Correspondence 154 Table 2 Lymphocyte subsets and immunoglobulin values during the study

Lymphocytes Baseline, Day +60, Day +120, Day +180, Day +240, Normal range subset/ml range 12 pts. 12 pts. 10 pts. 8 pts. 6 pts.

CD3 1515 229 526 660 765 1185–1540 908–5990 96–1474 346–720 593–726 602–806 CD4 796 117 158 215 417 670–950 374–1582 40–304 146–403 163–266 196–508 CD8 549 133 216 366 361 505–695 192–1650 46–1166 185–339 224–508 238–516 CD16/56 528 330 141 158 236 70–190 217–2357 164–570 116–166 146–169 184–268 IgG 1080 1036 1231 1228 1409 800–1800 503–1992 647–1898 1034–1268 1120–1980 1284–2020 IgA 57 113 179 275 141 70–400 26–200 21–216 124–201 125–307 120–328 IgM 52 49 53 178 71 50–250 19–108 20–142 50–143 50–198 58–196

The normal levels of immunoglobulin after alemtuzumab subcutaneous alemtuzumab (anti-CD52 monoclonal antibody, therapy could be explained by the cooperation between normal Campath-1H) treatment as first-line therapy for B-cell chronic residual T and B cells, which are depressed after transplant lymphocytic leukaemia. Leukemia 2004; 18: 484–490. because of the conditioning regimen.4 2 Laurenti L, Piccioni P, Piccirillo N, Sora’ F, Chiusolo P, Garzia MG et al. Immune recovery of lymphocyte subsets 6 years after As expected, in our study the follow-up was shorter than in autologous peripheral blood stem cell transplantation (PBSCT) for Lundin’s series because disease progression in these heavily lymphoproliferative diseases. A comparison between NHL, HD pretreated patients was more rapid. and MM in 149 patients’ group. Leukemia Lymphoma 2004; 45: Thus, we conclude that the previous chemotherapy, reduced 2063–2070. cumulative dose (median cumulative dose of 300 mg vs 3 Fegan C, Thomas H, Bailey-Wood R, Coleman S, Phillips S, Hoy T 1362 mg) and administration route (standard dose of 10 mg i.v. et al. In vitro LAK (lymphokine activated killer) activity following vs 30 mg s.c.) of Campath-1H therapy do not influence the long- autologous peripheral blood stem cell is significantly greater than that following autologous bone marrow and allogeneic bone lasting depletion of major blood lymphocyte subsets after the marrow transplantation. Bone Marrow Transplant 1995; 16: end of the treatment. 277–281.

1 1 4 Guillaume T, Rubinstein DB, Symann M. Immune reconstitution L Laurenti Divisione di Ematologia, Policlinico A Gemelli, and immunotherapy after autologous hematopoietic stem cell P Piccioni1 Universita` Cattolica del Sacro Cuore, Rome, Italy 1 transplantation. Blood 1998; 92: 1471–1490. M Tarnani 5 Laurenti L, Sora F, Piccirillo N, Chiusolo P, Cicconi S, Rutella S et al. 1 P Chiusolo Immune reconstitution after autologous selected peripheral blood 1 N Piccirillo progenitor cell transplantation: comparison of two CD34+ cell- C Rumi1 selection systems. Transfusion 2001; 41: 783–789. F Sora1 6 Rutella S, Rumi C, Laurenti L, Pierelli L, Sora’ F, Sica S et al. Immune S Sica1 reconstitution after transplantation of autologous peripheral G Leone1 CD34+ cells: analysis of predictive factors and comparison with unselected progenitor transplants. Br J Haematol 2000; 108: 105–115. References 7 Laurenti L, Sica S, Sora F, Piccirillo N, Ortu La Barbera E, Chiusolo P et al. Long-term immune recovery after CD34+ immunoselected 1 Lundin J, Porwit-MacDonald A, Rossmann ED, Karlsson C, Edman and unselected peripheral blood progenitor cell transplantation: a P, Rezvany MR et al. Cellular immune reconstitution after case–control study. Haematologica 1999; 84: 1100–1103.

