Chapter 130:  Non–Hodgkin’s Lymphomas

Follicular Lymphoma

Figure 130.1

Follicular lymphoma grade I (low power).

Figure 130.1

.

Follicular lymphoma grade I (low power).

Figure 130.2

Follicular lymphoma grade I (high power).3

Figure 130.2

.

Follicular lymphoma grade I (high power).3

Fig. 130.1

Fig. 130.2

Early studies suggested that follicular lymphoma and normal follicular center B cells were related by the expression of cell surface antigens, specifically C3 receptors.^32,33 Additional immmunologic studies of normal lymph node and follicular lymphomas have further supported this hypothesis. Virtually all follicular lymphomas express monoclonal sIg.³⁴ In most cases, the Ig isotype is μ±δ or μ±γ, although occasional cases lack sIg. Virtually all cases express HLA-DR, pan-B-cell antigens (CD19, CD20) CD21, CD10, but lack CD5. Lymphocyte functional antigen-1 (LFA-1) (CD11a/CD18) is more frequently noted on tumor cells at initial diagnosis (60–90% of cases) than at relapse. Other adhesion molecules including CD44, ICAM-1 (CD54), L-selectin (CD62L) and LFA-3 (CD58) are present in about half the cases examined.^35,36

FLs account for approximately 22% of NHLs, with grade I subtype being the most common.³⁰ While uncommon until the third and fourth decades, these lymphomas most frequently present in middle-aged individuals and the elderly, with a median age at diagnosis of 60 years. This histologic subtype is less common in Asians and blacks. Patients usually present with painless peripheral adenopathy in the cervical, axillary, inguinal, and femoral regions. Often, lymph node enlargement has been present for long periods of time, and the nodes have waxed and waned. Hilar and mediastinal nodes are often involved, but mediastinal masses are rare. Some patients present with asymptomatic large abdominal masses, with or without evidence of gastrointestinal and/or renal obstruction. Although patients may present with one or more sites of nodal disease, staging studies usually demonstrate widely disseminated disease with involvement of the spleen (40%), liver (50%), and bone marrow (60–70%). Bone marrow involvement in follicular lymphoma reveals a unique pattern of paratrabecular infiltration. Very few patients present with extranodal extramedullary disease, and only about 20% present with B symptoms or LDH elevation. Central nervous system involvement is uncommon although peripheral nerve compression and epidural tumor masses causing cord compression may develop. There are no characteristic laboratory abnormalities specifically associated with follicular lymphoma.

The course of this disease is quite variable. Some patients can be observed with waxing and waning disease for 5 years or more, without the need for therapy.³⁷ Others present with more disseminated disease and rapid growth and require treatment because massive nodal or organ enlargement leads to pain and lymphatic or organ obstruction. Peripheral blood involvement is reported in up to one-third of patients. Historically, both disease-free and overall survival rates for these patients have not changed in spite of many different therapeutic approaches. These patients survive long periods, however. The median survival for patients with stages III and IV disease is between 7 and 10 years. Regardless of the long natural history, it should be stressed that except for uncommon presentations of stage I disease, virtually all patients eventually die of this disease.³⁸

Histologic transformation from indolent to diffuse aggressive lymphoma occurs in up to 60% of patients with follicular lymphoma and is associated with rapid progression of lymphadenopathy, infiltration of extranodal sites, development of systemic symptoms, elevated serum LDH, and often a poor prognosis.^39–45 The progression from follicular to DLBCL occurs regardless of whether the follicular lymphoma is treated aggressively or conservatively and occurs at a rate of about 5 to 10% per year depending on the degree of the large cell component.³⁸ At autopsy, the overwhelming majority of patients (95%) with follicular lymphoma demonstrate some evidence of DLBCL.

Follicular lymphoma grade III is synonomous with what is often referred to as follicular large cell lymphoma. In contrast to other follicular lymphomas, this histologic variant has less infiltration of the marrow and presents with larger masses. Unlike the follicular small cleaved cell, the follicular large cell uncommonly circulates in the peripheral blood. Although the follicular morphology is preserved, the clinical presentation, behavior, and outcome with treatment are very similar to those of diffuse large B-cell lymphoma.^46,47

Small Lymphocytic Lymphoma

Figure 130.3

Small lymphocytic lymphoma.

Figure 130.3

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Small lymphocytic lymphoma.

Fig. 130.3

Figure 130.4

Diffuse large B-cell lymphoma.

Figure 130.4

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Diffuse large B-cell lymphoma.

Fig. 130.4

Lymphoplasmacytic Lymphoma (Immunocytoma)

Lymphoplasmacytic lymphoma is an indolent lymphoma composed of diffuse proliferation of small lymphocytes with evidence of maturation to plasma cells.⁵⁴ Evidence of Ig is seen in these cells by special stains or inclusions. These tumors express pan-B-cell antigens CD19, CD20, CD22, and sIgM, and, in general, absence of CD5, CD10, CD23. Adhesion molecules expressed on approximately half these tumors include L-selectin, ICAM-1, CD44, and CD11c. The majority express LFA-1.

Lymphoplasmacytic lymphoma represents about 1% of all NHLs.³⁰ Clinically, this disease is similar to SLL. The median age is early 60s, and virtually all patients have stage IV disease by virtue of bone marrow involvement. B symptoms and elevated serum LDH are uncommon. The disease can also involve peripheral blood. A serum M component is commonly seen. The median survival for these patients is less than that in SLL, in the range of 5 to 7 years.

Marginal Zone Lymphomas

Marginal zone lymphomas (MZL) are a group of distinct entities in REAL which includes nodal MZL, extranodal MZL, also known as the lymphomas of mucosal associated lymphoid tissues, and the splenic MZL.^55–57 In nodal MZL, the tumor cells cytologically resemble “normal” monocytoid B cells and often involve lymph node sinuses. Phenotypically these tumors are similar to hairy cell leukemias by their expression of sIgM, pan-B-cell antigens (CD20), and the adhesion molecule CD11c.

The extranodal MZL⁵⁸ tumor cells express pan-B-cells antigens (CD19, CD20), complement receptors (CD21 and CD35), and slgM (occasionally IgG or IgA) but lack IgD. It is hypothesized that these are malignancies of memory B cells. Cytologically, these tumor cells resemble monocytoid B cells as well as small cleaved cells. A pathopneumonic feature of extranodal MZL is a lymphoepithelial lesion associated with centrocytes. These tumors do not form follicles, but the malignant cells surround reactive follicles. When the extranodal MZL spreads to the lymph nodes, the neoplastic cells involve the marginal zones.

Splenic MZL is closely related to the other MZLs, with expansion of marginal zones in the spleen marrow and peripheral blood involvement (referred to as splenic lymphoma with villous or nonvillous lymphocytes) can be present. Cytologically, these cells range from small cells to large “blasts.” In contrast to the other MZLs, the splenic MZL cells express IgM and generally IgD, pan-B-cell antigens, and variable expression of CD21 and CD35. The majority of splenic MZL expresses many of the adhesion receptors, including LFA-1, CD11c/CD18, CD44, CD49d, CD29, and ICAM-1, but lack L-selectin.

