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Home , Arsenic trioxide, Cyclophosphamide

(2002) 16, 1835–1837  2002 Nature Publishing Group All rights reserved 0887-6924/02 $25.00 www.nature.com/leu Clinical activity of trioxide for the treatment of NC Munshi1, G Tricot1, R Desikan2, A Badros3, M Zangari1, A Toor4, C Morris1, E Anaissie1 and B Barlogie1

1University of Arkansas for Medical Sciences, Myeloma and Transplantation Medical Center, Little Rock, AR, USA; 2St Vincent’s Comprehensive Center, NewYork City, NY, USA; 3University of Maryland Medical Center, Baltimore, MD, USA; and 4Loyola University, Chicago, IL, USA

Arsenic has been used since ancient times as a therapeutic vage patients relapsing after remissions induced by ATRA agent. However, until recently its use in modern medicine has and .6 been restricted to the treatment of a limited number of parasitic infections. In the early 1990s, reports from China described Although the exact mechanism of antitumor activity for impressive results with in patients with de arsenic trioxide is unknown, it has been shown to inhibit cell novo, relapsed, and refractory acute promyelocytic leukemia proliferation and induce in a spectrumof malignant (APL). Other investigators subsequently confirmed these B cell lines including myeloma cells.7,8 At pharmacologic results leading to approval of its use for relapsed or refractory concentrations, arsenic trioxide dose- and time-dependently APL in the United States. Investigations of this agent have dem- inhibits survival and growth of several different human mye- onstrated that its efficacy in APL and preclinical tumor models 9,10 is dependent upon a number of mechanisms, including induc- loma cell lines. These experimental studies with MM cell tion of apoptosis, effects on cellular differentiation, cell cycling, lines and in a xenograft models suggest that arsenic trioxide and tumor angiogenesis. Subsequent preclinical studies may interrupt several key mechanisms of myeloma cell showed significant activity of arsenic trioxide in multiple myel- growth and survival and perhaps be effective in patients with oma (MM). Based on this, in a phase II trial, we have evaluated MM forming the rationale for a phase II trial of arsenic trioxide the activity of arsenic trioxide in 14 patients with relapsed MM, in patients with relapsed or resistant MM. refractory to conventional salvage therapy. With the dose and schedule used, treatment with arsenic trioxide produced responses in three patients and prolonged stable disease in a fourth patient, with the longest response lasting 6 weeks. Materials and methods Although treatment was reasonably well tolerated, in these patients with extensive prior therapy, 11 developed cytopenia, Clinical protocol five associated with infectious complications and three developed deep vein thromboses. The results of this small trial support further investigation of this novel drug for the treat- Patients with relapsed or resistant MM and at least one prior ment of patients with relapsed or refractory MM. cycle of high-dose chemotherapy with autologous stem cell Leukemia (2002) 16, 1835–1837. doi:10.1038/sj.leu.2402599 rescue were eligible for enrollment on this protocol. Patients Keywords: arsenic trioxide; antiangiogenesis; apoptosis; multiple were required to have normal renal and hepatic function. myeloma Exclusion criteria included a history of grand mal seizures, active infection, pregnancy, or breastfeeding. Written infor- med consent was required, and the protocol was reviewed Introduction and approved by the institutional review board of the Univer- sity of Arkansas for Medical Sciences. MM is a malignancy of committed, follicular center B cells1 with a median age at onset of 63 years.2 Despite numerous chemotherapy options including high-dose therapy and auto- Treatment with arsenic trioxide logous stemcell transplantation, MM remainsan incurable disease. There is significant variation in the survival of patients Patients meeting eligibility criteria received a 2-h daily intra- with MM; prognostic variables that identify groups with venous infusion of arsenic trioxide 0.15 mg/kg for 60 days ␤ widely different survival rates include 2-microglobulin level, (the same dosage used in the treatment of APL). Patients were plasma cell-labeling index, plasmablastic morphology, serum evaluated for response, defined as a reduction in myeloma LDH levels, C-reactive protein and .3 Relapsed paraprotein at days 30 and 60. Treatment was continued for or chemotherapy-resistant MM remains a serious clinical an additional 30 days in patients showing a response. problemrequiring novel therapeutic options. Retreatment was initiated in responders between 3 and 6 Molecular and preclinical studies suggest that arsenic triox- weeks after first treatment. ide may be effective in various . Initial studies from China reported remarkable clinical efficacy of arsenic trioxide therapy in patients with de novo and relapsed APL.4 Single- Statistical analysis agent chemotherapy with arsenic trioxide produced complete remissions in eight of 11 (72.7%) patients presenting with The primary efficacy variable was response to therapy as newly diagnosed APL, without causing myelosuppression.5 reflected in the serum‘M’ protein level. Objective responses Unlike all-trans retinoic acid therapy (ATRA), long-term were a Ն50% reduction, and minor responses a Ն25% arsenic trioxide therapy produced molecular remissions in sal- reduction in M-protein. Duration of progression-free survival in responders was a secondary efficacy variable. Safety was assessed by a numerical tabulation of adverse events assessed in accordance with the NCI Common Toxicity Criteria, ver- Correspondence: NC Munshi, Dana Farber Cancer Institute, 44 sion 2 (found at Http://ctep.info.nih.gov), eg grade I neutro- Binney Street, M557, Boston, MA 02115, USA; Fax: 617 632 2140 penia is defined as an absolute neutrophil count (ANC) of Received 28 September 2001; accepted 28 March 2002 1500–Ͼ2000/mm3, grade 2 when ANC is 1000–Ͻ1500/mm3, Arsenic trioxide in multiple myeloma NC Munshi et al 1836 Table 1 Patient characteristics (n = 14) in all patients. However, in one responding patient no change in bone marrow plasmacytosis was observed. Five of the non- Parameter Median (range) responders and one patient who relapsed after response to therapy with arsenic trioxide had alternate salvage therapies Age (years) 56.0 (43–70) (ie transplant, high-dose , B2M (mg/l) 4.4 (2.3–6.3) with or without ) without effect. Creatinine (mg/l) 1.2 (0.7–1.5) C reactive protein (mg/l) 23.9 (2.6–181.0) Hemoglobin (g/dl) 10.0 (7.2–13.1) PC aspirate (%) 23.0 (4–82) Adverse events PC biopsy (%) 70.0 (4–80) Labeling index 0.3 (0–1.8) Toxicities (grades 3–5) in this patient group were somewhat different fromthose reported in patients treated with arsenic ␤ B2M, 2 microglobulin; PC, plasma cell. trioxide for APL. Eleven patients developed with WBC Ͻ1000 cells/mm3 requiring growth factor support, while five of these patients developed infectious complication. grade 3 is 500–Ͻ1000/mm3 and grade 4 is when ANC is Three patients experienced deep vein thrombosis (two were Ͻ500/mm3. catheter related), two reported extreme fatigue, and five developed infections (pneumonia, Candida septicemia, and/or bacteremia). Due to progressive disease and/or limited toler- Results ance only five patients were able to receive 60 days of treatment. Patient characteristics

