Rituximab in combination with high-dose methylprednisolone for the treatment of chronic lymphocytic leukemia

J E Castro, D F James, J D Sandoval-Sus, S Jain, J Bole, L Rassenti, T J Kipps, J E Castro, D F James, J D Sandoval-Sus, S Jain, J Bole, L Rassenti, T J Kipps

Abstract

We observed that high-dose methylprednisolone (HDMP) and rituximab was well tolerated and had promising activity when used in combination to treat patients with fludarabine-refractory chronic lymphocytic leukemia (CLL). This prompted us to evaluate the use of these agents in frontline therapy. A total of 28 patients with a median age of 65 years enrolled in this study. Patients received HDMP at 1 g/m(2) each day for 3 days during each of the three 4-week cycles together with rituximab and prophylactic antimicrobial therapy. The treatment was well tolerated with few adverse events of grade III or higher. The overall response rate was 96% (N=27). Nine patients (32%) achieved a complete remission (CR), two of which were without detectable minimal residual disease (MRD). Six patients with MRD received consolidation with alemtuzumab; five of these patients achieved an MRD-negative CR. With over 3 years of follow-up median progression-free survival was 30.3 months with only 39% of patients requiring additional therapy, and an overall survival was 96%. This study demonstrates that HDMP and rituximab is an effective nonmyelosuppressive treatment combination for patients with CLL that warrants consideration particularly for patients with limited myeloid reserve that might not tolerate standard treatment regimens.

Figures

Figure 1. Platelet counts and hemoglobin throughout…
Figure 1. Platelet counts and hemoglobin throughout treatment with high-dose methylprednisolone (HDMP) and rituximab
Mean platelet counts (solid line) and hemoglobin levels (dashed line) of 28 patients from pre-treatment values on day one assessed throughout therapy until two month following treatment completion. Error bars represent standard error. Abbreviations: Wk, week; gm, gram; dl, deciliter; ml, microliter.
Figure 2. Individual patient hemoglobin, platelet count,…
Figure 2. Individual patient hemoglobin, platelet count, white blood cell and absolute lymphocyte count, total lymph node product, and spleen size prior to and following treatment with High-dose Methylprednisolone (HDMP) and Rituximab
Clinical disease characteristic prior to and following treatment with HDMP and Rituximab for individual patients in Group A (Left Panel) and Group B (right panel). Baseline and Final Hemoglobin (Hgb), platelets (plts), total white blood cell (WBC) count, absolute lymphocyte count (ALC), Bidimensional lymph node (LN) product, and splenomegaly measured centimeter (cm) below left costal margin (LCM).
Figure 3. Progression free survival (PFS), treatment…
Figure 3. Progression free survival (PFS), treatment free survival (TFS) and overall survival for patients treated with High-Dose Methylprednisolone (HDMP) and Rituximab
Kaplan-Meier curves for (A) PFS and (B) TFS by response to HDMP and Rituximab. (C) PFS and (D) TFS including responses following consolidation with alemtuzumab. (E) Overall survival over median 36.3 months follow-up. Abbreviations: Complete Response (CR) with or without (+ / −) Minimal Residual Disease (MRD), Partial Response (PR), Stable Disease (SD), nodular PR (nPR), NA signifies median time to PFS or TFS has not been reached.
Figure 4. Progression free survival (PFS) and…
Figure 4. Progression free survival (PFS) and treatment free survival (TFS) for all patients and excluding those patients who received aleumtuzumab as consolidation
Kaplan-Meier Curves demonstrate Median PFS (Top) and TFS (Bottom) projected at 30.5 and 33.3 months for 28 patients, excluding the six patients who received alemtuzumab consolidation PFS and TTNT is 20.5 and 31.5 months respectively.
Figure 5. Pharamcokinetics of rituximab for group…
Figure 5. Pharamcokinetics of rituximab for group 2 patients
Mean rituximab concentration for six group 2A patients (solid line) treated with rituximab 750 mg/m2 administered as consecutive daily dosing during cycle 1 and five group 2B patients (dashed line) treated with weekly rituximab- error bars represent standard deviation. Abbreviations: mu, microgram; ml, milliliter.

