International prognostic index-based outcomes for diffuse large B-cell lymphomas

Authors


Abstract

BACKGROUND

We present the results of doxorubicin-based chemotherapy with or without involved-field radiotherapy for patients with diffuse large B-cell lymphoma (DLBCL) according to the international prognostic index (IPI).

METHODS

From September 1988 through December 1996, 294 patients with Stage I–IV Working Formulation large B-cell or T-cell lymphomas were treated prospectively on two protocols at our center. Diagnoses were reclassified subsequently according to the new World Health Organization classification. Two-hundred and twenty-four patients had DLBCL, including 24 patients with primary mediastinal large B-cell lymphoma. Treatment consisted of a median of six cycles of cyclophosphamide, doxorubicin, vincristine, and prednisone (CHOP) chemotherapy with or without involved-field radiotherapy (median dose, 39.6 Gy).

RESULTS/CONCLUSIONS.

The median length of follow-up among surviving patients was 5.0 years. Patient subgroups differed from each other in terms of progression-free (P = 0.003), cause-specific (P = 0.003), and overall (P = 0.001) survival rates when analyzed by IPI. Five-year progression-free, cause-specific, and overall survival rates for 212 patients with an IPI of 0–2 were 73%, 84%, and 82%, respectively, versus only 37%, 33%, and 32% for 12 patients with an IPI of 3–4. To improve our results, we are conducting clinical trials with young DLBCL patients and with patients who are older than 60 years. The young DLBCL patients, who have more than two adverse prognostic features, are receiving high-dose chemotherapy and autologous stem cell rescue. The patients who are older than 60 years, regardless of IPI, are receiving rituximab immunotherapy and liposomal CHOP chemotherapy with or without involved-field radiotherapy. Cancer 2002;94:3083–8. © 2002 American Cancer Society.

DOI 10.1002/cncr.10583

Use of the Ann Arbor staging system is limited in predicting the outcome of patients with non-Hodgkin lymphomas because it does not address important patient characteristics and biological features.1 Its usefulness improves when it is combined with other prognostic factors.1

In 1993, the international prognostic index (IPI) was proposed based on overall survival rates of 2031 adults of all ages with aggressive lymphomas who were treated in the United States, Canada, and Europe with doxorubicin-based chemotherapy with or without involved-field radiotherapy (Tables 1, 2).2 An age-adjusted IPI was also proposed for adults younger than 61 years (Tables 1, 2).2 These two prognostic systems can be used to help determine treatment. They also allow results to be compared between centers.

Table 1. Prognostic Systems for Aggressive Lymphoma Patients: International Prognostic Indexa
VariableAdverse feature
  • a

    Each of the five adverse features is assigned one point in patients of all ages. The sum of the points is the international prognostic index (IPI). Risk groups in terms of IPI are defined as 0–1 low risk; 2, low-intermediate risk; 3, high-intermediate risk; and 4–5 high risk.

  • b

    Each of the first three adverse features is assigned one point in patients younger than 61 years. The sum of the points is the age-adjusted IPI. Risk groups in terms of age-adjusted IPI are defined as 0, low risk; 1, low-intermediate risk; 2, high-intermediate risk; 3, high risk.

Serum lactate dehydrogenase levelbAbove normal
Ann Arbor stagebIII or IV
Zubrod performance statusb≥ 2
Extranodal involvement> 1 site
Age> 60 yrs
Table 2. Prognostic Systems for Aggressive Lymphoma Patients: The University of Texas M. D. Anderson Cancer Center's Tumor Score Systema
VariableAdverse feature
  • PA: posteroanterior.

  • a

    Each adverse feature is assigned one point in patients of all ages. One point is assigned for each bulky mass. The sum of the points is the tumor score. A tumor score ≤ 2 indicates a good prognosis and a tumor score > 2 indicates a poor prognosis.

  • b

    Cases with extranodal head and neck presentations, not measurable bidimensionally, are assessed using the 1992 American Joint Committee on Cancer staging system wherein T3-T4 tumors are considered bulky. Other extranodal presentations such as in the stomach, kidneys, or liver, if not measurable, are considered bulky if two thirds or more of the organ is involved.

