1186
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`Thalidomide for Patients with Recurrent Lymphoma
`
`Barbara Pro, M.D.1
`Anas Younes, M.D.1
`Maher Albitar, M.D.2
`Nam H. Dang, M.D.1
`Felipe Samaniego, M.D.1
`Jorge Romaguera, M.D.1
`Peter McLaughlin, M.D.1
`Fredrick B. Hagemeister, M.D.1
`Maria A. Rodriguez, M.D.1
`Marilyn Clemons, R.N.1
`Fernando Cabanillas, M.D.1
`
`1 Department of Lymphoma/Myeloma, The Univer-
`sity of Texas M. D. Anderson Cancer Center, Hous-
`ton, Texas.
`
`2 Department of Hematopathology, The University
`of Texas M. D. Anderson Cancer Center, Houston,
`Texas.
`
`Address for reprints: Barbara Pro, M.D., Department
`of Lymphoma/Myeloma, The University of Texas
`M. D. Anderson Cancer Center, 1515 Holcombe Bou-
`levard, Unit 429, Houston, TX 77030; Fax:
`(713)
`794-5656; E-mail: bpro@mdanderson.org
`
`Received September 2, 2003; revision received
`November 18, 2003; accepted December 19,
`2003.
`
`© 2004 American Cancer Society
`DOI 10.1002/cncr.20070
`
`BACKGROUND. Thalidomide has significant clinical activity in patients with mul-
`tiple myeloma. However, its activity against other lymphoid tumors is unknown.
`The authors reported their experience with thalidomide in patients with recurrent/
`refractory non-Hodgkin lymphoma and in patients with Hodgkin disease.
`METHODS. Nineteen patients (median age, 62 years) who had undergone a median
`of 5 previous treatment regimens were treated with escalating doses of thalidomide
`(200 – 800 mg per day) until disease progression or prohibitive toxicity was ob-
`served. The authors measured serum levels of angiogenesis factors before and after
`treatment.
`RESULTS. One patient (5%) with evidence of recurrent gastric mucosa—associated
`lymphoid tissue lymphoma achieved a complete response, and 3 patients (16%)
`achieved stable disease.
`CONCLUSIONS. The current study suggests that thalidomide has limited single-
`agent activity in heavily pretreated patients with recurrent or refractory lymphoma.
`Cancer 2004;100:1186 –9. © 2004 American Cancer Society.
`
`KEYWORDS: thalidomide, multiple myeloma, Hodgkin disease, non-Hodgkin disease,
`single-agent activity.
`
`Thalidomide is an oral sedative with antiinflammatory, immuno-
`
`modulatory, and antiangiogenic properties.1 Several clinical trials
`have investigated the activity of thalidomide in solid and hematologic
`malignancies.2–5 In patients with recurrent and refractory multiple
`myeloma, thalidomide has an overall response rate of 30%.6 Because
`of this favorable response rate, thalidomide was recently combined
`with rituximab, achieving a high response rate in a small number of
`patients with recurrent mantle cell lymphoma.7 However, the single-
`agent activity of thalidomide in patients with recurrent lymphoma
`remains unknown. We report our experience with thalidomide in
`patients with recurrent and refractory non-Hodgkin lymphoma
`(NHL) and Hodgkin disease (HD).
`
`MATERIALS AND METHODS
`Patients were eligible for thalidomide treatment if they had recurrent
`or refractory NHL or HD, a Karnofsky performance status of ⬎ 60, and
`were ⬎ 16 years. Patients were excluded if there was evidence of
`central nervous system involvement with lymphoma, human immu-
`nodeficiency virus infection, had received antilymphoma therapy
`within 3 weeks, or required concurrent steroids. Patients of childbear-
`ing age were eligible provided that they were practicing adequate
`contraception. Negative results for serum pregnancy testing were
`required before study entry and monthly thereafter for all women of
`childbearing potential.
