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Non-Hodgkin's Lymphoma
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	Non-Hodgkin's Lymphoma
	- Introduction - Causes - Clinical Picture - Diagnosis - Pathology - Staging - Treatment

1. Indolent lymphomas

The standard management of low-grade NHL is controversial and ranges from the “watch and wait” approach pioneered at Stanford University to the use of combination regimens containing anthracycline, such as FND (fludarabine [Fludara], Novantrone [mitoxantrone], dexamethasone).

Stage IA-IIA

1. Radiation therapy

The treatment of choice is irradiation alone to the entire involved lymphoid region, as defined by the Rai and Ann Arbor staging classifications, or the involved region plus one additional uninvolved region on each side of the involved nodes.

The recommended dose is 30 Gy for nonbulky disease showing prompt regression, with 36 Gy delivered for bulky or slowly regressive disease.

Benefits

• 60% relapse-free rates at 10 years (70% for stage IA vs 30% for stage IIA).

Extended field irradiation

As the majority of relapses occur outside the radiation fields, often in adjacent or distal lymph nodes, extended-field or total lymphoid irradiation has been used to try to improve cure rates. Clinical series have shown improvement in freedom from relapse only, with no significant difference in long-term survival.

2. Adjuvant chemotherapy

The issue of whether adjuvant chemotherapy improves  the prognosis of patients with early-stage low-grade NHL remains unresolved.

Some have advocated adjuvant chemotherapy to selected patients with stage II disease with unfavorable prognostic factors, such as systemic symptoms or more than two (or discontiguous) nodal sites, and to those with follicular grade 2 histology.

Stage III/IV

Chemotherapy

Younger patients

• Median disease-free survival is almost always between 1.5 and 3 years, and median overall survival ranges from 5 to 7 years.
• 25% relapse free survival at 4years.

Single-agent chemotherapy

(chlorambucil [Leukeran] (daily dose, 0.1-0.2 mg/kg) or cyclophosphamide (1.5-2.5 mg/kg) with or without prednisone. Oral pulse chlorambucil (16 mg/m2 for 5 days at 3- week intervals) usually results in a faster antitumor response than daily single agent alkylator therapy.

• 60% complete remission rate, 25% Relapse free survival at 4years.

CVP

(cyclophosphamide, vincristine, and prednisone).

C(M)OPP

cyclophosphamide + vincristine + procarbazine + prednisone.

CHOP

cyclophosphamide + doxorubicin + vincristine + prednisone.

CHOP-B

More intensive combination, CHOP-B (bleomycin [Blenoxane]) , is reported not to have any advantage vs single-agent cyclophosphamide.

Purine analogs

The purine analogs, such as fludarabine and cladribine (2- CdA [Leustatin]), have significant antitumor activity in low-grade NHL and are being studied in combination regimens.

FND: fludarabine + mitoxantrone ± dexamethasone.

Rituximab (Rituxan)

Rituximab (Rituxan), either alone or combined with these agents (eg, CVP or CHOP), is being investigated.

Radiolabelled antibodies

Radiolabelled antibodies ibritumomab tiuxetan (Zevalin) and tositumomab/iodine-131 have shown encouraging results.

Interferon

The use of interferon (IFN)-alfa (Intron A, Roferon-A) concomitantly with or as an adjuvant to conventional chemotherapy in follicular lymphoma appears to prolong disease-free survival, but its impact on overall survival and curability is controversial.

BMT

For select patients, allogeneic stem-cell transplantation should be considered as a potentially curative approach.

Radiotherapy

Irradiation therapy here is used locally for palliation of symptomatic sites of disease and is extremely effective.

Total-body irradiation is used as part of preparative regimens for BMT and has produced up to 80% CRR, 25% Relapse free survival at 5yrs.

Older patients

Older patients with asymptomatic, indolent NHL are often observed closely without any initial therapy. The decision to use any of the standard or newer modalities should be individualized, based on the presence of poor prognostic features and the patient’s tolerance to planned  therapy.