Efficacy of melphalan, arsenic trioxide, and ascorbic acid combination therapy (MAC) in relapsed and refractory multiple myeloma

Leukemia (2005) 19, 154–156. doi:10.1038/sj.leu.2403541 TO THE EDITOR Published online 21 October 2004 Multiple myeloma (MM) is an incurable B-cell malignancy that is characterized by both relapsing and refractory disease. Correspondence: Dr JR Berenson, Institute for Myeloma & Bone Therapeutic strategies are needed to overcome drug resistance Cancer Research, 9201 Sunset Blvd., Suite 300, W. Hollywood, CA and to improve patient outcomes for this difficult-to-treat patient 90069, USA; Fax: þ 1 310 623 1120; population. Arsenic trioxide has been shown to be effective in E-mail: [email protected] Received 12 July 2004; accepted 31 August 2004; Published online the treatment of acute promyelocytic leukemia in newly 1,2 2,3 21 October 2004 diagnosed disease, as well as in refractory/relapsed disease.

Leukemia Correspondence 155 Arsenic trioxide, which has been clinically studied as a single week of a 6-week cycle, instead of twice weekly during those 4 agent4,5 and in combination with ascorbic acid,6 has been found days as was done in the first six patients. Treatment duration for to be safe and has shown some antimyeloma activity. In clinical these patients was 13–104 weeks. All 10 patients responded trials, arsenic trioxide at a dose of 0.25 mg/kg given intrave- to MAC therapy. Serum M-protein levels were reduced by nously twice weekly was well tolerated in a recent phase 1/2 29–90%, urine M-protein reductions ranged from 34 to 71%, clinical trial (Berenson J et al. Blood 2002; 100: 394b, abstract). and six of 10 patients exhibited a sustained response, including Oral melphalan has shown significant antimyeloma activity two patients with continuing responses for more than 1 year clinically at doses of 0.25 mg/kg/day for 4 days every 4–6 weeks. (Table 2). These six patients continue to receive arsenic Ascorbic acid given intravenously at a dose of 1 g following a trioxide and ascorbic acid although, after six cycles (36 weeks), dose of 0.25 mg/kg arsenic trioxide, also given intravenously, melphalan was discontinued, and the combination of arsenic twice weekly, has shown promising early clinical results.6 In this trioxide and ascorbic acid was changed to once weekly. The preliminary analysis, 10 patients with MM, who were refractory other four patients had a response followed by disease to their most recent therapeutic regimen, had failed multiple progression after 13, 21, 26, and 40 weeks, respectively. previous therapeutic regimens, and for whom other treatment None of the patients developed new skeletal complications or options were exhausted at the time of initiation of therapy, were hypercalcemia during the period of progression-free disease. In administered a combination of melphalan, arsenic trioxide, and the five patients with azotemia, significant reductions in ascorbic acid (MAC) therapy (Table 1). Arsenic trioxide was their serum creatinine levels (from 5.1-3.0, 6.1-1.9, administered intravenously at a dose of 0.25 mg/kg over 1–2 h 2.3-1.5, 5.1-2.1, and 4.0-2.2 mg/dl, respectively) were on a twice-weekly basis. A fixed dose of ascorbic acid (1 g) was observed. One patient with profound hypercalcemia (despite administered intravenously for 15 min after each dose of arsenic treatment with zoledronic acid) normalized her serum trioxide. As arsenic trioxide may potentiate the myelosuppres- calcium after 1 week of MAC therapy. To date, six patients sive effects of melphalan, a dose of 0.1 mg/kg (40% of remain on therapy and have maintained their response. conventional dose) was selected to achieve a balance between Overall, MAC therapy was generally well tolerated with only the therapeutic benefit and the reduced toxicity of the minor treatment delays due to QT interval prolongation, combination. Of note, six of the 10 patients had received thrombocytopenia, and neutropenia. The most common melphalan previously; four of these patients received melphalan adverse events noted with this combination were fatigue as part of their conditioning regimen for autologous peripheral (n ¼ 7, grade 1), marrow suppression (anemia (n ¼ 7, grades 1– blood stem cell transplantation (SCT), and the other two patients 3), leukopenia (n ¼ 7, grades 1–3), and thrombocytopenia were progressing on melphalan as part of the melphalan- (n ¼ 4, grades 1–3)), transient prolongation of the QT interval prednisone regimen when MAC was initiated (Table 1). No (n ¼ 5, grade 1), sensory neuropathy (n ¼ 4, grades 1–2), adjustment in dose or schedule was made for patients with renal gastrointestinal symptoms (n ¼ 4, grades 1–2), pulmonary and dysfunction (n ¼ 5). At the time of initiation of MAC therapy, the peripheral edema responsive to treatment with diuretics and first six patients were taking ongoing oral glucocorticoids (oral pulse oral glucocorticoids (n ¼ 2, grade 3), reactivation of herpes methylprednisolone, prednisone, or dexamethasone) that were zoster (n ¼ 2, grade 2), headache (n ¼ 2, grade 1), and skin rash continued at the same dose and then discontinued within 6–8 (n ¼ 3, grade 2). One patient with fatigue had her arsenic weeks of initiation of MAC therapy. The last four patients who trioxide dose reduced by half, with a marked reduction in her were given this regimen had their regimen modified so that they symptoms, and has been on ongoing therapy for 2 years. were receiving arsenic trioxide and ascorbic acid daily Another patient with grade 1 neuropathy experienced improve- on the same 4 days along with oral melphalan during the first ment in symptoms after the arsenic trioxide and ascorbic acid