Serum lactate dehydrogenase level≥ 1.1 × upper limit of normal, i.e., ≥ 685 IU/L at M. D. Anderson
Ann Arbor stageIII or IV
Symptoms“B” = 1) unexplained, recurrent or sustained fevers (T > 38 °C); 2) drenching night sweats; or 3) weight loss > 10% over the 6 mos before diagnosis
Tumor bulkbMass(es) ≥ 7 cm or a mediastinal mass visible on a standing PA chest X-ray
Serum β-microglobulin level≥ 1.5 × upper limit of normal for aggressive lymphomas arising outside of the mediastinum, i.e, ≥ 3.0 mg/L at M. D. Anderson. For primary mediastinal large B-cell lymphomas, ≥ 0.8 × upper limit of normal, i.e., ≥ 1.6 mg/L at M. D. Anderson.15

Recently, the World Health Organization (WHO) classification of lymphoid neoplasms was introduced.3 The purpose of this study is to report IPI-based outcomes in adults with WHO diffuse large B-cell lymphoma (DLBCL) who participated in clinical trials and were treated prospectively with cyclophosphamide, doxorubicin, vincristine, and prednisone (CHOP) chemotherapy with or without involved-field radiotherapy.

MATERIALS AND METHODS

From September 1988 through December 1996, 294 patients with newly diagnosed, favorable, clinical Stage I–IV, Working Formulation4 intermediate-grade B-cell or T-cell lymphomas were enrolled in two prospective phase II clinical trials (DM 88-087 and DM 93-003) at The University of Texas M. D. Anderson Cancer Center. The 102 patients registered on protocol DM 88-087 had no bulky mediastinal adenopathy on chest X-ray and two or fewer extranodal sites of disease. The M. D. Anderson tumor score system5 (Tables 1, 2) was introduced in 1992 when this protocol was nearly completed. In retrospect, all patients on this protocol had tumor scores of 2 or lower. The 192 patients on protocol DM 93-003 were required to have tumor scores of 2 or lower. The difference in eligibility criteria for these two trials represents an evolution of the prognostic system in use at our institution. Patients with primary central nervous system lymphoma were ineligible. Tissue biopsies were reviewed in every case by pathologists at our center before study enrollment. None of the patients had previously undergone treatment for lymphoma. Informed consent was obtained from all patients in accordance with institutional review board guidelines.

Reclassification of Working Formulation diagnoses according to the new WHO classification of lymphoid neoplasms3 was possible for 264 of the patients. In 239 cases, immunophenotypic studies were performed using either flow cytometry or immunohistochemical methods. These methods demonstrated either B-cell or T-cell lineage. In addition, 25 lymphomas were not immunophenotyped, but could be classified in terms of the WHO classification based on histologic findings that reliably predict immunophenotype. There were 224 DLBCLs (42 had a follicular component), 17 Grade 3 follicular lymphomas, 9 peripheral T-cell lymphomas not otherwise characterized, 12 anaplastic large-cell lymphomas T/null cell (7 cutaneous and 5 systemic), 1 extranodal natural killer/T-cell lymphoma nasal type, and 1 enteropathy-type intestinal T-cell lymphoma. Because the aforementioned diagnoses have different prognoses,6, 7 only patients with DLBCL were selected for study. Immunophenotypic data were not available for 30 of the 294 patients treated on protocols DM 88-087 and DM 93-003; diagnoses for these patients could not be specified in terms of WHO classification terminology. Of the 30 patients, 28 were referred from other institutions and paraffin blocks were not available for review. The remaining two cases were diagnosed by fine needle aspiration and material was insufficient for immunophenotypic analysis.

Characteristics of the 224 DLBCL patients are presented in Table 3. Information regarding all components of the IPI and tumor score was available in every case. All 12 patients with an IPI higher than 2 were older than 60 years. Tumor sizes, which were based on computed tomography scans, were measured after biopsy and before chemotherapy. Waldeyer's ring was coded as an extranodal site8 and the spleen was coded as a nodal site (Table 3).9

Table 3. Characteristics of Diffuse Large B-Cell Lymphoma Patients
  1. Percentages are shown in parentheses.

