, the BFM regimen adds a re-induction phase and features a less complicated and less intense maintenance phase. In its original report, the BFM protocol included prophylactic cranial irradiation during re-induction. Patients receiving this treatment had a 6-year event-free survival of 79%.

Table 2. Therapy for Stage III and IV non–B-Cell Disease^* According to BFM Protocol 86

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Source.—Berlin-Frankfurt-Munster Group.
Ara-C = cytarabine; IT = intrathecal; IV = intravenous; PO = oral; SC = subcutaneous.
^* Diagnoses included lymphoblastic lymphoma of the T-cell or precursor B-cell type, immunoblastic T-cell lymphoma, and other peripheral T-cell lymphomas. Of note, patients with Ki-1+ anaplastic LCLs were not included.
^† Continued until 24 months after diagnosis.

Children's Oncology Group protocols

The most recent Children's Oncology Group phase 3 protocol (A5971) for children with advanced-stage T-cell lymphoblastic lymphoma featured a 4-way randomization between BFM therapy, a Children's Cancer Group modified version of BFM therapy (which did not include high-dose methotrexate/leucovorin during consolidation), and intensified versions of these 2 protocols (with early introduction of daunomycin and cyclophosphamide). Results from this comparison are still pending.

The Children's Oncology Group is developing specific protocols to treat T-cell diseases—both T-lymphoblastic lymphoma and T-cell ALL. In particular, researchers will examine the role of nelarabine (previously known as compound 506U78), a prodrug of the deoxyguanosine analog 9-beta-D-arabinofuranosylguanine (Ara-G) that has shown efficacy in T-cell malignancies.

Additional treatment details

For advanced-stage lymphoblastic lymphoma, as for ALL, relatively long intervals of treatment have been most successful. The maintenance phase typically lasts 18-30 months. Protocols shorter than this have also been investigated. For example, Children's Cancer Group protocol 5941 examined an aggressive, 11-month multiagent regimen. Results of this trial were recently published: the 5-year event-free survival was 78% ± 4.5% and overall survival was 85% ± 3.9%. These results suggest that the experimental approach is safe and just as effective as more prolonged regimens.³⁵

Localized lymphoblastic lymphoma is unusual. In the previously mentioned BFM study, 6 of 77 subjects with non–B-cell non-Hodgkin lymphoma had stage I or II disease.

When results from several series were combined, patients appeared to have an excellent prognosis. Long-term survival was approximately 80%.

Despite these findings, a consensus about optimal therapy is lacking. Treatment options include the LSA₂ L₂ protocol and the BFM protocol 86 for non-Hodgkin lymphoma (with the re-induction phase eliminated). Patients with localized lymphoblastic lymphoma are included in Children's Oncology Group protocol A5971; they receive a Children's Cancer Group modified version of the BFM protocol (as described above) that includes re-induction but with fewer doses of intrathecal chemotherapy during the maintenance phase.

Regimens simpler than these have demonstrated comparable results. For example, protocol 77-04 from the NCI included alternating cycles of cyclophosphamide, doxorubicin, vincristine, and prednisone (CHOP) and high-dose methotrexate (with leucovorin as rescue therapy). Aggressive intrathecal prophylaxis with cytarabine and methotrexate was included. However, local radiation therapy was not offered routinely. The total duration of therapy is 15 cycles (approximately 60 wk).

Small Noncleaved Cell Lymphoma

Since the mid-1980s, survival rates for patients with Burkitt or Burkittlike lymphomas have increased dramatically. In general terms, several lessons have been learned, as summarized below:

• Long-term maintenance chemotherapy appears to have no role. Therefore, chemotherapy can be short. A typical duration is 2-6 cycles, each lasting 3-4 weeks. However, the intensity of treatment is high for most patients, and inpatient treatment is required.
• When observed, relapses occur early, either during therapy or within 6-12 months of its completion. Salvage rates for patients with relapse have been disappointing.
• Even patients with widely disseminated disease (eg, bone marrow involvement) have a long-term survival rate of 90%.
• Involvement of the CNS at diagnosis continues to be an adverse prognostic indicator.

Treatment protocol from a Cooperative Group trial

Three cooperative groups conducted a recent international trial for patients with SNCCL: the French Society of Pediatric Oncology (SFOP) in France, Belgium, and the Netherlands; the Children's Cancer Group in the United States, Canada, and Australia; and the United Kingdom Children's Cancer Study Group (UKCCSG) in the United Kingdom and Ireland.

Chemotherapy was based on the SFOP LMB-89 study, in which event-free survival rates ranged from 100% in group A to 87.5% in group C (see Table 3). Patients with B-cell ALL were included in this protocol. Subjects were staged (as described above), then assigned to clinical risk groups, as presented in Table 3.