Fourteen high-risk patients with extensive prior therapy were Discussion enrolled (Table 1). Patients had advanced disease; 11 patients had CRP Ͼ2.5 mg/l and 10 patients had Ͼ30% bone marrow Since its introduction in the 1960s, combination therapy with plasmacytosis. All but one patient had a history of at least two intermittent courses of and prednisone has been high-dose induction therapies followed by autologous periph- the standard chemotherapy for patients with MM with the eral blood stemcell transplants. Following relapse after high- median survival of 3 years or less.11 With the introduction of dose therapy, 11 of 14 patients had undergone two additional high-dose chemotherapy, response rates as well as event-free salvage therapies with combinations such as DCEP and overall survival have improved.12 A randomized trial of (dexamethasone, cyclophosphamide, , and cis- 200 previously untreated patients, the Intergroupe Franc¸ais du platinum) and thalidomide. Ten of 14 patients had stage III Mye´lome (IMF-90), demonstrated a response rate of 81% in disease. Cytogenetic abnormalities were present in 13 of 14 patients treated with high-dose therapy and autologous bone patients, and nine of 14 evaluable patients had chromosome marrow transplantation vs a 57% response in patients treated 13 abnormalities. with conventional chemotherapy (P Ͻ 0.001).11 High-dose therapy with stemcell support was also superior with respect to the number of complete responses (22% vs 5%), event-free Efficacy (28% vs 10%; P = 0.01), and overall 5-year survival (52% vs 12%; P = 0.03). Treatment-related mortality was similar in Responses are summarized in Table 2. Three patients both groups. The superiority of high-dose chemotherapy with responded to a single infusion cycle; two patients had Ͼ50% stemcell support has also been subsequently confirmedin reduction in M protein, one of which with Ͼ75% reduction. other studies.13,14 However, despite the improvements in One additional patient had Ͼ25% reduction with a total response and survival, MM remains an incurable malignancy response rate of 21%. The duration of response was 6 weeks for the majority of patients. Therefore, new treatment stra- for the patients with 25% and 50% reductions in ‘M’ protein; tegies are required. Treatment modalities under various stages the patient with the 75% response died 1 week post-therapy of investigation include , chemokine/cytokine of infection- and disease-related complications. Eight patients manipulation, inhibition of angiogenesis, and strategies tar- were considered non-responders, and three patients pro- geted at bone marrow microenvironment. Although some gressed while on the protocol. One patient who did not achi- advances have been made in this area with thalidomide and eve a definitive response, nonetheless experienced prolonged bisphosphonates, arsenic trioxide targets multiple mech- stable disease. Bone marrow cytoreduction was not monitored anisms of disease progression in patients with MM and offers an important new avenue of investigation. In the present study, arsenic trioxide administered in Table 2 Responses accordance with the protocol that was successfully used to induce remission in patients with APL, produced responses in = Response Reduction in M protein n 14 three of 14 patients who had failed high-dose chemotherapy (%) and two different salvage regimens. In addition, another patient experienced stable disease for over 6 months. The Objective Ն75 1 Ն50–75 1 patient with the best response died within a week of com- Minor Ն25–50 1 pletion of therapy due to complications related to the disease; None 8a the other two patients had a 6-week duration of response. Progressive disease 3 Although the rate and duration of response were low, this very resistant patient population had failed all previous therapies aIncluding one patient with stable disease. and also failed to respond to salvage maneuvers attempted

