Thalidomide in hematologic malignancies: Future directions

Thalidomide in Hematologic Malignancies: Future Directions Raymond Alexuniun, Kenneth C. Anderson, Bart Burlogie, David I. Stirling, and Deborah A. Thomas Alternatives to traditional cytotoxic agents are needed to target the biologic processes associated with progression of multiple myeloma. Recent studies suggest that angiogenesis is sustained when patients with multiple myeloma achieve remission and may contribute to disease relapse and poor patient survival. Antiangiogenic therapy has been proposed as a strategy for reducing the risk of disease recurrence in patients with multiple myeloma. Accumulating evidence suggests that the combination of cytotoxic chemotherapy and antiangiogenic therapy has increased antitumor effects compared with either strategy alone. Preliminary findings of phase II studies suggest that thalidomide, an agent with antiangiogenic properties, has major activity in patients with refractory multiple myeloma. Based on this promising activity, a number of clinical trials are ongoing or planned to further assess the therapeutic potential of thalidomide as a single agent and in combination with chemotherapy in multiple myeloma and other hematologic malignancies. Semin Hematol37(suppl3):3539. Copyright 0 2000 by W.B. Saunders Company,

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ESPITE BIOLOGIC INSIGHT into multiple myeloma in recent years,1-3 virtually no progress in expected clinical outcomes has been achieved with chemotherapeutic strategies. Total therapy (a series of non-crossresistant induction regimens followed by two cycles of high-dose chemotherapy and maintenance interferon alfa) appears to offer patients with newly diagnosed multiple myeloma the best chance for achieving complete remission (CR) and 5-year surviva1425; however, even this aggressive approach is incapable of overcoming unfavorable prognostic features.6 It is clear that alternatives to traditional cytotoxic agents are needed to target the biologic processes underlying the progression of multiple myeloma and other hematologic malignancies associated with a poor prognosis from currently available therapies. Recently, researchers at the Mayo Clinic demonstrated that microvessel density (MVD) does not decrease significantly when patients with multiple myeloma achieve CR with myeloablative chemotherapy and autologous stemcell rescue.7 This sustained angiogenesis may reflect continued stimulus of microvessels by minimal residual disease undetectable by traditional measures;7 therefore, agents that inhibit angiogenesis in the bone marrow stroma have the potential to reduce the risk of disease recurrence through indirect effects on minimal Seminars

in Hematology,

residual disease. Furthermore, acquired drug resistance, which is considered the primary factor for low rates of CR and long-term survival in multiple myeloma,s did not occur with the use of antiangiogenic therapy in experimental cancer models.9 Accumulating in vitro and clinical evidence suggests that the combination of cytotoxic chemotherapy and antiangiogenic therapy is more effective than either strategy alone in producing antitumor effects.iO-i3 The prognostic value of angiogenesis has been established for several solid tumors (including breast, bladder, and non-small-cell lung cancers)14-17 and is being investigated in multiple myeloma. 18-2o Preliminary results from the University of Arkansas indicate that an MVD of less than four vessels per field is associated with longer durations of CR and overall survival in newly diagnosed patients undergoing “total therapy.“” Visual evaluation of bone marrow samples from

From the University of Texas M.D. Anderson Cancer Center. Houston, TX; Dana-Farber Cancer Institute, Boston, MA; University of Arkansas for Medical Sciences, Little Rock, AR; and Celgene Carp, Warren, NJ. Address reprint requests to Kenneth C. Anderson, MD, Dana-Farber Cancer Institute, 44 Binney St, Room DL189, Boston, MA 02115. Copyright 0 2000 by W.B. Saunders Company 0037-1963/00/3701-3006$10.00/0