Table 3. Clinical Risk Groups in the International Trial for Patients With SNCCL (Children's Cancer Group study 5961)

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Table 4. Standard Therapy for Subjects in the International Trial for Patients With SNCCL, Group A^*

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G-CSF = granulocyte colony-stimulating factor; IV = intravenous; PO = oral; SC = subcutaneous.
^* See Table 3 for the definition of group A. All subjects received 2 cycles.

The results of the international trial were recently published; with median follow-up of more than 4 years, the 4-year event-free survival for group A subjects was 98.3%, and overall survival was 99.2%.³⁶

In this trial, patients with advanced disease (groups B and C) received an initial moderately intensive reduction phase of chemotherapy. This was intended to reduce the tumor burden with a minimal risk of inducing or exacerbating tumor lysis syndrome. The experimental treatment arms for these patients involved incremental reductions in the intensity and/or duration of chemotherapy. For patients in group B with an "early response" to therapy (at least 20% tumor decrease after 7 d of treatment), outcomes with standard therapy were not superior to outcomes on any of the experimental (reduced therapy) arms. Thus, pediatric patients with intermediate-risk B-non-Hodgkin lymphoma who have an early response and achieve a complete remission after the first consolidation course are effectively treated using a 4-course regimen with a total dose of only 3.3 g/m² cyclophosphamide and 120 mg/m² doxorubicin.³⁷

Table 5. Standard Therapy for Subjects in International Trial for Patients With SNCCL, Group B^*

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Ara-C = cytarabine; G-CSF = granulocyte colony-stimulating factor; IT = intrathecal; IV = intravenous; PO = oral, SC = subcutaneous.
^* See Table 3 for the definition of group B.

Based on published results from this trial, equivalent outcomes are expected with a reduced (50%) dose of cyclophosphamide in induction phase 2, elimination of maintenance phase 1, or both.

Group C patients in remission after 3 cycles were randomized to standard versus reduced-intensity therapy (omitting the last 3 cycles of maintenance). The 4-year event-free survival after randomization was 90% ± 3.1% versus 80% ± 4.2%, whereas survival was 93% ± 2.7% versus 83% ± 4%. Patients with either combined marrow and CNS disease at diagnosis or a poor response to reduction therapy had significantly inferior event-free survival and survival (P <0.001).³⁸ Therefore, decreasing therapy in this subgroup of patients appears unwise; standard-intensity therapy is recommended for children with high-risk B-non-Hodgkin lymphoma.

Table 6. Standard Therapy for Subjects in International Trial for Patients With SNCCL, Group C^*

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Ara-C = cytarabine; G-CSF = granulocyte colony-stimulating factor; IT = intrathecal; IV = intravenous; PO = oral, SC = subcutaneous.
^* See Table 3 for the definition of group C.
^† For patients with CNS involvement, during consolidation cycle 1 only.

An alternative treatment approach has been developed over a series of randomized trials by the German Berlin, Frankfurt, Muenster group.³⁹ In particular, the role of intermediate-dose or high-dose methotrexate has been investigated among the different clinical risk groups.

Future protocols for patients with B-cell non-Hodgkin lymphoma will include monoclonal antibodies (eg, anti-CD20 rituximab) for children with high-risk disease (ie, patients with CNS disease at diagnosis or those with advanced-stage disease and elevated levels of lactate dehydrogenase).

Large Cell Lymphoma

B cell–derived LCLs

Patients with B cell-derived LCLs are treated effectively by using the regimens for SNCCL (discussed above).^40,41,42 In fact, the recent international protocol allowed clinicians to enroll of subjects with LCL, as well as those with SNCCL. Outcomes are similar between the groups.

An alternative therapy is the APO regimen consisting of doxorubicin (Adriamycin), prednisone, vincristine [Oncovin].⁴³ Methotrexate and 6-mercaptopurine were later added. A randomized study of children with LCLs (including B-cell LCLs) showed no advantage when cyclophosphamide was added to this regimen.⁴⁴ Therefore, this therapy has the advantage of avoiding exposure to an alkylating agent. However, the cumulative dose of doxorubicin is 450 mg/m².

Anaplastic (T cell–derived) LCLs

The therapy for anaplastic (T-cell) LCLs is somewhat controversial. Good results (event-free survival rates of 65-80%) have been reported with a number of protocols. Some were based on ALL therapy, whereas others were similar or identical to those used to treat B-cell lymphomas.

The BFM group reported what may be the best results with treatment for Ki-1+ anaplastic LCLs.⁴⁵ The group administered a regimen for B-cell lymphomas that did not include local radiation therapy. Among 62 patients (none with bone marrow disease and 1 with CNS involvement), 4 did not achieve remission, 1 died from infection, and 7 had a relapse. At the time of the report, 50 patients remained in a continuous first episode of complete remission, and 56 were alive. The calculated event-free survival rate at 9 years was 83%.