Extranodal MZL constitutes about 5% of all NHLs.³⁰ B symptoms are uncommon. Patients with extranodal MZL generally present with stage I or II disease. There is no age predilection for these tumors, which most commonly involve the gastrointestinal tract (stomach, most commonly), lung, lacrimal and salivary glands, skin, thyroid, and breast, but usually not peripheral blood and marrow. Patients can present with peptic ulcer disease, abdominal pain, and sicca syndrome, or a mass at the site of involvement.⁵⁹ These lymphomas can disseminate to other mucosal associated lymphoid tissue (MALT) sites or marrow in about 30% of cases, more typically later in the course of the disease. These diseases have high complete remission rates and potentially long survival, as high as 80% at 10 or more years.^60,61 There are a subset of gastric lymphomas which have high-grade features as well as evidence of “low-grade” MZL. The survival rates of these patients appear to be lower than those of patients with gastric MZL or DLBCL involving the stomach.

Nodal MZL constitutes 1% of all NHLs; the median age of patients is reported to be 44 years to as high as 58 years.³⁰ Over 70% of patients present with stage III/IV disease, although bulky adenopathy is uncommon. The majority are asymptomatic. Bone marrow involvement is less common than in most indolent lymphomas, and gastrointestional involvement is unusual. The median suvival of these patients is in excess of 12 years.^55,61

Splenic MZL constitutes <5% of all NHLs, with a median age of 65 years, uncommon before age 50 years.³⁰ Patients present with splenomegaly (often with hypersplenism), often with peripheral blood and focal bone marrow involvement, and therefore, over 90% have stage IV disease. The liver is also involved as evidenced by biopsies. The survival of patients is in excess of 70% at 10+ years, with splenectomy being the treatment of choice.⁵⁷

Similar to other indolent lymphomas, MZL has the potential to transform into a higher-grade lymphoma. There are also patients who present with extranodal MZL, with dissemination to nodal sites, spleen and bone marrow. In these cases, it is unclear exactly where the disease originated.

Mantle Cell Lymphoma

Although mantle cell lymphoma (MCL) is grouped with the “indolent” lymphomas in REAL, from a clinical viewpoint, MCL is more appropriately grouped with the aggressive diseases.^62–66 MCL has been previously referred to as intermediate lymphocytic lymphoma, mantle zone lymphoma, centrocytic lymphoma, and lymphocytic lymphoma of intermediate differentiation.^67,68 In the Rappaport and Working Formulation classifications, the majority of cases of diffuse small cleaved cell lymphomas on review are MCLs.²⁹ These tumors are neoplastic counterparts of naive “mantle zone” B cells. Morphologically, MCLs can have either diffuse architecture or a vaguely nodular appearance, occasionally with expansion of the mantle zone of secondary lymphoid follicles. Cytologically, the neoplastic cells are medium sized, with irregular nuclei. Some cases of MCL have a predominance of “blastic” cells with a high mitotic rate. The immunophenotype can be variable, with cells expressing pan-B-cell antigens, IgM±D, and CD5 but, in contrast to follicular lymphoma and SLL, lack CD10 and CD23, respectively.⁶⁹ When MCL involves the gastrointestinal tract (lymphomatous polyposis),^70,71 the tumor cells express the adhesion molecule α4β7 integrin, which is normally involved in lymphocyte homing to the endothelial cells in the gastrointestional tract. Overexpression of cyclin D1 protein (intracellular) further distinguishes these tumors from other entities.

MCL constitutes about 5% of all NHLs.^30,66 About three-fourths of patients are males, with a median age of 63 years. Approximately 70% of patients have stage IV disease, and systemic B symptoms are observed in approximately one-third of patients. Typical sites of involvement include diffuse adenopathy, spleen, liver, and bone marrow. Peripheral blood involvement is present in approximately 25% of patients at presentation. Mantle cell lymphoma can involve any region of the gastrointestinal tract, occasionally presenting as multiple intestinal polyposis. Over the course of the disease, MCL behaves progressively more aggressive. The median survival of patients with MCL is 3 to 4 years.

Diffuse Large B-Cell Lymphoma

Fig. 130.4

DLBCL constitutes about 30% of all NHLs and is the most common histologic subtype.³⁰ Patients who are generally middle-aged or older (median age 64 years) present with either nodal enlargement (especially in the neck or abdomen) or extranodal disease (in the gastrointestinal tract, testis, bone, thyroid, salivary glands, skin, and brain). These tumors present in a localized (stage I or IE) manner approximately 20% of the time. The disease is confined to one side of the diaphragm (stage I or II) in approximately 30 to 40% of patients. Disseminated stage IV disease is seen in approximately 40% of patients and is usually defined by extranodal extramedullary infiltration.^76–78 B symptoms are observed in approximately 30% of patients, and unlike most NHLs, the serum LDH is elevated in over half the patients. During the course of the disease, the liver, kidneys, and lung may be involved. DLBCL is highly invasive, with local compression of vessels or airways, involvement of peripheral nerves, and destruction of bone. Although bone marrow involvement initially is found in only 10 to 20% of patients, its detection is important because of its strong correlation with later spread to the CNS.^78–80 Extranodal disease and elevated LDH are other risks for CNS dissemination.⁸⁰ Therefore, cytologic examination of spinal fluid is important in patients with bone marrow infiltration.

Within DLBCL is a distinct clinical entity known as primary mediastinal large B-cell lymphoma.^81–83 Histologically, the cellular infiltrate is heterogeneous, the neoplastic cells are pleomorphic, and sclerosis is frequently present. The immunophenotype of these lymphomas includes pan-B-cell antigens (CD19, CD20, CD22) but they are often negative for surface and cytoplasmic immunoglobulin.

Primary mediastinal large B-cell lymphoma has a female predominance, with age range of 30 to 40 years. Over 70% of these patients present with stage I/II bulky disease involving the mediastinum and pleural and pericardial effusions in about one-third. Similar to DLBCL, an elevated LDH is present in the majority, whereas bone marrow involvement is infrequent. The prognosis of patients with primary mediastinal larrge B-cell lymphoma is similar to that of patients with DLBCL.⁸⁴

Precursor T- or B-Lymphoblastic Leukemia/Lymphoma

Figure 130.5

T lymphoblastic lymphoma.

Figure 130.5

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T lymphoblastic lymphoma.

Fig. 130.5

The vast majority of lymphoblastic lymphomas are of T-cell lineage.^102–106 Several investigators have noted that most (49%) T-cell LLs correspond to common (stage II) thymocytes (CD4+, CD1a+, CD8+) with the remaining cases early (30%) or late (20%) thymocytes (CD38+ or CD3+, CD4+ or CD8+, respectively).¹⁰⁷ Crist and colleagues have examined the relationship between clinical outcome and maturational stage and found no differences among these subgroups.¹⁰⁸ Most T-cell LLs also lack surface CD3 but express CD5, CD1, CD71, CD38, CD7, and the p75 subunit of the IL-2R.^{103,104,106,107,109–111} In addition, one-third of cases are HLA-DR+, and most express LFA-1 (CD11a/CD18).⁷² Again, as observed in T-cell LLs, the majority of the CD3- cases expressed cytoplasmic CD3. In contrast to these findings, T-cell LLs have been observed to be highly heterogeneous, with CD2 and CD38 (+/-CD1) expression being the most consistent cell surface phenotype. From a clinical point of view, as well as by cell surface markers, T-cell ALL and T-cell LLs have considerable overlap. Approximately 50% of T-cell LLs express the homing receptor/cell adhesion molecule CD44, and this expression correlates with stages of intrathymic differentiation. The CD4- CD8- T cell LLs are CD44+, whereas the CD4+ CD8+ cells are CD44-. The presence of CD44 did not correlate with leukemic presentation, however. One difference which has been noted is that approximately 40% of T-cell LLs express CD10, whereas less than 10% of T-cell ALLs are CD10+. Several cases of non–T-cell LL have been reported. These include rare cases where the neoplastic cells express antigens present on NK cells. Approximately 10 to 15% of LLs have a pre–B-cell phenotype by expression of HLA-DR, CD10, CD24, and, in some cases, cytoplasmic μ as well as surface IgM.