References

    1. Cephalon I. Treanda (Bendamustine) Package Insert. 2008 Mar; (PI-40014–00 )
    1. Demko S, Summers J, Keegan P, Pazdur R. FDA drug approval summary: alemtuzumab as single-agent treatment for B-cell chronic lymphocytic leukemia. Oncologist. 2008 Feb;13(2):167–174.
    1. Wierda W, O'Brien S, Wen S, Faderl S, Garcia-Manero G, Thomas D, Do KA, Cortes J, Koller C, Beran M, Ferrajoli A, Giles F, Lerner S, Albitar M, Kantarjian H, Keating M. Chemoimmunotherapy with fludarabine, cyclophosphamide, and rituximab for relapsed and refractory chronic lymphocytic leukemia. J Clin Oncol. 2005 Jun 20;23(18):4070–4078.
    1. Bosch F, Ferrer A, Lopez-Guillermo A, Gine E, Bellosillo B, Villamor N, Colomer D, Cobo F, Perales M, Esteve J, Altes A, Besalduch J, Ribera JM, Montserrat E. Fludarabine, cyclophosphamide and mitoxantrone in the treatment of resistant or relapsed chronic lymphocytic leukaemia. Br J Haematol. 2002 Dec;119(4):976–984.
    1. Cheson BD. Monoclonal antibody therapy of chronic lymphocytic leukemia. Cancer Immunol Immunother. 2006 Feb;55(2):188–196.
    1. Byrd JC, Peterson BL, Morrison VA, Park K, Jacobson R, Hoke E, Vardiman JW, Rai K, Schiffer CA, Larson RA. Randomized phase 2 study of fludarabine with concurrent versus sequential treatment with rituximab in symptomatic, untreated patients with B-cell chronic lymphocytic leukemia: results from Cancer and Leukemia Group B 9712 (CALGB 9712) Blood. 2003 Jan 1;101(1):6–14.
    1. Kay NE, Geyer SM, Call TG, Shanafelt TD, Zent CS, Jelinek DF, Tschumper R, Bone ND, Dewald GW, Lin TS, Heerema NA, Smith L, Grever MR, Byrd JC. Combination chemoimmunotherapy with pentostatin, cyclophosphamide, and rituximab shows significant clinical activity with low accompanying toxicity in previously untreated B chronic lymphocytic leukemia. Blood. 2007 Jan 15;109(2):405–411.
    1. Bosch F, Ferrer A, Villamor N, Gonzalez M, Briones J, Gonzalez-Barca E, Abella E, Gardella S, Escoda L, Perez-Ceballos E, Asensi A, Sayas MJ, Font L, Altes A, Muntanola A, Bertazzoni P, Rozman M, Aymerich M, Gine E, Montserrat E. Fludarabine, cyclophosphamide, and mitoxantrone as initial therapy of chronic lymphocytic leukemia: high response rate and disease eradication. Clin Cancer Res. 2008 Jan 1;14(1):155–161.
    1. Keating MJ, O'Brien S, Albitar M, Lerner S, Plunkett W, Giles F, Andreeff M, Cortes J, Faderl S, Thomas D, Koller C, Wierda W, Detry MA, Lynn A, Kantarjian H. Early results of a chemoimmunotherapy regimen of fludarabine, cyclophosphamide, and rituximab as initial therapy for chronic lymphocytic leukemia. J Clin Oncol. 2005 Jun 20;23(18):4079–4088.
    1. Eichhorst BF, Busch R, Hopfinger G, Pasold R, Hensel M, Steinbrecher C, Siehl S, Jager U, Bergmann M, Stilgenbauer S, Schweighofer C, Wendtner CM, Dohner H, Brittinger G, Emmerich B, Hallek M. Fludarabine plus cyclophosphamide versus fludarabine alone in first-line therapy of younger patients with chronic lymphocytic leukemia. Blood. 2006 Feb 1;107(3):885–891.
    1. Byrd JC, Murphy T, Howard RS, Lucas MS, Goodrich A, Park K, Pearson M, Waselenko JK, Ling G, Grever MR, Grillo-Lopez AJ, Rosenberg J, Kunkel L, Flinn IW. Rituximab using a thrice weekly dosing schedule in B-cell chronic lymphocytic leukemia and small lymphocytic lymphoma demonstrates clinical activity and acceptable toxicity. J Clin Oncol. 2001 Apr 15;19(8):2153–2164.