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patients treated in the Eastern Cooperative Oncology Group (ECOG) E9486 or Intergroup 0141 trials showed that patients with low-grade angiogenesis at diagnosis had significantly longer survival than those with intermediate- or high-grade angiogenesis (5 3 2, 48 months; P = .OlS); a similar negative trend in survival rates was noted with higher mean MVD.’ Studies assessing the correlation of fibroblast growth factor levels with treatment response and prognosis in patients with newly diagnosed multiple myeloma are in progress.20 If the prognostic significance of angiogenesis is established, long-term studies will be warranted to determine how MVD and/or levels of angiogenic cytokines relate to other prognostic features in multiple myeloma, including those of the Durie-Salmon classification,21&-microglobulin,22-25 C-reactive protein25 plasma cell labeling index,23-25 and unfavorable cytogenetic abnormalities (such as deletion of chromosome 13).6,26,27 Because of the favorable results from clinical experience with thalidomide at the University of Arkansas and the University of Texas M.D. Anderson Cancer Center (MDACC), a number of clinical trials designed to further assess thalidomide in multiple myeloma and other hematologic malignancies are ongoing or planned. It is anticipated that more than 1,400 patients with multiple myeloma will be treated with thalidomide over the next 5 years. The preliminary findings of the phase II clinical trials of thalidomide in multiple myeloma reviewed in this supplement suggest that thalidomide has major activity in patients with refractory disease, including those relapsing after repeated cycles of high-dose chemotherapy. The salvage protocol (dexamethasone, cyclophosphamide, etoposide, cisplatin [DCEP] with or without thalidomide in “difficult disdexamethasone with or ease” and high-dose without thalidomide in “easy disease”) for patients with refractory multiple myeloma reviewed by Dr Barlogie in this supplement is currently being conducted in cooperation with the Southwest Oncology Group (SWOG). The up-front protocol (dexamethasone with or without thalidomide) for newly diagnosed patients will test the hypothesis that timely administration of antiangiogenic agents will lead to more pronounced disease response. Because of the

remarkable antitumor activity of a single course of DCEP plus doxorubicin and thalidomide (D.T. PACE) in plasma cell leukemia and multiple myeloma, this regimen currently is being compared with melphalan-based highdose chemotherapy and tandem transplantation in refractory multiple myeloma.1° Anticipated pilot studies of thalidomide for multiple myeloma include single-agent thalidomide in indolent (Durie-Salmon Stage I) disease at the Mayo Clinic, combination use in newly diagnosed patients (MDACC), and combination maintenance therapy with interferon alfa (Memorial Sloan-Kettering Cancer Center). In addition, international myeloma research groups from Canada, Australia, and Scandinavia have shown enthusiastic interest in initiating clinical trials of thalidomide. A multicenter trial of single-agent thalidomide for patients with refractory multiple myeloma is being planned (accrual goal, 40 patients). Patients relapsing after at least one course of high-dose chemotherapy/stem-cell rescue (regardless of maintenance therapy) will be randomized to receive a daily thalidomide dose of 200 mg or 400 mg. The new SWOG criteria will be used to evaluate clinical response (paraprotein reduction of 50% or 90% in serum or urine, respectively, for at least 6 months; if serum and urine are elevated, both need to respond). For patients randomized to receive thalidomide 200 mg daily who do not achieve a clinical response, dosage will be increased to 400 mg daily. The planned follow-up period for this study is 8 months. It is hoped that the results of this multicenter clinical trial will reproduce the University of Arkansas and MDACC experiences, providing justification for Food and Drug Administration approval of thalidomide in multiple myeloma refractory to high-dose chemotherapy. Experience with thalidomide in refractory multiple myeloma led to pilot studies of singleagent thalidomide therapy in acute myeloid leukemia (AML), high-risk myelodysplastic syndromes, chronic myeloid leukemia, and myeloproliferative disorders with poor prognoses (reviewed by Dr Thomas in this supplement). Inclusion of more patients and longer follow-up will provide better insight into the role of