Special types of indolent lymphoma

MALT marginal zone lymphoma

• Combination therapy (eg, omeprazole [Prilosec], metronidazole, and amoxicillin) directed at the infection results in the regression of most early lesions. Tumors invading beyond the submucosa and lesions with t(11;18) or bcl-10 overexpression are associated with a failure to respond to H pylori eradication.
• Localized MALT marginal zone  gastric lymphoma that does not respond to antibiotics may be cured with local irradiation,  consisting of 30 Gy in 1.5-Gy daily fractions directed to the stomach and perigastric lymph   nodes. This treatment is safe, extremely effective, and allows gastric preservation. Benefits: a single-institution experience reported a 96% complete response and 90% freedom-from- treatment failure at a median follow-up of 4 years.
• If local irradiation fails, chemotherapy or rituximab can be used and, in some instances, surgery.

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Relapsed low grade lymphoma

In general, treatment with standard agents rarely produces a cure in patients whose disease has relapsed.

Favorable survival after relapse has been associated with:

• Age younger than 60 years
• Complete remission rather than partial remission
• Duration of response longer than 1 year

Even the most favorable subset, however, has a 10-fold greater mortality compared with age-adjusted US population rates.

Long-term freedom from second relapse, however, is uncommon and multiple relapses will usually occur.

Bone marrow transplantation

Bone marrow transplantation is still under evaluation but should be considered in the context of a clinical trial. This is usually preceded by 2 cycles of CHOP, however, preparative drug regimens have varied; some investigators also use total-body irradiation.

Benefits

• The 5-year progression-free survival was 65% for transplantation (versus 33% for interferon) (P<.0001), but with no difference in overall survival (German Low-Grade Lymphoma Study Group).

Alkylating agents

For relapse that remains low grade, chemotherapy with single alkylating agents (often given orally) or with combinations such as cyclophosphamide, vincristine, and prednisone is often used.

Fludarabine

Significant activity for fludarabine and 2-chlorodeoxyadenosine has been demonstrated in relapsed low-grade lymphomas, both as single agents and in combination with other drugs.

Rituximab

Rituximab results in a 40% to 50% response rate in patients who relapse with indolent B-cell lymphomas. Rituximab can also be combined with combination chemotherapy.

Radiolabeled monoclonal antibodies

Durable responses to radiolabeled monoclonal antibodies, such as yttrium-90 ibritumomab (commercially available) and iodine-131 tositumomab, have also been reported; subsequent chemotherapy regimens can be delivered at the time of relapse following radioimmunotherapy.

• In a randomized study, patients with refractory low-grade (follicular or small lymphocytic lymphoma) received either rituximab or ibritumomab tiuxetan. The response rate for ibritumomab tiuxetan was 80% and complete response (confirmed and unconfirmed) was seen in 34% of patients, whereas for rituximab, it was 56% and 20%.

Histological conversion

Histologic transformation of low-grade NHL to a more aggressive histology is well recognized, occurring in 30%-70% of patients during the course of their. Indolent lymphomas may relapse with an aggressive histology (i.e., histologic conversion). Sometimes, an aggressive lymphoma may relapse as a small cell (indolent) lymphoma. Such a situation occurs with indolent lymphoma in the bone marrow and with aggressive lymphoma in a nodal site. Patients may present in such a manner, and chemotherapy might successfully eradicate the peripheral disease while failing to eliminate the small cell component from the bone marrow. The clinical significance and natural history of this pattern of disease are not well defined. Progression to DLBC lymphoma at 5% per year.

Histologic conversions should be treated with the regimens described in the aggressive, recurrent adult non-Hodgkin's lymphoma. The durability of the second remission may be short, and clinical trials, such as bone marrow transplantation, should be considered.

2. Intermediate to high grade lymphoma

Stage I/IIA nonbulky (limited stage)

Prior to the 1970s, most patients with stage I/II large cell lymphoma (intermediate grade in the Working Formulation) were treated with irradiation alone, with overall cure rates of 40%-50%. Patients with pathologically favorable stage I/II disease had even better outcomes, but relapse rates, even in these patients, were still 20%-30%. Pathologic staging, therefore, selected a group suitable for irradiation alone.

Combined-modality therapy

Combined-modality therapy includes 3 cycles of CHOP in addition to irradiation.