Table 7. Prephase Therapy for Ki-1+ Anaplastic LCLs in All Patients According to the BFM-90 Protocol

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Ara-C = cytarabine; IT = intrathecal; IV = intravenous; PO = oral.

Subsequent therapy is based on the stage, which is determined by using a modified St Jude system. Treatments are listed below, and cycles A, B, AA, BB, and CC are defined in Table 8.

• Patients with stage I or resected stage II disease receive cycles A-B-A.
• Patients with unresected stage II or stage III disease receive cycles A-B-A-B-A-B.
• Patients with stage IV disease or multifocal bone disease receive cycles AA-BB-CC-AA-BB-CC.

Table 8. Subsequent Therapy for Ki-1+ Anaplastic LCLs According to the BFM-90 Protocol

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Ara-C = cytarabine; IT = intrathecal; IV = intravenous; PO = oral.

A recent report of 89 children described the results of virtually identical therapy in which dexamethasone was used instead of prednisone in the prephase. The overall event-free survival rate at 5 years was 76%.

A recent report of 89 children described the results of virtually identical therapy in which dexamethasone was used instead of prednisone in the prephase. The overall event-free survival rate at 5 years was 76%.⁴⁶

As noted previously, good results have also been observed with the relatively uncomplicated APO regimen.

A recent randomized study of children with LCL (including both B-cell LCL and anaplastic LCL) showed no apparent advantage when intermediate-dose methotrexate and high-dose cytarabine were added to an APO backbone.⁴⁷

A report from the SFOP described surprising efficacy of monotherapy with vinblastine for relapsing anaplastic LCL, even in patients who previously underwent myeloablative therapy with autologous bone marrow transplantation.⁴⁸ The role of vinblastine in front-line therapy for anaplastic LCL is being examined in a Children's Oncology Group protocol. Investigators are comparing the standard APO regimen with an experimental therapy that includes vinblastine.

Treatment of Relapsed Disease

As front-line therapies for pediatric non-Hodgkin lymphoma continue to evolve and improve, treatment of relapses is becoming increasingly problematic.

Reinduction regimens use novel chemotherapy combinations, such as ifosfamide, carboplatin, and etoposide (ICE). Depending on the presence of certain cell-surface markers, monoclonal antibodies (eg, anti-CD20 rituximab) may be added to the regimen.^49,50

In most cases, myeloablative chemotherapy with either autologous stem-cell rescue or allogeneic bone marrow transplantation may offer the best option for curative consolidative therapy.

Surgical Care

Even for patients with bulky non-Hodgkin lymphoma, debulking surgery is not crucial to effective therapy. For example, chemotherapy is effective in relieving partial airway or bowel obstruction (see Media file 3, Media file 4). In rare instances, resection may be required for this purpose.

The chief role for surgery is obtaining tissue for diagnosis. Thus, excision of an easily accessible lymph node (when present) is preferable to a thoracotomy or laparotomy, unless symptoms dictate otherwise. Even moderately aggressive surgery generally is not necessary or helpful.

One exception, and a potential therapeutic dilemma, involves abdominal B-cell non-Hodgkin lymphoma. The patient can be assigned to clinical group A (see Table 5 above), if the following conditions are met:

• An intestinal primary lesion can be resected along with all involved adjacent lymph nodes
• The marginal lymph nodes are free of disease
• The patient has no evidence of further dissemination (eg, to CNS or marrow)

In this situation, the prescribed chemotherapy regimen is far less toxic than it otherwise is.

Therefore, a surgeon treating a reasonably small abdominal non-Hodgkin lymphoma is advised to perform lymph node dissection and to try to excise all visible areas of tumor. However, this surgery is performed only if it can be accomplished without causing clinically significant morbidity. Heroic attempts at resection are best avoided because unresected disease can still be cured in most patients. Furthermore, prolonged postoperative recovery may delay the start of chemotherapy and potentially compromise its effectiveness.

Second-look surgery may be helpful for assessing the viability of residual masses. Second-look procedures require highly individualized approaches. As an alternative, uptake of⁶⁷ Ga suggests viability of residual masses in patients whose tumors are gallium avid.