Table 1 Patient characteristics at the time of initiation of MAC therapy and during prior therapies

Patient Age (y)/ Subtype b2-microglobulin Serum Prior treatments sex (mg/dl) creatinine (mg/dl) Melphalan High-dose VAD a PSCT b BLTc/ Bortezomib steroids Thal7Dex d

1 61/F IgGk 15 5.1 + À ++ + + 2 71/F Light-chain k 0.4 1.0 + + ÀÀ ++ disease 3 47/F IgAk 2.5 6.1 À ++–+ + 4 60/M IgAl 3.8 2.3 + À ++ + À 5 54/F IgGl 11 5.1 À ++ÀÀ À 6e 51/F IgAl 3.2 0.9 À ++À + À 7 62/M IgGk 0.5 1.1 À + ÀÀ À À 8 76/M IgAk NDf 1.1 + À ++ + + 9g 70/F IgGl 16.9 4.0 + + ÀÀ À + 10 52/M IgGk 4.0 1.0 + À ++ + + aVincristine, doxorubicin, and dexamethasone. bPeripheral stem cell transplantation (autologous). cClarithromycin, low-dose glucocorticoids, and thalidomide. dDexamethasone and thalidomide. eSerum calcium 19.1 mg/dl. fND ¼ not done. gFailed to respond to arsenic trioxide alone and melphalan+bortezomib.

Leukemia Correspondence 156 Table 2 Response to MAC treatment

Patient Weeks of Baseline Response to MAC Baseline Response to MAC treatment Serum M-protein 24-h Urine M- Serum M-protein Urine M-protein Serum creatinine Serum creatinine (g/dl) protein (g) change (%) change (%) (mg/dl) change (%)

121a NAb,c 3.4 NA À58 5.1 À41 226a NAc 1.2 NA À54 1.0 NA 3 64 9.4 4.3 À29 À71 6.1 À69 440a 2.2 2.8 À46 À34 2.3 À35 5 104 4.0 0.63 À46 À56 5.1 À59 6d 50 6.1 NA À90 NA 0.9 NA 7 32 5.4 NA À38 NA 1.1 NA 8 20 4.3 NA À66 NA 1.1 NA 9 22 1.9 3.8 À47 À54 4.0 À45 10 13a 6.2 NA À37 NA 1.0 NA aProgression of disease. bNA ¼ not applicable. cPatient 1, light-chain disease; patient 2, no significant amount of M-protein in serum. dNormalized serum calcium by the end of first week of MAC therapy.