Benefits

• Combined-modality therapy (3 cycles of CHOP and irradiation) produced a disease progression-free survival at 5 years of 77% vs 64% for 8 cycles of CHOP alone (P = .03).
• Overall survival at 5 years was 82% vs 72%, respectively (P = .02) (The SWOG study)

Stage I/IIA bulky

Chemotherapy + adjuvant radiotherapy

For patients with bulky disease, a minimum of six cycles of CHOP is typically administered. Irradiation doses of 30-35 Gy, delivered in 1.75-3.0 Gy over 3-4 weeks after completion of systemic therapy, appear to be adequate.

Stage III/IV disease

The following recommended treatment strategies should be adjusted according to the level of risk, as defined by the prognostic factors validated by the IPI:

1. Age ≤ 60 years at low or intermediate risk (IPI)

Younger patients at low or intermediate risk (ie, normal LDH level and ambulatory performance status) have 5-year survival rates > 50%. They should be treated with six to eight cycles of a standard doxorubicin-containing regimen, such as CHOP.

Chemotherapy

1. CHOP + rituximab

The addition of rituximab to CHOP has become routine in the United States and is also being employed with combined-modality therapy.

Benefits:

• Complete response (76% vs 63%, P = .005), event-free survival of 53% vs 35% (P = .00008) and overall survival of 62% vs 51% (P = .008), with median follow-up of 3.1 years.

2. CHOP

The classic regimen is CHOP. Newer regimens, such as m-BACOD (methotrexate, bleomycin, Adriamycin, cyclophosphamide, Oncovin, and dexamethasone; Dana-Farber Cancer Center), ProMACE-CytaBOM (prednisone, methotrexate, Adriamycin, cyclophosphamide, etoposide, cytarabine, bleomycin, and Oncovin; National Cancer Institute [NCI]), and MACOP-B (methotrexate, Adriamycin, cyclophosphamide, Oncovin, prednisone, and bleomycin; Vancouver). Randomized comparisons have failed to show an advantage of the third-generation regimens over CHOP.

Benefits:

• Early SWOG studies with CHOP reported complete response rates of 50%-55%, with 30%-35% long-term disease-free survival. Moreover, the newer regimens were more toxic and expensive.

A recently reported investigation suggests an advantage with the addition of etoposide to the CHOP regimen (CHOEP) given every 2 or 3 weeks.

3. Bone marrow transplantation

Bone marrow transplantation can be used in the setting of a clinical trial. Several randomized prospective trials evaluated the role of autologous bone marrow or stem cell transplantation consolidation versus chemotherapy alone in patients in first remission with diffuse large cell lymphoma. Although most of these trials demonstrated significant increases in EFS (by 10% to 20%) among patients who received high-dose therapy, significant differences in OS could not be demonstrated prospectively in any of the series.

2. Age ≤ 60 years at high intermediate or high risk

The 5-year survival rate in younger patients deemed at high intermediate or high risk (high LDH level and/or nonambulatory performance status) is < 50%. Since the clinical features that correlate with relapse are also associated with a decreased likelihood of achieving an initial remission, these patients should be offered participation in clinical trials of dose-intensive treatment strategies aimed at improving the rates and durability of complete responses.

3. Age > 60 years

All patients older than age 60 should undergo evaluation of cardiac, pulmonary, and renal function and coexistent illness, which may complicate therapy.

Most older patients with advanced-stage aggressive NHL have 5-year survival rates < 50% as a result of decreased initial response, poor tolerance to therapy, and the need for dose reduction because of age. Approaches to elderly patients should include interventions aimed at preserving or increasing dose intensity and improving tolerance of therapy with the use of cytokines and infusional chemotherapy.

Patients with compromised cardiac function require individualized approaches, such as the use of a regimen that does not contain an anthracycline (eg, CVP, C [cyclophosphamide]-MOPP, or CEPP [cyclophosphamide, etoposide, procarbazine, and prednisone]); a reduction in total anthracycline dose (eg, by alternating CHOP with C-MOPP or CEPP); or the administration of doxorubicin by continuous infusion. Similarly, bleomycin should not be used in patients with compromised pulmonary function.

Irradiation may be added if there is localized residual disease after chemotherapy completion to improve local control. Irradiation can also be delivered to prechemotherapy areas of bulky disease, again to enhance local control. These recommendations are based on the observation that when DLBCL relapses after definitive chemotherapy, it usually does so in initially
involved or bulky areas of disease.