Although LLs represent a major subgroup of childhood NHLs, they are much less common in adults (2% of adult NHLs).³⁰ Patients are usually males in their 20s or 30s who present with lymphadenopathy in the cervical, supraclavicular, and axillary regions (50%) or with a mediastinal mass (50–75%).¹¹² In most patients, the mediastinal mass is anterior, bulky, and associated with pleural effusions. These masses can be associated with such complications as superior vena caval syndrome, tracheal obstruction, and pericardial effusions (with or without tamponade). Less commonly, patients present with extranodal disease (e.g., skin, testicular, or bony involvement). Abdominal involvement is very unusual, but when it does occur, it is found primarily in the liver and spleen. Greater than 80% of patients present with stage III or stage IV disease and almost 50% have B symptoms, and majority have elevated LDH. Although the bone marrow is frequently normal at presentation, approximately 60% of patients develop bone marrow infiltration and a subsequent leukemic phase indistinguishable from T-cell ALL.¹¹³ Patients with bone marrow involvement have a very high incidence of CNS infiltration. Regardless of whether the patients present with bone marrow involvement, evaluation of the spinal fluid is essential. Prior to current aggressive acute leukemia-type therapy, this disease was rapidly fatal. B-cell LL is a very rare variant, affecting patients with a median age of 39 years.¹¹⁴ B-cell LL presents without a mediastinal mass but instead involves lymph nodes and extranodal sites. The prognosis for these patients may be better than that for adults with T-cell LL.

Burkitt’s and Burkitt’s-Like Lymphoma

Cytologically, Burkitt’s lymphoma (BL) cells resemble the small noncleaved cells within normal germinal centers of the secondary lymphoid follicle. These cells differ from LL cells in two respects: (1) they have intermediate-sized nonconvoluted nuclei with coarse chromatin, and (2) the cells have more abundant cytoplasm. Due to the high mitotic rate, frequent mitotic figures are seen, and analogous to normal germinal centers, tingible body macrophages are seen giving the classical “starry sky” appearance. Although the Burkitt-like is similar to BL, the cells have greater pleomorphism and fewer nucleoli.¹¹⁵

BL is a tumor of B-lineage derivation by the expression of a variety of B-cell restricted antigens, including CD19, CD20, sIgM±D, as well as HLA-DR.^116–120 Further examination of these lymphomas has demonstrated that these tumors express CD10.¹²¹ The expression of CD21, the EBV/C3d receptor is dependent upon the EBV status of the tumors. The endemic BL which are EBV positive express CD21, whereas the vast majority of nonendemic BL are EBV negative and lack CD21 expression. BL generally lack the adhesion molecules LFA-1 (CD11a/CD18), p150/95 (CD11c), and CD44. The normal B lymphocyte from which these lymphomas are derived is controversial. Studies of normal lymphoid tissues, including the observation that CD10, several B-cell activation antigens, and the BL–associated glycolipid antigen CD77 are detected in the germinal centers of lymph nodes, suggest that BL may be the neoplastic counterpart of a subset of normal activated B cells. The immunophenotype of Burkitt’s -like lymphomas is very similar to BL, although the expression of CD10 and CD21 is more variable.

BL is, in general, a childhood tumor that has two major clinical presentations. The endemic (African) form presents as a jaw or facial bone tumor that spreads to extranodal sites, including the ovary, testis, kidney, breast, and especially the bone marrow and meninges. The nonendemic or American form has an abdominal presentation with massive disease, ascites, and renal, testicular, and ovarian involvement and, like the endemic form, also spreads to the bone marrow and central nervous system. BL has a male predominance. Prior to aggressive therapeutic programs, all patients died rapidly. These tumors are now treated with aggressive chemotherapeutic programs with more gratifying results. BL is rare in adults, typically seen in patients less than 35 years of age, and occurs virtually always in the nonendemic form . Burkitt’s-like lymphomas, also a rare disease, occurs in patients with a median age of 55 years, but also has a male predominance. This is an aggressive disease involving the lymph nodes, the nasopharynx, and the gastrointestional tract. Occasionally, B-LL presents as solitary bone tumor. Like Burkitt’s lymphoma, these tumors have a high propensity to invade the bone marrow and CNS. LDH is often elevated and B symptoms present in about one-third of patients.

Early-Stage Indolent NHL

The majority of patients with indolent NHL present with advanced disease. Only 15 to 30% of patients have clinical stage I/II disease, and less than 10% have pathologic stage I/II.¹⁸⁰ For this reason, limited studies are available concerning treatment for early-stage-disease. In the largest study with exceedingly long follow-up of 177 patients from Stanford, 44% patients had stage I and 56% had stage II disease.²⁵² Patients were treated with either involved field irradiation (IF), extended field irradiation (EFI), with a limited number receiving total lymphoid irradiation (TLI). Survival rates at 10, 15, and 20 years were 64%, 44%, and 35%, respectively. The relapse-free survival at 10, 15, and 20 years, was 44%, 40%, and 37% respectively. The freedom from recurrance (FFR) was significantly better for patients under age 60 years and for patients who received radiation to both sides of the diaphragm (although there was no difference in overall survival). Late second tumors have been noted in 17% of the patients treated with extensive radiotherapy, whereas the incidence of second solid tumors was 6.8% in patients who received involved or extended field radiation. Patients treated with EFI generally relapsed in contiguous lymphatic sites, in contrast to patients treated with TLI who generally relapsed in extralymphatic sites. Several other studies have similarly observed that early stage patients treated with radiotherapy have 10-year relapse-free survival of 45 to 60%, with overall 10-year survivals of 60 to 80%.^253,254

In low-stage disease, chemotherapy alone has rarely been used due to the radioresponsiveness of these tumors. Several studies have employed local radiotherapy with adjuvant chemotherapy (CVP), and there appears to be no significant advantage of combined modality over local radiotherapy.^254–257 Monfardini and colleagues reported a 5-year relapse-free survival of 55% and overall survival of 62% for patients treated with radiotherapy, while patients treated with combined modality therapy had a 5-year relapse-free survival and overall survival of 63% and 93%, respectively. There was no statistically significant difference between these treatment arms. A retrospective study by McLaughlin and colleagues reported that the relapse-free survival was 64% versus 37% for patients receiving CHOP chemotherapy plus radiotherapy or radiotherapy alone, respectively. Whether these improved results are due to the more aggressive regimen used remains to be determined in a prospective randomized study. The benefit of chemotherapy in stage I/II indolent NHL remains uncertain.

The extranodal MZLs often present with localized disease involving the gastrointestional tract, salivary glands, thyroid, orbit, conjunctiva, breast, and lung.^56,61 The gastric MZLs are managed differently from those involving other sites. Since many cases of gastric MZL appear to be a B-cell clonal expansion in response to Helicobacter pylori, treatment has been directed at the chronic gastritis. Therapy with antibiotics (metronidazole, amoxicillin, clarithromycin) and often a proton pump inhibitor induce regression of superficial low-grade MZL of the stomach in over 70% of patients. The long-term remission status of these patients remains unclear. For patients with localized disease who progress after antibiotic therapy or are H. pylori-negative, IFI with or without surgical resection has a 10-disease-free survival year of about 90%. For other sites of extranodal MZL, since these diseases tend to remain localized for long periods of time prior to systemic spread, surgery remains a highly effective approach, often with adjuvant IFI. The use of chemotherapy with alkylating agents for MZL has received limited attention.