was changed to a once-weekly schedule. Delays in the References administration of MAC therapy occurred in seven patients. Delays secondary to hematologic toxicity occurred in two patients for 1 Mathews V, Balasubramanian P, Shaji RV, George B, Chandy M, ANC o500 Â 109/l and platelets o50 Â 109/l, attributable to Srivastava A. Arsenic trioxide in the treatment of newly diagnosed melphalan. Only one patient required transient G-CSF support for acute promyelocytic leukemia: a single center experience. Am J neutropenia. Delays of only a few days occurred in five patients Hematol 2002; 70: 292–299. 2 Niu C, Yan H, Yu T, Sun HP, Liu JX, Li XS et al. Studies on treatment whose QTc intervals were prolonged (4460 ms), attributable to of acute promyelocytic leukemia with arsenic trioxide: remission arsenic trioxide. Of note, no grade 4 adverse events were observed induction, follow-up, and molecular monitoring in 11 newly and no treatment discontinuations occurred among patients on diagnosed and 47 relapsed acute promyelocytic leukemia patients. MAC therapy. In this small series of patients treated, MAC therapy Blood 1999; 94: 3315–3324. has been shown to be an active new therapeutic regimen for 3 Soignet SL, Frankel SR, Douer D, Tallman MS, Kantarjian H, Calleja patients with refractory MM. A formal large multi-center phase 1/2 E et al. United States multicenter study of arsenic trioxide in relapsed acute promyelocytic leukemia. J Clin Oncol 2001; 19: clinical trial is underway to further investigate this novel 3852–3860. combination for patients with relapsed or refractory MM, and 4 Munshi NC, Tricot G, Desikan R, Badros A, Zangari M, Toor A et al. extend the promising findings of this pilot study. Clinical activity of arsenic trioxide for the treatment of multiple myeloma. Leukemia 2002; 16: 1835–1837. 5 Hussein MA, Saleh M, Ravandi F, Mason J, Rifkin RM, Ellison R. Duality of interest Phase 2 study of arsenic trioxide in patients with relapsed or refractor multiple myeloma. Br J Haematol 2004; 125: Dr Berenson has an ongoing financial relationship with Cell 470–476. 6 Bahlis NJ, McCafferty-Grad J, Jordan-McMurry I, Neil J, Reis I, Therapeutics, Inc., which includes research grants, honoraria, Kharfan-Dabaja M et al. Feasibility and correlates of arsenic trioxide speaker’s bureau, and consultant work only. combined with ascorbic acid-mediated depletion of intracellular glutathione for the treatment of relapsed/refractory multiple 1,2 1 MJ Borad Institute for Myeloma and Bone Cancer myeloma. Clin Cancer Res 2002; 8: 3658–3666. R Swift1 Research, Los Angeles, CA, USA; and JR Berenson1 2Department of Hematology/Oncology, Tulane University School of Medicine, New Orleans, LA, USA

Single-agent thalidomide for treatment of first relapse following high-dose chemotherapy in patients with multiple myeloma

Leukemia (2005) 19, 156–159. doi:10.1038/sj.leu.2403564 TO THE EDITOR Published online 28 October 2004 The use of thalidomide has improved the treatment of patients with multiple myeloma (MM). Thalidomide has shown to have Correspondence: Dr R Fenk, Department of Hematology, Oncology therapeutic activity as a single agent in patients with relapsed and Clinical Immunology, University of Duesseldorf, Moorenstr. 5, and/or refractory MM.1,2 Thalidomide monotherapy can induce Duesseldorf 40225, Germany; Fax: þ 49 211 8118853; remissions in about one-third of relapsing or refractory E-mail: [email protected] 1,2,4–8 Received 26 August 2004; accepted 17 September 2004; Published patients and combinations of thalidomide with dexa- online 28 October 2004; methasone and/or chemotherapy can further improve response

Leukemia