No. of patients224
Age (yrs) 
 Median55
 Range16–87
 > 6084 patients (38)
Male (%)108 patients (48)
Ann Arbor clinical stage (%) 
 I110 patients (49)
 II71 patients (32)
 III21 patients (9)
 IV22 patients (10)
B symptoms (%)16 patients (7)
Elevated lactate dehydrogenase level (%)37 patients (17)
Zubrod performance score ≥ 2 (%)3 patients (1)
Prechemotherapy tumor size ≥ 7 cm (%)56 patients (25)
Mediastinal involvement (%)24 patients (11)
More than one extranodal site (%)19 patients (7)
International prognostic index (%) 
 099 patients (44)
 181 patients (36)
 232 patients (14)
 310 patients (5)
 42 patients (1)
 50 patients (0)
Age-adjusted international prognostic index (%) 
 099 patients (71)
 136 patients (26)
 25 patients (3)
 30 patients (0)

Treatment consisted of CHOP-based chemotherapy with or without involved-field radiotherapy. The chemotherapy doses for each 3-week cycle were 750 mg/m2 cyclophosphamide intravenously on Day 1, 25 mg/m2 per day doxorubicin intravenously by continuous infusion on Days 1 and 2, 1.4 mg/m2 (maximum, 2 mg) vincristine intravenously on Day 1, and 100 mg prednisone orally on Days 1 through 5. A median of six cycles of chemotherapy was delivered. If patients had Stage III–IV disease, lymphomas measuring 7 cm or more in greatest dimension, or disease that was still responding after three cycles of CHOP chemotherapy, six rather than three cycles of chemotherapy were administered. Response to treatment was assessed according to international working group guidelines.10 Gallium or positron emission tomography scans were not obtained routinely.

In general, patients with lymphomas measuring at least 5 cm in lateral dimension were referred for involved-field radiotherapy beginning 3–4 weeks after the completion of chemotherapy. Of 181 Stage I–II patients, 144 (80%) received radiotherapy, as did 24 of 43 (56%) Stage III–IV patients. The prechemotherapy tumor volume was typically irradiated unless there was hepatic, pulmonary, or bone marrow involvement (these sites were treated with chemotherapy alone to reduce treatment-related toxicity). There was one other exception to inclusion of the entire prechemotherapy tumor volume in the radiotherapy fields. If there was a large retroperitoneal or mediastinal mass, the volume of normal liver, kidneys, or lungs in the radiotherapy fields was minimized to reduce treatment-related toxicity. Total radiation doses ranged from 30.0 to 50.4 Gy (median, 39.6 Gy using a daily fraction size of 1.8 Gy). Radiotherapy was delivered over 21–48 days.

The two-sided Pearson chi-square and two-sided Fisher exact test were used to compare patient groups. Kaplan–Meier analysis11 was used to determine the probability of progression-free, cause-specific, and overall survival rates in terms of IPI. Progression-free survival was defined as no evidence of disease progression or death due to lymphoma and cause-specific survival was defined as no evidence of death due to lymphoma.10 Curves were compared using the log rank test.12

RESULTS AND DISCUSSION

The median length of follow-up of surviving patients was 5.0 years (range, 0.8–10.7 years). In general, treatment was tolerated reasonably well, with the main toxicity being moderate myelosuppression. One patient died of sepsis. One patient developed myelodysplastic syndrome 4.2 years after receiving chemotherapy and radiotherapy. With regard to second cancers, one patient developed an adenocarcinoma of the prostate 12.2 years after being treated with chemotherapy alone.

Eighty-one percent of the DLBCL patients experienced a complete response, 15% experienced a partial or unconfirmed complete response, and 4% experienced less than a partial response to CHOP chemotherapy. Similarly, in the Eastern Cooperative Oncology Group study,13 89% of Working Formulation intermediate-grade non-Hodgkin lymphoma patients achieved at least a partial response to eight cycles of CHOP chemotherapy. In our study, which included patients with Stage III–IV DLBCL, the 5-year progression-free, cause-specific, and overall survival rates were 71%, 81%, and 80%, respectively. These rates are comparable to the 5-year progression-free and overall survival rates of 76% and 82% observed for Stage I–II aggressive lymphoma patients treated with three cycles of CHOP chemotherapy followed by involved-field radiotherapy on the Southwest Oncology Group protocol 8736.14

Patients with a follicular component did not differ significantly from other patients in terms of IPI, serum β-2-microglobulin (β-2M) levels, or bulky disease. The presence of a follicular component did not significantly affect progression-free (P = 0.40), cause-specific (P = 0.30), or overall survival (P = 0.11) rates.