Advanced-Stage Indolent NHL

The long natural history of indolent NHLs and the lack of symptoms in the majority of patients at diagnosis have fostered close observation as the initial approach to some of these patients.^37,38 The advantages of this approach include a prolonged period free of treatment during which tumor cells will not be selected for drug resistance by continuous exposure to drugs. Moreover, spontaneous remissions of longer than 1 year have been reported from Stanford in 23% of patients, making treatment unnecessary in this subgroup of patients.^37,258,259 Withholding therapy requires a cooperative patient and the need for close follow-up. The possibility of developing aggressive disease either by virtue of site or histologic change can occur despite close observation. In the study from Stanford University, where patients were randomized either to initial therapy or to deferred treatment until the time of symptoms (usually progressive bulky disease), there was no difference in the 4-year actuarial survival between the two groups. The median time until therapy was administered for the entire group of indolent lymphoma patients was 3 years. However, for the three histologic subtypes, the median time until requiring therapy differed: 16.5, 48, and 72 months for FL grade II (follicular mixed small cleaved and large cell), FL grade I (follicular small cleaved cell), and SLL, respectively.²⁶⁰

In general, systemic chemotherapy has been used for the treatment of advanced-stage indolent NHL. However, fractionated total body irradiation (TBI) has been employed in the treatment of patients with stage III/IV disease with a high CR rate (70–85%).^260,261 The relapse-free survival has been reported to be approximately 25% at 5 years in studies from both Stanford University and the National Cancer Institute (NCI).

Indolent NHLs are very sensitive to both single-agent and combination chemotherapy.³⁸ The CR rates of previously untreated patients to single alkylating agents range between 30 and 60%. However, the median duration of CR with either single alkyating agents, such as cyclophosphamide, or with combinations, such as CVP, is only about 2.5 years. A study from Stanford University which compared daily single alkylating agent treatment, combination chemotherapy (CVP), and TBI, in patients with FL grade I/II and SLL has similarly reported that there is no significant difference in relapse-free survival or overall survival with these different regimens.²⁶⁰ They did note that the median time to achieve CR was 12 months, 5 months, and 3 months for single-agent CVP and TBI, respectively. In general, with either single agents or CVP, only 20 to 25% of patients are disease free at 4 years.⁴² Following relapse, these diseases continue to be sensitive to single agents and CVP; and the median relapse-free survival progressively decreases with each subsequent relapse.

In an attempt to improve the relapse-free survival and overall survival in patients with indolent NHL, more aggressive combination chemotherapy regimens have been used.^262–265 Regimens such as MOPP, BACOP, M-BACOD, CHOP, and BVCP have been observed to give CR rates of 35 to 70%, but the median disease-free survival remains similar to that seen with CVP, in the range of 1.5 to 3 years.

It has been suggested that the response of FL grade II (follicular mixed small cleaved and large cell) to aggressive therapy is different from FL grade I. Studies from the 1970s suggested that patients with FL grade II treated with combination chemotherapy (C-MOPP, CHOP-Bleo), had a high CR rate and significant number of patients (>50%) were still in CR 5-7 years after treatment. This suggested that FL grade II might be curable with aggressive combination chemotherapy.^266–268 However, a prospective randomized trial comparing cyclophosphamide-prednisone, C-MOPP, and BCVP failed to demonstrate significant long-term disease-free survival for patients with FL grade II.²⁶⁹ With the difficulty of reproducible grading of these histologies, it is unclear whether patients with this histology have a different outcome than do patients with FL grade I.

Several randomized trials have looked at the impact of combination chemotehrapy in patients with advanced FL.²⁷⁰ When patients were randomized to cyclophosphamide-prednisone, BCVP, or CVPP, the progression-free survival was greater with CVPP, but no differences in survival were noted. When the role of Adriamycin was examined by comparing COP-Bleo with CHOP-Bleo (and CHOP-BCG), no differences were seen. Finally, when CHOP-Bleo was compared with cyclophosphamide alone in patients with FL, there was a survival advantage for the patients with FL grade II, although there has not been a recent update of this data.

The rationale for combined modality therapy stems from the observation that systemic extranodal sites of relapse are common following radiation therapy, and that radiation therapy provides excellent local control for low-grade lymphomas. Studies from the NCI and Stanford University failed to demonstrate an improved disease-free survival or overall survival for patients treated with CVP±TBI or CVP±TLI, respectively. Investigators at M.D. Anderson Cancer Center report in stage III patients with FL treated with CHOP-bleomycin and IFI an 81% CR rate, a 75% 5-year survival, and 52% relapse-free survival for the entire patient population.²⁷¹ A study from NCI attempted to address two issues: first, the role of aggressive combined modality therapy; and second, whether early institution of aggressive therapy affects the natural history of the disease.²⁷² In this study, patients with stage III/IV follicular and SLL were randomized to either no initial therapy or ProMACE-MOPP followed by TLI. Of the 104 patients, 14% were not randomized but required initial treatment with a 71% CR rate, but only 33% are in unmaintained remission with a median follow-up of 23+ months. The patients who were randomized to initial aggressive treatment had a high CR rate (78%), and 86% are in first CR from 1+ to 82+ months. In contrast, 44% of the patients initially randomized to observation have crossed over with a lower CR rate (43%) than those treated initially with combined modality treatment, and 71% of those treated remain in CR from 4+ to 40+ months. To date, there is no difference in the overall survival between patients treated initially and those treated after a period of observation, with over 75% of patients alive at 5 years. From this study, it appears that patients who have disease requiring initial treatment or progressive disease necessitating treatment have a lower CR rate than those treated initially.

Interferon-α is an active agent in relapsed indolent NHL (predominantly, follicular NHL). Several prosective randomized trials have examined the role of interferon when added to combination chemotherapy for advanced-stage disease patients.^273–277 These studies have generally reported a significant effect on progression-free survival, with only two trials which involved maintenence interferon-α observing a significant prolongation in overall survival.

The purine analogues 2-chlorodeoxyadenosine (2-CdA) and fludarabine, which are very active agents in hairy-cell and chronic lymphocytic leukemia, respectively, are also active agents in indolent NHL.^278–284 In previously treated patients, 2-CdA induced responses in about 40% of patients, half of which were CRs and the other half PRs, with a median duration of response of 5 months. The response rate (RR) to fludarabine ranges from 45 to 65%, with less than 20% CR. In previously untreated patients, the response rate to fludarabine was 84% RR, with 32% CR. Fludarabine has been used in combination with other drugs, including cyclophosphamide (100% RR, 89% CR) as well as mitoxantrone (91% RR, 43% CR, progression-free survival 63% at 2 years),²⁸⁵ with encouraging results. Ongoing phase III trials will attempt to address the efficacy of these combinations, as compared with standard regimens.