Leukemia Arsenic trioxide in multiple myeloma NC Munshi et al 1837 following arsenic trioxide therapy.15 Although arsenic trioxide acute promyelocytic leukemia by Ailing-1 (cancer-cure-1) therapy was otherwise well tolerated, we observed unexpected tox- combined with syndrome differentiation treatment of traditional icity in the formof cytopenias that mayhave been related to chinese medicine. Chin J Comb Trad Chin Med West Med 1992; 12: 170–171. the limited bone marrow reserve after autotransplant and/or 5 Niu C, Yan H, Yu T, Sun H-P, Liu J-X, Li X-S, Wu W, Zhang F- advanced disease. In the APL population, arsenic trioxide is Q, Chen Y, Zhou L, Li J-M, Zeng X-Y, Ou Yang R-R, Yuan M-M, not associated with significant myelosuppression.6,14 Normal Ren M-Y, Gu F-Y, Cao Q, Gu B-W, Su X-Y, Chen G-Q, Xiong S- hematologic values were also not an entry criterion in our M, Zhang T-D, Waxman S, Wang Z-Y, Chen Z, Hu J, Shen Z-X, study; the substantial cytopenias observed in 80% of patients Chen S-J. Studies on treatment of acute promyelocytic leukemia in the present study may reflect the marginal bone marrow with arsenic trioxide: remission induction, follow-up, and molecu- lar monitoring in 11 newly diagnosed and 47 relapsed acute pro- reserve in these heavily pretreated population. In a different myelocytic leukemia patients. Blood 1999; 94: 3315–3324. study of arsenic trioxide in patients with a variety of advanced 6 Shen Z-X, Chen G-Q, Ni J-H, Li X-S, Xiong S-M, Qiu Q-Y, Zhu J, hematologic malignancies, patients who entered the study Tang W, Sun G-L, Yang K-Q, Chen Y, Zhou L, Fang Z-W, Wang with pre-existing myelosuppression experienced exacerbation Y-T, Ma J, Zhang P, Zhang T-D, Chen S-J, Chen Z, Wang Z-Y. Use of the condition during treatment, while patients with rela- of arsenic trioxide (As2O3) in the treatment of acute promyelocytic tively normal blood counts did not.16,17 Additionally, the leukemia (APL): II. Clinical efficacy and in relapsed patients. Blood 1997; 89: 3354–3360. majority of patients in this study had undergone at least one 7 Zhu X-H, Shen Y-L, Jing Y-K, Cai X, Jia P-M, Huang Y, Tang W, high-dose chemotherapy with stem cell support, while none Shi G-Y, Sun Y-P, Dai J, Wang Z-Y, Chen S-J, Zhang T-D, Waxman of the APL patients had such therapy. It is possible that the S, Chen Z, Chen G-Q. Apoptosis and growth inhibition in malig- damage to the marrow and the stromal elements may add to nant lymphocytes after treatment with arsenic trioxide at clinically the higher risk for development of cytopenias and explain achievable concentrations. J Natl Cancer Inst 1999; 91: 772–778. the discrepancy between treatment toxicities in APL and 8 Jing Y, Dai J, Chalmers-Redman RM, Tatton WG, Waxman S. Arsenic trioxide selectively induces acute promyelocytic leukemia multiple myeloma. cell apoptosis via a -dependent pathway. Blood In conclusion, despite improved response rates achieved 1999; 94: 2102–2111. with high-dose chemotherapy and stem cell transplantation, 9 Park WH, Seol JG, KimES, Hyun JM, Jung CW, Lee CC, KimBK, MM remains a largely incurable malignancy. Preclinical data Lee YY. Arsenic trioxide-mediated growth inhibition in MC/CAR and the current support a potential role for arsenic myeloma cells via arrest in association with induction trioxide in the therapy of patients with relapsed or resistant of cyclin-dependent kinase inhibitor, p21, and apoptosis. Cancer Res 2000; 