Future Directiom With Thalidomide

thalidomide in these other hematologic malignancies. Plans are underway to conduct pilot studies of single-agent thalidomide in lymphoblastic leukemias refractory to other treatments, including acute lymphoblastic leukemia, chronic lymphoblastic leukemia, and B-cell malignancies. Based on the activity of D.T. PACE in multiple myeloma, a phase II study of anthracycline-based combination chemotherapy with or without thalidomide in poorrisk karyotype AML is under development. Expanded use of thalidomide in both hematologic malignancies and solid tumors is needed to characterize its safety profile in patients with cancer, who are likely to have comorbid condi.tions and concomitant therapies. Thus far, the most commonly reported adverse events during treatment with thalidomide for advanced-stage solid tumors and hematologic malignancies have been somnolence, constipation, and skin rashes.28-33Most adverse effects associated with thalidomide appear to be dose related and reversible with dose reduction or temporary discontinuation of therapy. Constipation, although likely to be an important issue with older patients (especially those on narcotic analgesics or vinca alkaloids), appears to be manageable with the use of laxatives. A prospective evaluation of clotting panels and intervention guidelines is being developed in response to a possible increased risk of deep vein thrombosis in the up-front protocol for newly diagnosed disease.Other interventions capable of preventing or minimizing potentially serious adverse events, including refined methods to detect thalidomide-induced peripheral neuropathy, should be sought. The incidences of peripheral neuropathy, cardiovascular complications (bradycardia, hypotension, thromboembolic events), and hypothyroidism in cancer patients receiving thalidomide and their relation to previous or concomitant use of chemotherapeutic agents require further investigation. Thalidomide has several safety advantages compared with cytotoxic agents used in the treatment of multiple myeloma. Few patients have presented with gastrointestinal complaints other than constipation, and hair loss is not a concern. Importantly, thalidomide does not appear to aggravate myelosuppression, making

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it a suitable addition to cytotoxic chemotherapy regimens. The risk of secondary AML in patients receiving melphalan and other alkylating agents is well recognized.“*-s6 Although thalidomide is a potent teratogen, it does not appear to have mutagenic or carcinogenic properties.37,38 As with all new anticancer agents, determining an appropriate dosage regimen is of paramount importance. The lack of an intravenous formulation of thalidomide hinders estimation of drug absorption, thereby confounding determination of a dose-responseeffect. Future pharmacokinetic and pharmacodynamic studies need to establish the typical extent of drug absorption, reasons for interpatient variability in absorption in defined populations, and the relationship between the extent of drug absorption and toxicityleffcacy. A low starting dose (50 mg or 100 mg daily) with gradual dose escalation results in good tolerability of thalidomide in certain populations (scleroderma, pulmonary/cutaneous sarcoidosis)39S40;however, this approach is not reasonable for the treatment of a rapidly progressing hematologic malignancy such as multiple myeloma. Experience to date indicates that patients receiving thalidomide for hematologic malignancies should be initiated on 200 mg to 400 mg daily, with subsequent dosing based on tolerability and demonstrated efficacy. Clarification of the biologic activity of thalidomide will help determine an appropriate dosing schedule and length of therapy. For example, effects mediated through antiangiogenesis would warrant long-term use without breaks in therapy, whereas direct cytotoxic or cytokine-mediated apoptotic effects would likely justify a cyclic regimen. Each year, thousands of patients are eligible to participate in clinical trials assessingnew therapeutic approaches to myeloma management; however, less than 5% of patients are enrolled.*l The standard of care for newly diagnosed and refractory multiple myeloma should be within context of well-designed clinical trials based on the likelihood that most patients will relapse and eventually succumb to drug-resistant disease.41,42Remarkable responsesin phase II clinical trials of single-agent

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thalidomide in heavily pretreated patients suggest that this agent has curative potential in multiple myeloma. In addition, thalidomide has shown promise in other hematologic disorders with limited treatment options, especially myeloproliferative disorders. Although thalidomide is suspected to exert antitumor activity through antiangiogenesis, further research is needed to clarify its precise biologic activities in neoplastic conditions. Overall, thalidomide should be viewed as a serious drug for multiple myeloma and possibly other difficult-to-manage hematologic malignancies.

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