Monoclonal antibody (mAb) therapies have received much attention for the treatment of indolent NHL.²⁸⁶ The “humanized” anti-CD20 mAb Rituxin has a 50 to 60% RR, with 6% CR, in patients with previously treated FL.²⁸⁷ In SLL, the response rate is significantly lower, about 10%. The median duration of responses is about 9 months. The major toxicity of Rituxin is largely infusion related, with fevers, rigors, and hypotension usually associated with the first infusion. Rituxin has been combined with CHOP chemotherapy, with encouraging preliminary results. There are several radioimmunoconjugates which are being investigated in the treatment of indolent B-cell NHL, to deliver targeted radiotherapy.²⁸⁶ Bexxar which is a murine anti-CD20 mAb conjugated to 131-iodine appears to have a higher response rate than Rituxin in patients with relapsed disease (67% RR, 17% CR, median disease-free survival 20 months).²⁸⁸ A limited study in previously untreated patients with indolent lymphoma has shown very high CR rates, but follow-up is very limited. Another labelled antibody, 90-y/trium conjugated to the humanized anti-CD20 mAb also looks promising in indolent lymphomas.

Histologic Transformation

It is well recognized that part of the natural history of low-grade NHL is the progression to a higher-grade histologic subtype.^38–41,43 The implications of histologic conversion on prognosis are controversial. Armitage and colleagues compared similarly treated patients who had histologic conversion to DLBCL with “de novo” DLBCL patients and found no instances of prolonged CR in the former group, and a significantly shorter median survival (12 vs. 40 months).⁴⁰ The median survival of a large series of patients with follicular NHL undergoing histologic conversion is 11 months.⁴⁴ An update from Stanford University suggests that patients who were never treated had a better prognosis, as were patients with limited disease.⁴⁵ Although the median survival for the entire group was only 22 months, patients who achieved a CR after conversion had an actuarial survival of 75% at 5 years. As detailed below, a subgroup of patients with a history of indolent NHL who transform to a more aggressive histology may be cured by high-dose therapy and autologous bone marrow transplantation (ABMT).²⁸⁹

Early-Stage Aggressive NHL

Less than 20% of patients with DLBCL have truly localized disease. DLBCLs with nonbulky stage I (I or IE) or limited stage II (II or IIE) disease have been treated with radiotherapy alone with variable results.^253,290,291 Dosages in the range of 4,500 to 5,000 cGy appear to be necessary to maximize local control. Approximately 40% of clinically staged patients experience long-term disease-free survival with radiotherapy alone. A number of studies have demonstrated that patients who received local involved field radiation therapy followed by adjuvant chemotherapy did significantly better than patients who received radiation therapy alone.^292–295 To address the role of radiotherapy in localized diffuse aggressive NHL, a randomized trial of patients with localized DLBCL compared eight cycles of CHOP to three cycles of CHOP plus IFI.²⁹⁶ Patients treated with three cycles of CHOP plus radiotherapy had a significantly better 5-year progression-free survival and overall survival than did patients treated with eight cycles of CHOP (77% vs. 64% for progression-free survival, 82 vs. 72% for overall survival). Overall life-threatening toxicity and cardiac toxicity were significantly higher in the patients receiving CHOP alone. The benefit of attenuated chemotherapy was largely in patients over the age of 60 years.

Advanced-Stage Aggressive NHL

The high CR rate and long-term disease-free survival observed for patients with DLBCL is one of the major success stories of aggressive combination chemotherapy. The treatment of DLBCL chronicles aggressive combination chemotherapy from its inception to the later concepts of resistance, dose intensity, addition of newer agents, and timing of therapy.^{119,297–299} Certain principles have been important in considering the management of aggressive lymphomas in the 1990s. First, aggressive combination chemotherapy should always be administered and dose reduction avoided, if at all possible. Second, attention to prognostic variables is important since they may suggest the need to be more or less aggressive. Third, newer approaches to assess response may ultimately dictate the type of therapy and its duration.

Table 130.8

Combination Chemotherapeutic Regiments for the Treatment (more...)

Table 130.8

Combination Chemotherapeutic Regiments for the Treatment of Intermediate-Grade Non–Hodgkin’s Lymphoma

	Regimen	Dose (mg/m2)	Days Administered	Frequency
First-Generation
C-MOPP	Cyclophosphamide	650 IV	1 and 8	q 28 d
	Vincristine	1.4 IV	1 and 8
	Procarbazine	100 PO	1 to 14
	Prednisone	100 PO	1 to 14
	Cyclophosphamide	750 IV	1	q 21 d
CHOP	Doxorubicin	50 IV	1
	Vincristine	1.4 IV	1
	Prednisone	100 PO	1 to 5
BACOP	Bleomycin	5 IV	15 and 21	q 28 d
	Doxorubicin	25 IV	1 and 8
	Cyclophosphamide	650 IV	1 and 8
	Vincristine	1.4 IV	1 and 8
	Prednisone	60 PO	15 to 28
COMLA	Cyclophosphamide	1500 IV	1	q 91 d
	Vincristine	1.4 IV	1, 8 and 15
	Methotrexate	120 IV	22 and then q week × 7
	Leucovorin	25 IV	q6h × 4 with MTX
	Cytosine arabinoside	300 IV	22 and weekly × 7
CAP-BOP	Cyclophosphamide	650 IV	1	q 21 d
	Doxorubicin	50 IV	1
	Procarbazine	100 PO	1 to 7
	Bleomycin	10SC	1
	Vincristine	1.4 IV	15
	Prednisone	100 PO	15 to 21
Second-Generation
M-BACOD	Methotrexate	200 IV	8 and 15	q 21 d
	Bleomycin	4 IV	1
	Doxorubicin	45 IV	1
	Cyclophosphamide	600 IV	1
	Vincristine	1 IV	1
	Dexamethasone	6 PO	1 to 5
	Leucovorin	10 PO	24 h after MTX then q6h for 8 doses
ProMACE/MOPP	Prednisone	60 PO	1 to 15	q 28 d
	Methotrexate	1500 IV	15
	Doxorubicin	25 IV	1 and 8
	Cyclophosphamide	650 IV	1 and 8
	Etoposide	120 IV	1 and 8
	Leucovorin	50 IV	24 h after MTX then q6h for 5 doses
	Standard MOPP		After remission	q 28 d
Third-Generation
ProMACE/CytaBOM	Prednisone	60 PO	1 to 14	q 28 d
	Methotrexate	1500 IV	15
	Doxorubicin	25 IV	1
	Cyclophosphamide	650 IV	1
	Etoposide	120 IV	1
	Cyclosine arabinoside	300 IV	8
	Bleomycin	5 IV	8
	Vincristine	1.4 IV	8
	Methotrexate	120 IV	8
	Leucovorin	25 IV	24 h after MTX then q6h for 5 doses
MACOP-B	Methotrexate	400 IV	8	q 28 d × 3
	Doxorubicin	50 IV	1 and 15
	Cyclophosphamide	350 IV	1 and 15
	Vincristine	1.4 IV	8 and 22
	Prednisone fixed dose	75 PO	daily for 12 weeks
	Bleomycin	10 IV	28
	Leucovorin	15 PO	24 h after MTX then q6h for 6 doses
COP-BLAM III	Cyclophosphamide	350 IV	1	q 21 d
	Vincristine	1.0 IV	1 and 2 (on alternate cycles)
	Prednisone	40 PO	1 to 5
	Bleomycin	7.5 IV	daily infusion × 5 d
	Doxorubicin	35 IV	1
	Procarbazine	100 PO	1 to 5

Table 130.9

Treatment of Intermediate Grade Non–Hodgkin’s (more...)