Consultations

• Intensive care specialist
  • Patients with childhood non-Hodgkin lymphoma frequently present in a tenuous condition because of airway compromise, metabolic derangements, and/or infection. In the initial stages of therapy, the patient's condition may be unstable or deteriorating. Therefore, the support of a pediatric intensive care unit is highly desirable.
  • If available, a pediatric intensivist should be made aware of the patient in the event that respiratory management or pressor support becomes necessary.
• Radiation oncologist
  • Consider consultation with a radiation oncologist. In general, radiation therapy has a limited role in the treatment of childhood non-Hodgkin lymphoma, and it is applied almost exclusively in situations deemed to be real or potential emergencies.
  • Mediastinal irradiation may be helpful in patients with impending airway obstruction, especially if the use of general anesthesia is being contemplated for biopsy or central line placement.
  • For patients with lymphoblastic lymphoma, low-dose radiation therapy is often is used to treat neurologic involvement (eg, cranial nerve palsies, intracerebral extension of tumor, paraplegia).
  • Irradiation has minimal efficacy in patients with SNCCL, presumably because of the rapid growth of these cells. Although a dose of radiation may result in significant cell kill, rapid regrowth of surviving cells between doses largely negates the benefit. Hyperfractionated radiotherapy (ie, >1 dose per day) offers a theoretic advantage, as does low-dose continuous irradiation; however, the unfeasibility of the latter all but precludes its use.⁵¹
  • Finally, consider radiotherapy in any patient with documented residual disease after chemotherapy and in patients with bulky disease at the time of relapse.
• Nephrologist: Notify a nephrologist if the patient has substantial tumor lysis syndrome and if dialysis is under consideration.

Medication

As discussed Medical Care, the agents described below are used in combination regimens, and doses are tailored to the histologic subtype of lymphoma and stage of disease present.

Corticosteroids

Corticosteroids elicit anti-inflammatory properties and cause profound and varied metabolic effects. They modify the body's immune response to diverse stimuli.

Methylprednisolone (Medrol)

Mechanism of cytotoxicity unknown but apparently mediated by glucocorticoid receptors.

Dexamethasone (Decadron)

Mechanism of cytotoxicity unknown, but apparently mediated by glucocorticoid receptors; apparently enhanced CNS penetration (relative to prednisone).

Antineoplastic Agents

Cancer chemotherapy is based on an understanding of tumoral cell growth and on how drugs affect this growth. After cells divide, they enter a period of growth (ie, phase G1), followed by DNA synthesis (ie, phase S). The next phase is the premitotic phase (ie, G2), then finally mitotic cell division (ie, phase M).

Cell division rates vary for different tumors. Most common cancers grow slowly compared with normal tissues, and the growth rate may further decrease in large tumors. This difference allows normal cells to recover from chemotherapy more quickly than malignant cells, and is the rationale for current cyclic dosage schedules.

Antineoplastic agents interfere with cell reproduction. Some agents are cell cycle specific, whereas others (eg, alkylating agents, anthracyclines, cisplatin) are not phase specific.

Cellular apoptosis (ie, programmed cell death) is another potential mechanism of many antineoplastic agents.

Daunorubicin (Cerubidine)

Anthracycline. Multiple mechanisms of action involve DNA intercalation, topoisomerase-mediated DNA strand breakage, and oxidative damage due to free radical production.

Doxorubicin (Adriamycin)

Anthracycline. Multiple mechanisms of action involve DNA intercalation, topoisomerase-mediated DNA strand breakage, and oxidative damage due to free radical production.

Cytarabine (Cytosine arabinoside, Ara-C, Cytosar-U)

Antimetabolite. Cytotoxic analog of deoxycytidine. Interferes with DNA replication and repair by incorporating into DNA and inhibiting DNA polymerase.

6-mercaptopurine (6-MP, Purinethol)

Purine analog. Metabolites incorporated into DNA, inhibiting synthesis.

6-thioguanine (Purinethol)

Purine analog. Metabolites are incorporated into DNA, inhibiting synthesis

Methotrexate (MTX, Folex PFS)

Cytotoxic folate antagonist. Inhibits dihydrofolate reductase.

Vincristine (Oncovin)

Inhibits microtubule formation in mitotic spindle, causing metaphase arrest.

Etoposide (VP-16, Toposar)

Inhibits topoisomerase, causing DNA strand breaks.

Cyclophosphamide (Cytoxan)

Alkylates and cross-links DNA.

Ifosfamide (Ifex)

Alkylates and cross-links DNA.

Carmustine (BCNU, BiCNU)

Alkylates DNA and RNA; may also act by carbamoylation of enzymes.

L-asparaginase (Elspar)

Enzyme produced by Escherichia coli, which catalyzes conversion of L-asparagine to aspartic acid; former is nonessential amino acid for most normal tissues. Many lymphoid malignancies have low levels of asparagine synthase and, therefore, depend on circulating pool of L-asparagine.

Nelarabine (Arranon)

Prodrug of deoxyguanosine analog 9-beta-D-arabinofuranosylguanine (Ara-G). Converted to active 5'-triphosphate (ara-GTP), a T-cell–selective nucleoside analog. Leukemic blast cells accumulate ara-GTP, allowing for incorporation into DNA; result is inhibition of DNA synthesis and cell death.
Approved by US Food and Drug Administration as orphan drug to treat T-cell lymphoblastic lymphoma not responding to or relapsing with at least 2 chemotherapy regimens.

Hydroxyurea (Hydrea)

Apparently inhibits DNA synthesis.

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