60: 3065–3071. MM. Subsequent studies should assess dose and scheduling 10 Rousselot P, Labaume S, Marolleau J-P, Larghero J, Noguera M-H, adjustments for more prolonged administration, as well as Brouet J-C, Fermand J-P. Arsenic trioxide and melarsoprol induce combination therapy with ascorbic acid, interferon-␣ and apoptosis in plasma cell lines and in plasma cells from myeloma dexamethasone. Additional basic research is needed to deter- patients. Cancer Res 1999; 59: 1041–1048. mine the exact mechanisms responsible for the actions of 11 Attal M, Harousseau J-L, Stoppa A-M, Sotto J-J, Fuzibet J-G, Rossi arsenic trioxide in patients with MM, particularly the effects J-F, Casassus P, Maisonneuve H, Facon T, Ifrah N, Payen C, Bataille R, Intergroupe Franc¸ais du Mye´lome. A prospective, ran- of this novel agent on angiogenesis. Finally, recent clinical domized trial of autologous bone marrow transplantation and experience demonstrating significant efficacy and acceptable chemotherapy in multiple myeloma. N Engl J Med 1996; 335: toxicities with arsenic trioxide, even in pediatric patients with 91–97. APL, provides a strong rationale for the use of this agent in 12 Jagannath S, Vesole DH, Glenn L, Crowley J, Barlogie B. Low-risk MM patients earlier in their disease. intensive therapy for multiple myeloma with combined autolog- ous bone marrow and blood stem cell support. Blood 1992; 80: 1666–1672. 13 Barlogie B, Jagannath S, Naucke S, Mattox S, Bracy D, Crowley Acknowledgements J, Tricot G, Alexanian R. Long-termfollow-up after high-dose ther- apy for high-risk multiple myeloma. Bone MarrowTransplant 1998; 21: 1101–1107. This work was done at University of Arkansas for Medical 14 Desikan R, Barlogie B, Sawyer J, Ayers D, Tricot G, Badros A, Sciences, Myeloma and Transplantation Medical Center. This Zangari M, Munshi NC, Anaissie E, Spoon D, Siegel D, Jagannath study was supported in part by an unrestricted educational S, Vesole D, Epstein J, Shaughnessy J, Fassas A, LimS, Roberson P, Crowley J. Results of high-dose therapy for 1000 patients with grant fromCell Therapeutics, Inc. multiple myeloma: durable complete remissions and superior sur- vival in the absence of chromosome 13 abnormalities. Blood 2000; 95: 4008–4010. 15 Munshi NC. Arsenic trioxide: an emerging therapy for multiple References myeloma. Oncologist 2001; 6 (Suppl. 2): 17–21. 16 Soignet SL, Frankel SR, Douer D, Tallman MS, Kantarjian H, Cal- 1 Drach J, Kaufmann H, Urbauer E, Schreiber S, Ackermann J, Huber leja E, Stone RM, Kalaycio M, Scheinberg DA, Steinherz P, Sievers H. The biology of multiple myeloma. J Cancer Res Clin Oncol EL, Coutre´ S, Dahlberg S, Ellison R, Warrell RP Jr. United states 2000; 126: 441–447. multicenter study of arsenic trioxide in relapsed acute promyelo- 2 Kyle RA. Multiple myeloma, macroglobulinemia, and the mono- cytic leukemia. J Clin Oncol 2001; 19: 3852–3860. clonal gammopathies. Curr Pract Med 1999; 2: 1131–1137. 17 Soignet SL, Novick S, Bienvenu B, Chanel S, Ho R, Spriggs D,

3 Rajkumar SV, Greipp PR. Prognostic factors in multiple myeloma. Ellison R, Warrell RP Jr. Arsenic trioxide (AS2O3): a dose-ranging Hematol Oncol Clin N Am 1999; 13: 1295–1314. and clinical pharmacologic study in patients with advanced hema- 4 Sun H-D, Ma L, Hu C-X, Zhang T-D. Thirty-two cases of treating tologic cancers. Cancer Res 2000; 41: 543 (Abstr. 3462).

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