Table 130.9

Treatment of Intermediate Grade Non–Hodgkin’s Lymphomas: Complete Remission and Approximate Percentage of Long-Term Survivors

Regimen	Complete Remission Rate (%)	Unmaintained Continuous Complete Remissions (%)
First-generation
C-MOPP	40	30
CHOP	50	30
BACOP	50	35
COMLA	50	30
CAP-BOP	65	35
Second-generation
ProMACE-MOPP	75	50
M-BACOD	70	50
Third-generation
ProMACE-CytaBOM	80	60
COP-BLAM III	85	65
MACOP-B	85	65

There are several issues which arose from the above studies. When responses were reported, the follow-up for most of the regimens was short, and when re-examined at more than 2 years, the true disease-free survival rate significantly decreased. Approximately 10% of patients relapsed beyond 4 years. Moreover, these single-institution response rates could not be repeated in single and multi-institution studies. Because of these results, the Southwest Oncology Group (SWOG) undertook a four-sided phase III study to enroll patients in a randomized trial comparing CHOP, m-BACOD, MACOP-B, and ProMACE-CytaBOM.³⁰⁸ The completed randomized four-arm study, in an analysis of 897 eligible patients with intermediate- or high-grade NHL found no difference in outcome, however, at a median follow-up of 31 months for CHOP, m-BACOD, ProMACE-CytaBom or MACOP-B. Irrespective of stage III or IV, the third-generation regimens failed to improve on CHOP for remission rate or survival. At 4 years, the patients alive without disease were CHOP 36.4%, m-BACOD 34.4%, ProMACE-CytaBOM 45.1%, MACOP-B 38.8% (p = .14). Fatal toxicities were 1%, 5%, 4%, and 6%, respectively.³⁰⁸ There have been additional randomized trials, including comparisons of MACOP-B versus ProMACE-MOPP,³⁰⁹ escalated versus, standard doses of doxorubin in the BACOP regimen,³¹⁰ and CHOP versus m-BACOD,³¹¹ which have clearly demonstrated that more intensive regimens offer no improvement in remission rate and disease-free or overall survival, but increased toxicity.

In the context of the IPI for diffuse aggressive lymphomas,²¹¹ new therapeutic programs for the treatment of DLBCL are being developed. For those patients with the best prognosis, present therapeutic regimens are reasonably effective. In contrast, for those patients who fall into the worst prognostic subgroups, aggressive combination regimens are inadequate. More aggressive regimens, where the doses of cyclophosphamide and Adriamycin are escalated with hematopoietic growth factor support have shown impressive CR rates and durable remissions in phase I/II studies. Similarly, a number of studies have looked at the role of consolidative high-dose therapy and stem cell support for high-risk patients in first remission (see “Stem cell transplant” section).

For the myriad peripheral T-cell lymphomas, similar treatment approaches have been taken for patients with localized and advanced-stage disease. When patients are stratified by the IPI, the failure-free survival and overall survival are generally inferior for patients with aggressive T-cell lymphomas than for patients with B cell disease.

Aggressive Lymphoma in Older Patients

A significant proportion of patients with diffuse aggressive lymphoma are over age 60 years. In the analysis which led to the development of the IPI, the outcome for patients over age 60 years was significantly different from those age 60 years and less. The clinical characteristics of patients above or below age 60 years was similar, and the CR rates were similar or slightly lower than that seen in patients ≤ age 60 years. The relapse-free survival and overall survival for patients over age 60 years in the low- and low-intermediate-risk groups were significantly less than those for patients ≤ 60 years. The reasons for these differences may be related to less intensive treatment delivered as well as the presence of comorbid diseases.³¹² In some studies, increased deaths unrelated to lymphoma or its treatment have been reported, whereas in others an increased treatment-related mortality has been reported, often related to poor performance status.^313,314

Several attempts have been made to modify the chemotherapy for elderly patients.³¹⁵ One approach has been to divide the standard dose of CHOP where the total dose is given over 3 weeks rather than once every 3 weeks. In a randomized trial comparing weekly CHOP with the standard dose, the CR rate and progression-free survival were similar, while the overall survival was better with standard dose CHOP.³¹⁶ In studies where anthracycline-containing regimens were compared with regimens without anthracycline, the myelosuppression has been higher, although treatment-related mortality was not significantly different. More importantly, the CR rate, time to treatment failure, and 5-year survival were better for the anthracycline-containing combination. Substitution of mitoxantrone for Adriamycin has resulted in lower CR rates and 3-year survival.³¹⁷ To date, other regimens have not been shown to be superior to standard dose CHOP for elderly patients with diffuse aggressive NHL.³¹⁸

Follicular Lymphoma Grade III (follicular large cell)

Follicular large cell lymphoma is clinically similar to DLBCL.^{38,46,47,319,320} Although stage I disease is very uncommon, there is a reported cure rate of nearly 90% with IFI or regional radiotherapy.³²⁰ However, many investigators argue that all patients should be treated with aggressive combination chemotherapy, with CR rates of about 80% and 50%, and overall survival of approximately 70% and 60% for stage I/II and III/IV patients, respectively.⁴⁶

Mantle Cell Lymphomas

The median survival of patients with MCL is 3 to 4 years. The treatment of MCL generally involves alkylating agents, resulting in 30 to50% of patients having a CR, with median duration of 1 to 3 years.^63,65,66,69 A randomized trial comparing CVP with CHOP demonstrated no benefit for the addition of doxorubicin in terms of overall survival. Generally, single alkylating agents offer similar results as combination chemotherapy. Newer agents, such as fludarabine and Rituxin, are giving response rates in the range of 30%, with remissions duration similar to that of alkylating agents.^284,321,322 More intensive treatment is being examined in MCL. The results of high-dose therapy and autologous bone marrow transplantation have been generally disappointing in both previously untreated or relapsed patients. A more aggressive induction followed by stem cell transplantation has been investiagted at the M.D. Anderson Cancer Center. Hyper-CVAD regimen, with escalated doses of cyclophosphamide, high-dose methotrexate and cytarabine, has a very high response rate (38% CR).³²³ In this report, all patients went on to either autologous or allogeneic stem cell transplantation. The results for previously untreated patients was encouraging with 3-year event-free survival of 72%. Further study into new induction regimens, including combinations of mAbs and chemotherapy, as well as the role of allogeneic transplantation may impact on the outcome of these patients.

Lymphoblastic, Burkitt’s, and Burkitt’s-like Lymphomas

Lymphoblastic lymphoma in adults has been treated with some success, although inferior to that seen in children.^110,324 A 56% disease-free survival at 3 years has been reported in patients treated with CHOP plus high-dose methotrexate, L-asparaginase, and intrathecal methotrexate. When treated with regimens initially developed for childhood acute lymphoblastic leukemia (e.g., LSA2L2), about 40% of adults are reported to survive at 5 years. CNS prophylaxis is critical in treating this disease, since the CNS is a sanctuary site for recurrence in the absence of prophylaxis. The Burkitt’s and Burkitt’s-like lymphomas in HIV-1–negative adults have been similarly treated with regimens designed for the pediatric populations, which involve the use of high doses of cyclophosphamide, cytosine arabinoside, and CNS prophylaxis with methotrexate.^325–328 Although CR rates are very high, the cure rate is generally less than is observed for DLBCL.³²⁹ In selected series, survivals of 50 to 70% have been reported, although with marrow or CNS disease, the long-term survival ranges from 0 to 30%. An analysis of 65 adults treated on the LMB pediatric protocol reported a CR rate of 89%, with 3-year survival of 74%.³²⁸ Future prospective trials will assess the efficacy of these regimens in Burkitt’s and Burkitt’s-like lymphomas in adults.