`Thalidomide was administered orally at a starting dosage of 200
`mg per day. The dosage was increased every 2 weeks up to a maxi-
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`TABLE 1
`Patient Characteristics
`
`Characteristic
`
`Median age in yrs (range)
`Median no. of previous treatment regimens (range)
`Histology
`Diffuse large cell
`Follicular small cleaved
`Small lymphocytic
`Mucosa-associated lymphoid tissue
`Mantle cell
`Hodgkin disease
`Pretreatment LDH
`Normal
`High
`
`LDH: lactate dehydrogenase.
`
`No. of patients (%)
`
`62 (30–78)
`5 (2–7)
`
`6 (32)
`4 (21)
`3 (16)
`1 (5)
`3 (16)
`2 (11)
`
`14 (74)
`5 (26)
`
`mum of 800 mg per day. Treatment was continued
`with the maximum tolerated dose until disease pro-
`gression or intolerable toxicity. Restaging studies were
`conducted after 8 weeks of treatment and every 3
`months thereafter. Toxicity was graded according to
`the National Cancer Institute Common Toxicity Crite-
`ria (Version 2.0). We evaluated toxic effects every 2
`weeks during the dose escalation phase and then
`monthly. The primary objective was to assess the ac-
`tivity and safety profile of thalidomide. Secondary ob-
`jectives were to analyze the effects of thalidomide on
`serum expressions of vascular endothelial growth fac-
`tor (VEGF), basic fibroblast growth factor (bFGF), he-
`patocyte growth factor, tumor necrosis factor alpha,
`and interleukin 6 and to correlate the levels of these
`cytokines with clinical responses. We obtained speci-
`mens for measuring these angiogenic factors at the
`time of registration, every 2 weeks for 8 weeks, and
`every 3 months thereafter. Serum concentrations of
`cytokines were determined using enzyme-linked im-
`munosorbent assays (Quantikine; R&D Systems, Min-
`neapolis, MN).
`
`RESULTS
`Between August 2000 and October 2001, after obtain-
`ing informed consent from each patient and approval
`from the institutional review board, we registered 21
`patients for the study. Two patients withdrew consent
`after registration,
`leaving 19 patients evaluable for
`treatment toxicity or response. Patients had a median
`age of 62 years (range, 30 –78 years) and had received
`a median of 5 previous treatment regimens (range, 2–7
`regimens). Seventeen patients had NHL, and two had
`HD (Table 1).
`Treatment was discontinued during the first 2
`weeks for 3 patients, due to either pancytopenia (n
`
`Thalidomide in Lymphoma/Pro et al.
`
`1187
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`⫽ 1) or rapidly progressing disease (n ⫽ 2). All other
`patients received ⱖ 8 weeks of therapy with a median
`dosage of 400 mg of thalidomide. Treatment was rea-
`sonably well tolerated, with the most common side
`effects being of Grade I/II. Peripheral neuropathy was
`observed in 76% of the patients, fatigue in 52%, edema
`in 52%, and constipation in 41%. The thalidomide
`dose was escalated to the scheduled level of 800 mg
`per day in 7 patients (41%).
`One male patient with recurrent mucosa-associ-
`ated lymphoid tissue (MALT) lymphoma of the stom-
`ach achieved a pathologic complete response 2
`months after initiation of thalidomide. He previously
`experienced treatment failure after receiving cyclo-
`phosphamide, doxorubicin, vincristine, and pred-
`nisone (CHOP), fludarabine, radiotherapy, and ritux-
`imab. Pretreatment
`endoscopy
`revealed patchy
`erythema of the gastric body with some mucosa cob-
`blestoning. Multiple biopsies confirmed the diagnosis
`of recurrent MALT lymphoma. After 4 months of treat-
`ment, a follow-up endoscopy showed a scarred area at
`the site that was previously abnormal. Multiple biop-
`sies were negative for evidence of disease. He received
`a reduced dose of thalidomide (100 mg per day) due to
`fatigue and lethargy and response was maintained at
`the lower dose. Treatment was continued for 9
`months, at which time treatment was discontinued
`due to bradycardia. His disease remains in remission
`19 months after his initial response was documented.