The 24 patients with primary mediastinal large B-cell lymphoma did not differ significantly from the other 200 patients in terms of IPI. However, primary mediastinal large B-cell lymphoma patients had elevated serum β-2M levels more often than other DLBCL patients (67% vs. 3%, P < 0.001) based on the definitions proposed by our group5, 15 (Tables 1, 2). As expected,16 primary mediastinal large B-cell lymphoma patients also had DLBCLs measuring at least 7 cm in greatest dimension more often than other DLBCL patients (54% vs. 21%, P = 0.002). Because an elevated serum β-2M level15 and bulky disease17 are adverse factors for progression-free survival, patients with primary mediastinal large B-cell lymphomas experienced worse progression-free survival rates than other patients (5-year rates: 45% vs. 74%, P = 0.0003).

With regard to progression-free survival rates, subgroups differed significantly from each other based on IPI (P = 0.003; Fig. 1). The 5-year progression-free survival rates were 77%, 71%, 62%, and 37% for patients with an IPI of 0, 1, 2, or 3–4, respectively.

Figure 1.

Progression-free survival rates in terms of the international prognostic index.

With regard to cause-specific survival rates, subgroups also differed significantly from each other in terms of IPI (P = 0.003; Fig. 2A). The 5-year cause-specific survival rates were 87%, 83%, 79%, and 33% for patients with an IPI of 0, 1, 2, or 3–4, respectively.

Figure 2.

Cause-specific (A) and overall survival (B) rates in terms of the international prognostic index.

With regard to overall survival rates, subgroups were significantly different from one another based on IPI (P = 0.001; Fig. 2B). The 5-year overall survival rates were 86%, 79%, and 32% for patients with an IPI of 0, 1–2, or 3–4, respectively. The IPI-based progression-free and overall survival curves in this study (Figs. 1, 2B) are similar to those reported by Armitage and Weisenburger7 for DLBCL.

Patients with an IPI of 0–2 were grouped together because they enjoyed dramatically better progression-free (P = 0.002), cause-specific (P = 0.0004), and overall survival (P = 0.001) rates than those with an IPI of 3–4. For patients with an IPI of 0–2, the 5-year progression-free, cause-specific, and overall survival rates were 73%, 84%, and 82%, respectively. For patients with an IPI of 3–4, the 5-year progression-free, cause-specific, and overall survival rates were only 37% (Fig. 1), 33% (Fig. 2A), and 32% (Fig. 2B), respectively. All of the patients with an IPI greater than 2 were older than 60 years. To improve our results in DLBCL patients older than 60 years, we are currently studying rituximab immunotherapy18 and liposomal CHOP chemotherapy19 with or without involved-field radiotherapy.

As with the IPI, there was a significant difference in progression-free (P = 0.0004), cause-specific (P = 0.0009), and overall survival (P = 0.001) rates in terms of the tumor score (0 vs. 1 vs. 2).

Progression-free survival rate in terms of the age-adjusted IPI is presented in Figure 3. Based on the excellent results in patients with an age-adjusted IPI of 0–2, our current study (DM 95-121) involving high-dose chemotherapy and autologous stem cell rescue is limited to young DLBCL patients with more than two adverse prognostic features. Patients older than 60 years are excluded from protocol DM 95-121 due to concerns regarding treatment-related toxicity.

Figure 3.

Progression-free survival in terms of the age-adjusted international prognostic index.

In conclusion, the IPI can be used to help determine treatment in patients with DLBCL and can be used to compare treatment results between centers. Patients older than 60 years with an IPI > 2 did poorly with CHOP chemotherapy with or without involved-field radiotherapy (Figs. 1, 2). Based on the results of the Groupe d'Etude des Lymphomes de l'Adulte study,18 we believe that rituximab immunotherapy should be added to CHOP chemotherapy in DLBCL patients older than 60 years. Based on our excellent results with CHOP chemotherapy with or without involved-field radiotherapy in patients with an age-adjusted IPI of 0–2 (Fig. 3), we believe that clinical trials involving high-dose chemotherapy and autologous stem cell rescue are best suited to young DLBCL patients with more than two adverse prognostic features.20, 21 In the future, gene expression profiling may be used in addition to the IPI as a means of helping to determine treatment in patients with DLBCL.22, 23

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