Conventional Salvage Therapy

The vast majority of patients with relapsed or refractory NHL have limited benefit from conventional salvage regimens. Patients with primary refractory disease who do not achieve a CR with initial therapy rarely achieve a CR when treated with a non–cross-resistant conventional regimen. Following relapse after a first CR, although a subset of patients achieves CR with standard-dose therapy, these remissions are generally not durable, and long-term disease-free survivors are rare. In a report of approximately 400 patients with relapsed NHL, treated with a variety of salvage regimens, only 3% were in continuous CR at 2 years.³³⁰

In an attempt to improve the disease-free survival for patients with relapsed or refractory disease, a number of regimens have been developed with non–cross-resistant drugs at higher doses. These regimens have included single-agent regimens, as well as combinations of cisplatin/carboplatin, etoposide, ifosfamide, and cytosine arabinoside.^332–336 The response rates for these salvage regimens have ranged from 20 to 77% with upward of 30% CRs reported. The duration of these responses and overall survival of these patients is generally short. Another approach for salvage therapy has been the use of continuous infusions of cyclophosphamide, etoposide, doxorubicin (CDE, EPOCH). The overall responses are in the range of 40 to 80%, with approximately 20% CRs.^337,338 Patients who relapse within 12 months of diagnosis of aggressive NHL have a significantly lower response rate to salvage therapy (DHAP) than patients who relapse 12 months or more after diagnosis (40% versus 69%).³³⁹ Although a higher response is seen in indolent NHLs, the response rate of patients with relapsed aggressive NHL to Rituxin is 31% (22% PR, 9% CR).³²²

Syngeneic and Allogeneic Bone Marrow Transplantation in NHL

Only a limited number of patients with NHL have undergone syngeneic BMT. The largest published series involved 8 patients, seven with aggressive NHL and 1 with indolent NHL.³⁴⁰ All were treated with cyclophosphamide and TBI followed by identical twin marrow re-infusion. The majority of patients were in resistant relapse, with 1patient in CR after BMT. Seven of the patients achieved CR and 4 patients were reported to remain in continuous complete remission (CCR) from 12 to 126 months after syngeneic BMT.

Allogeneic stem cell transplantation has received increasing attention for patients with relapsed and refractory NHL.^341–346 Allogeneic transplant offers potential benefit of a tumor-free marrow and possible graft-versus-lymphoma effect. The majority of patients had aggressive lymphomas, although increasingly patients with indolent lymphomas are being considered for allogeneic transplantation. Nearly all patients had relapsed disease, many of whom were resistant to conventional-dose therapy. The majority of patients treated achieved a CR following high-dose ablative therapy, and the relapse rate is generally less than 20%. However, the treatment-associated mortality in these studies ranged from 20% to as high as 50%, usually due to complications of graft-versus-host disease (GVHD), opportunistic infections, or pneumonitis. The probability of long-term disease-free survival is in the range of 20 to 40%. In a prospective comparative trial of allogeneic or autologous BMT, there was no significant difference in event-free survival between the two sources of marrow; however, the probability of relapse was significantly greater in the autologous patients.³⁴⁶ Similar results have been seen in patients with indolent NHL. In an effort to reduce the morbidity and mortality associated GVHD, several groups have employed T-cell depletion for the prevention of GVHD.^347,348 The incidence of significant (grade 2–4) GVHD in these studies is about 20%, and it is largely grade 2. The treatment related mortality is less than 20%, and the disease-free and overall survival between 50 and 60%. Other approaches to improve results of allogeneic transplants, such as nonmyeloablative conditioning and donor lymphocyte infusions, are under way.³⁴⁹

Autologous Stem Cell Transplantation (ASCT) for Relapsed Aggressive NHL

The disease sensitivity at the time of ASCT has remained the most significant prognostic variable for predicting treatment outcome.^350–353 Several large series have shown that patients who undergo ASCT when the disease is resistant to the initial induction therapy have less than 10% probability of disease-free survival. Although many patients die of progressive lymphoma, in some studies, the treatment-related mortality has been higher in this patient population (20–30%). Those patients in sensitive relapse have a 30 to 60% probability of long-term disease-free survival. In contrast, 10 to 20% of patients with resistant disease are long-term survivors.

The question as to how autologous BMT compares with conventional salvage therapy for relapsed aggressive NHL was addressed by a multi-center trial known as the PARMA trial.³⁵⁴ Patients with relapsed aggressive NHL (largely DLBCL) received two cycles of DHAP and, if responsive, were randomized to continued DHAP for four additional cycles or high-dose chemotherapy (BEAC) and autologous BMT. With median follow-up in excess of 5 years, patients randomized to the high-dose arm had superior event-free survival (46% vs. 12%) and overall survival (53% vs. 32%). In a subsequent analysis of prognostic factors for the patients in this study, patients with IPI of > 0 at the time of relapse, prior to re-induction with two cycles of DHAP, had a significantly better overall survival when treated with autologous BMT.³⁵⁵ Furthermore, IPI at relapse was highly correlated with overall survival in patients treated with DHAP, but not those who underwent autologous BMT.

Analogous to relapsed highly aggressive lymphomas in the pediatric population, adult lymphoblastic lymphoma has been reported to be a disease where high-dose therapy has a role. A retrospective analysis of 109 patients undergoing marrow transplantation in second CR resulted in a 31% rate of actuarial overall survival at 6 years.³⁵⁶ Similar to other lymphomas, patients with resistant disease at the time of transplantation did relatively poorly with 15% overall survival at 6 years. In a retrospective analysis of EBMT registry data of allogeneic versus autologous BMT for lymphoma patients undergoing allogeneic BMT for lymphoblastic lymphoma in greater than first remission, the allogeneic transplant patients had a significantly lower rate of relapse when compared with patients undergoing autologous BMT, although the procedure-related mortality was significantly higher for the allogeneic BMT patients.³⁴⁵ For patients with Burkitt’s and Burkitt’s-like lymphoma, adults who underwent ASCT with sensitive disease have 3-year overall survival of 37%, while for chemoresistant patients the overall survival is 7%.³⁵⁷

The majority of relapses are seen in the first 2 to 3 years after ASCT. Approximately two-thirds of patients relapse in prior sites of disease, and nearly one-third relapse in entirely new sites. It is not possible to determine whether relapse results from endogenous tumor cells or re-infused cells contaminating the stem cell product (marrow or peripheral blood stem cells). Since most patients relapse in prior sites of bulk disease, re-infused tumor cells may not contribute to relapse or may selectively localize back to an affected site. The contribution of re-infused lymphoma cells to relapse is supported by gene marking studies as well as studies of minimal residual disease in the stem cell product.^358,359 In studies by Gribben and colleagues, following ex vivo marrow treatment, PCR amplification of bcl-2 rearrangement detected residual lymphoma cells in the purged marrow in 50% of patients.²⁰⁹ The disease-free survival was highly significantly better in the patients who had no residual detectable bcl-2+ cells in the purged marrow, compared with those in whom cells were detectable after purging by PCR. Similarly, patients in whom lymphoma cells can be cultured from stem cell collections have a higher risk of relapse,³⁶⁰ In a study of mafosfamide purging of autologous marrow, patients who received a lower dose of CFU-GM re-infused had a better event-free survival. A lower CFU-GM cell dose re-infused was a surrogate marker for more effective ex vivo purging.