`Three patients had stable disease, two with large cell
`histology and one with small lymphocytic lymphoma
`(SLL). The first patient with transformed large B-cell
`lymphoma was a 65-year-old male who previously
`experienced treatment failure after CHOP-type che-
`motherapy and autologous bone marrow transplanta-
`tion. Pretreatment radiographic studies revealed left
`paraaortic adenopathy and bulky left external iliac
`lymph node disease. This patient received thalido-
`mide for 4 months, at which time treatment was dis-
`continued due to progressive disease. The second pa-
`tient with large B-cell lymphoma was a 56-year-old
`female who had experienced failure after 3 previous
`treatment regimens,
`including cisplatin-based and
`methotrexate-based regimens. At the time of study
`entry, she had enlarging multicompartment cervical
`adenopathy. Both patients had stable disease after 2
`months of treatment. The patient with SLL was a 75-
`year-old male who previously experienced treatment
`failure after receiving fludarabine-based chemother-
`apy and rituximab. Before treatment, he had paraaor-
`tic and mesenteric adenopathy. Stable disease was
`maintained for ⬎ 9 months. Serum levels of angio-
`genic factors were determined before and after ther-
`apy in seven patients (Fig. 1). Treatment with thalid-
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`FIGURE 1. Serum levels of (A) vascular endothelial growth factor (VEGF), (B) basic fibroblast growth factor (bFGF), (C) hepatocyte growth factor (HGF), (D)
`tumor necrosis factor alpha (TNF-␣), and (E) interleukin 6 (IL-6) before treatment with thalidomide and at the time of evaluation of response. In the one
`patient who achieved a complete response (solid line), levels of VEGF and bFGF decreased from 85 pg/mL and 14 pg/mL (pretreatment) to 36 pg/mL and
`7 pg/mL, respectively. In patients with stable disease (dashed lines) and patients with progressive disease (dotted lines), serum levels of angiogenic factors
`were variably affected.
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`omide variably affected the level of these factors.
`However, in the one patient who achieved a complete
`response, serum levels of VEGF and b-FGF were sig-
`nificantly decreased.
`
`DISCUSSION
`The current results indicate that thalidomide used as a
`single agent has minimal activity in heavily pretreated
`patients with lymphoma. These findings differ strik-
`ingly from those of a recent study that treated patients
`with recurrent mantle cell lymphoma. In that study,
`the thalidomide dosage was escalated from 200 mg
`per day to 400 mg per day on Day 15. Rituximab was
`administered at 375 mg/m2 weekly for 4 doses. The
`combination induced clinical responses in 10 of 11
`patients (91%), including complete responses in 3 pa-
`tients.7 In our series, three patients with mantle cell
`lymphoma received thalidomide and no responses
`were observed. Although patient selection may ac-
`count for this difference, other factors may also exist.
`Most antiangiogenesis agents such as thalidomide are
`cytostatic. Increased activity may be observed only
`when used in combination with other agents.8 It is
`also possible that thalidomide enhanced rituximab
`activity by modulating the immune response. Alterna-
`tively, thalidomide may have made mantle cell lym-
`phoma cells more sensitive to rituximab by modulat-
`ing intracellular resistance pathways such as nuclear
`factor Kappa B (NF-kB). Our data certainly do not
`support the use of thalidomide as a single agent in
`patients with recurrent and refractory lymphoma. Al-
`
`Thalidomide in Lymphoma/Pro et al.
`
`1189
`
`though the findings presented by Drach et al.7 are
`encouraging, the number of patients reported on is
`insufficient, and therefore, it is too early to conclude
`whether thalidomide-based therapy will be of clinical
`value for patients with recurrent lymphoma.
`
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