Special types of aggressive disease

Disease site or potential toxicities may influence the treatment plan:

In younger patients, a brief period of chemotherapy (3-4 cycles of CHOP) followed by local irradiation may be used to prevent sterility in men and early menopause in women.

Lymphomas of the head and neck: chemotherapy alone to avoid the acute mucositis and long-term xerostomia associated with radiation therapy fields.

Gastric or small intestinal lymphoma at high risk of perforation or life-threatening hemorrhage may require surgical resection. Alternatively, chemotherapy followed by local irradiation may allow gastric preservation in some patients. Fully resected gastric or small intestinal lymphoma should be followed by chemotherapy.

Primary brain lymphomas continue to be problematic. At present, the recommended approach is chemotherapy, high-dose methotrexate ± other drugs that penetrate the CNS (i.e. cytarabine [Ara-C], procarbazine, vincristine, thiotepa [Thioplex], temozolomide [Temodar]), in conjunction with radiation therapy. Optimal dose and scheduling of radiation therapy remain to be determined (long-term neurotoxicity may be excessive in older populations).

Testicular lymphoma: orchiectomy followed by combination chemotherapy with an anthracycline-containing regimen has improved the results of therapy for primary testicular lymphoma. Because of the increased risk of recurrence in the CNS and opposite testis, intrathecal chemotherapy (though controversial because relapse is primarly CNS parenchymal disease) and irradiation to the contralateral testis are recommended.

Relapsed high grade lymphoma

Bone marrow transplantation

Bone marrow transplantation is the treatment of choice for patients whose lymphoma has relapsed. Preparative drug regimens have varied; some investigators also use total-body irradiation. Similar success has been achieved using autologous marrow, with or without marrow purging, and allogeneic marrow.

Benefits

• Preliminary studies indicate that approximately 20% to 40% of patients will have a long-term disease-free status, but the precise percentage depends on patient selection and the specific treatment used.

• Event-free survival was significantly improved with transplantation vs. chemotherapy and involved field radiation (46% vs. 12%). Overall survival was also significantly better with transplantation (53% vs. 32%). Salvage bone marrow transplantation was unsuccessful for patients on the nontransplant arm whose disease relapsed (PARMA trial).

Chemotherapy

In general, retreatment with standard agents rarely produces a cure in patients whose lymphomas relapse. Patients who relapse with aggressive lymphoma after 3 years in remission have similar prognoses to de novo lymphoma using curative therapy. Several salvage chemotherapy regimens are available.

• MINE: 70% response rate, 50% complete remission rate, median survival of 2yrs
• ESHAP: 60% response rate,  median survival of 1.8yrs
• DHAP: 55% response rate, 25% survival at 2yrs (In patients who have relapsed after more than 1yr, the response rate is 70% vs 40%)

Rituximab

Rituximab can induce responses in 33% of patients with relapsing aggressive lymphoma of appropriate phenotype (CD20-positive).

Ibritumomab

Radiolabeled anti-CD20 monoclonal antibodies, such as iodine-131 tositumomab and yttrium-90 ibritumomab, induce 60% to 80% response rates in patients with relapsed or refractory B-cell lymphoma.

Denileukin difitox, a fusion protein combining diptheria toxin and interleukin-2, resulted in a 25% objective response rate in 45 heavily pretreated patients with aggressive B-cell non-Hodgkin's lymphoma (CD25, i.e., interleukin-2 receptor, expression was not correlated with response).

AIDS related lymphoma

Outside the context of a clinical trial, low-dose chemotherapy should be considered for most patients with HIV infection and a CD4 lymphocyte count under 200. Although m-BACOD was used in the randomized trial, many clinicians now employ half-dose cyclophosphamide, doxorubicin, vincristine, and prednisone (CHOP).

Prognosis and survival

Indolent lymphomas usually have a long overall survival (8-12 years). Median disease-free survival is almost always between 1.5 and 3 years, and median overall survival ranges from 5 to 7 years. Patients with stage III disease have a better prognosis than patients with stage IV disease. Overall, 75% of patients with stage III disease can be expected to survive 5 years.

International Prognostic Index Scoring  for intermediate to high grade lymphoma

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