Autologous Stem Cell Transplantation for Relapsed Indolent NHL

In contrast to relapsed aggressive NHL, fewer patients with indolent NHL have undergone high-dose therapy and ASCT.^361–365 Most of these studies have included patients with follicular NHL, although some patients with SLL and other indolent B-cell NHLs have undergone autologous BMT. The lack of interest in autologous BMT for indolent lymphomas has largely been based on the belief that this is a disease with a very long natural history where excessive treatment related toxicities associated with aggressive therapy would not be acceptable. Moreover, the high frequency of overt bone marrow and peripheral blood infiltration, has been a major obstacle. Many of these patients had disease resistant to conventional therapy prior to autologous BMT and the vast majority were selected for lack of bone marrow infiltration.

A large number of patients who received purged autologous bone marrow following high-dose therapy for follicular lymphoma have been reported. The Dana-Farber Cancer Institute has treated 153 patients with a history of follicular NHL in sensitive relapse or incomplete first remission with cyclophosphamide/TBI-conditioning and anti–B-cell, mAb-treated autologous BMT between 1985 and 1995.³⁶⁶ At diagnosis, 90% of patients had stage IV disease, 28% had B symptoms, and 30% had extranodal disease exclusive of the bone marrow. At bone marrow harvest, only 30% were in CR. As of March 1999, the disease-free survival and overall survival at 8 years following autologous BMT are 42% and 66%, respectively. The survival from diagnosis for the entire group of patients is 69% at 12 years.

St. Bartholomew’s Hospital have similarly treated 64 relapsed indolent lymphoma patients with anti–B-cell, mAb-purged autologous BMT.³⁶⁵ These patients were treated with the same cyclophosphamide/TBI-conditioning regimen. At autologous BMT, 34 were in CR, with 7 having bone marrow involvement at harvest. Following high-dose therapy, the treatment-related mortality has been very low, and 35 patients remain in CCR from 1+ to 8+ years. This study performed a retrospective analysis of patients undergoing autologous BMT in second remission and compared them with patients treated with conventional therapy. The patients undergoing autologous BMT have a significantly better disease-free survival as compared with those undergoing standard therapy. However, there was no difference in overall survival between the two groups of patients.

Since bone marrow involvement is so frequent in these diseases, the number of patients receiving unpurged bone marrow is limited. The University of Nebraska reported 13 patients with indolent FL undergoing autologous BMT with unmanipulated marrow.^361,367 The 4-year failure-free and overall survival rates in these patients were 62% and 76%, respectively. An alternative to marrow purging for tumor-involved marrow in indolent NHL has been the use of PBSCs. The University of Nebraska has reported 100 patients treated (included were 26 patients treated with one prior regimen), with 4-year failure-free and overall survival rates of 44% and 65%, respectively.³⁶⁷ In this series, there was no statistically significant difference in the outcome between patients receiving unpurged marrow and those receiving PBSC. Similar results using PBSCs have been reported by Bastion and co-workers.³⁶⁸

Histologic conversion from indolent to an agggressive histology has been associated with a poor prognosis. There have been two recent studies of patients with chemosensitive disease and a good performance status after histologic transformation for follicular NHL. Nineteen patients in a minimal disease state from St. Bartholomew’s Hospital received an anti–B-cell purged autologous BMT within 1 year of histologic transformation.³⁶⁹ The median survival was 4.4 years, with three patients in remission at over 4 years of follow-up. In the series from Dana-Farber Cancer Institute, where 21 patients have undergone anti–B-cell purged autologous BMT for transformed FL, no acute in hospital deaths were seen, and the Kaplan-Meier estimate of the percentage of patients alive and disease free at 5 years is 46%, with follow-up from 12 to 120+ months.²⁸⁹ Patients who underwent histologic transformation within 18 months of diagnosis of FL had a significantly better overall survival, compared with patients whose disease transformed later. When pathology at relapse was available, all patients with DLBCL had recurrences. Aggressive therapy with ASCT is a reasonable treatment option for selected patients.

Autologous Stem Cell Transplantation for NHL in First Remission

In an attempt to improve the prognosis for patients with a poor prognosis following induction therapy, several studies have examined the role of high-dose therapy and ASCT in first CR/PR for patients with aggressive NHL.^370–373 The disease-free survival at 3 years in most of these studies is 70 to 80%. The European Bone Marrow Transplant Group has reported a multi-center study of patients stratified by histology transplanted in first CR.³³⁰ The disease-free survival is approximately 50% for Burkitt’s lymphoma, 60% for lymphoblastic lymphoma, and 80% for other aggressive NHLs.³⁷⁴ All these studies suggest that early high-dose therapy may be highly effective in patients who are at high risk of relapse following conventional therapy. However, randomized trials which have examined the role of autologous BMT in first remission versus conventional therapy for patients with adverse prognostic factors at diagnosis have left this question largely unanswered. In four randomized trials, a significant difference in the event-free survival and freedom from progression in favor of high-dose therapy and stem cell transplantation was seen in only one study.^375–379 However, in a retrospective analysis of one of the randomized trials, where patients were stratified by the IPI at diagnosis, a benefit for consolidative autologous BMT was seen for high-intermediate- and high-risk patients who achieved a CR with induction treatment. Additional prospective randomized studies evaluating high-dose therapy and ASCT versus conventional therapy for higher-risk patients defined by the IPI are ongoing. It remains controversial whether patients with aggressive NHL who attain only a PR with induction therapy have an improved prognosis with high-dose therapy and stem cell support. One randomized trial failed to show a benefit.³⁸⁰ The role of autologous BMT in patients with indolent NHL during first remission is being actively investigated.^381,382 ASCT is clearly not the complete answer for curing patients with relapsed or high-risk lymphoma. Development of new strategies, particularly toward resistant cells and minimal residual disease, may make additional impact following high-dose therapy.

New Therapeutic Approaches

Although great strides have been made in the treatment of NHL with conventional, salvage, and high-dose ablative therapies, the majority of patients are not cured. Unlike most other cancers, many patients with NHL can achieve a CR. This suggests that the major obstacle to cure is subpopulations of resistant neoplastic cells. There are a number of approaches to the treatment of NHL, which may potentially overcome resistance. Conventional-dose therapy can be escalated to near-ablative doses by employing hematopoietic growth factor.³⁸³ There are a growing number of cytokines which may be either cytostatic or cytotoxic to neoplastic cells. Antisense oligonucleotides to, for example, bcl-2, are in clinical trials and may be useful agents for inducing apoptosis. Monoclonal antibodies, either unconjugated, conjugated to a toxin, or conjugated to radionuclides, are being used to treat NHLs.²⁸⁶ Combining anti-body based therapies with chemotherapy may be synergistic.³⁸⁴ Studies employing anti–B-cell (anti-CD20) mAbs conjugated to ¹³¹I have shown promising results with limited follow-up. This type of targeted therapy may be useful as a substitute for TBI as well as in the adjuvant setting.^288,385 Endogenously or exogenously activated lymphocytes or natural killer cells can be used specifically to attack lymphoma cells. Infusion of cytokines (such as interleukin-2, or-12) which augment antitumor immunity are in clinical trials and may well have a role in treating the minimal disease state. Further ways to enhance host immunity against the patients’ own tumor cells has involved vaccination studies with the Ig-idiotype to induce specific immunotherapy against residual tumor cells.^386–390 Another approach is to modify the tumor cells to make them more immunogenic and more susceptable to endogenous effector mechanisms.³⁹¹ It is likely that multiple approaches will need to be put together to optimally eradicate tumor cells. Ongoing and future studies in these areas may provide novel alternatives and complement conventional therapy.