    1. O'Brien SM, Kantarjian H, Thomas DA, Giles FJ, Freireich EJ, Cortes J, Lerner S, Keating MJ. Rituximab dose-escalation trial in chronic lymphocytic leukemia. J Clin Oncol. 2001 Apr 15;19(8):2165–2170.
    1. Thornton PD, Matutes E, Bosanquet AG, Lakhani AK, Grech H, Ropner JE, Joshi R, Mackie PH, Douglas ID, Bowcock SJ, Catovsky D. High dose methylprednisolone can induce remissions in CLL patients with p53 abnormalities. Ann Hematol. 2003 Dec;82(12):759–765.
    1. Chanan-Khan A, Porter CW. Immunomodulating drugs for chronic lymphocytic leukaemia. Lancet Oncol. 2006 Jun;7(6):480–488.
    1. Burger JA. No cell is an island unto itself: the stromal microenvironment in chronic lymphocytic leukemia. Leuk Res. 2007 Jul;31(7):887–888.
    1. Chiorazzi N, Rai KR, Ferrarini M. Chronic lymphocytic leukemia. N Engl J Med. 2005 Feb 24;352(8):804–815.
    1. Caligaris-Cappio F, Ghia P. Novel insights in chronic lymphocytic leukemia: are we getting closer to understanding the pathogenesis of the disease? J Clin Oncol. 2008 Sep 20;26(27):4497–4503.
    1. Lagneaux L, Delforge A, Bron D, De Bruyn C, Stryckmans P. Chronic lymphocytic leukemic B cells but not normal B cells are rescued from apoptosis by contact with normal bone marrow stromal cells. Blood. 1998 Apr 1;91(7):2387–2396.
    1. Burger M, Hartmann T, Krome M, Rawluk J, Tamamura H, Fujii N, Kipps TJ, Burger JA. Small peptide inhibitors of the CXCR4 chemokine receptor (CD184) antagonize the activation, migration, and antiapoptotic responses of CXCL12 in chronic lymphocytic leukemia B cells. Blood. 2005 Sep 1;106(5):1824–1830.
    1. Burger JA, Tsukada N, Burger M, Zvaifler NJ, Dell'Aquila M, Kipps TJ. Blood-derived nurse-like cells protect chronic lymphocytic leukemia B cells from spontaneous apoptosis through stromal cell-derived factor-1. Blood. 2000 Oct 15;96(8):2655–2663.
    1. Tsukada NKS, Reed JC, Kipps TJ. Combination Rituximab and Methylprednosolone Mitigate the Protective Activity of Nurse-Like Cells on Leukemia Cell Viability In Vitro. Blood. 2001;(98):3767a.
    1. Castro JE, Sandoval-Sus JD, Bole J, Rassenti L, Kipps TJ. Rituximab in combination with high-dose methylprednisolone for the treatment of fludarabine refractory high-risk chronic lymphocytic leukemia. Leukemia. 2008 Aug 28;
    1. Castro JESSJ, Bole J, Rassenti L, Kipps TJ. Leukemia. 2008. Rituximab in Combination with High Dose Methylprednisolone for the Treatment of Fludarabine Refractory-High Risk Chronic Lymphocytic Leukemia. accepted pending publication.
    1. Cheson BD, Bennett JM, Grever M, Kay N, Keating MJ, O'Brien S, Rai KR. National Cancer Institute-sponsored Working Group guidelines for chronic lymphocytic leukemia: revised guidelines for diagnosis and treatment. Blood. 1996;87:4990–4997.
    1. Cheson BD, Bennett JM, Grever M, Kay N, Keating MJ, O'Brien S, Rai KR. National Cancer Institute-sponsored Working Group guidelines for chronic lymphocytic leukemia: revised guidelines for diagnosis and treatment. Blood. 1996 Jun 15;87(12):4990–4997.
    1. Rawstron AC, Villamor N, Ritgen M, Bottcher S, Ghia P, Zehnder JL, Lozanski G, Colomer D, Moreno C, Geuna M, Evans PA, Natkunam Y, Coutre SE, Avery ED, Rassenti LZ, Kipps TJ, Caligaris-Cappio F, Kneba M, Byrd JC, Hallek MJ, Montserrat E, Hillmen P. International standardized approach for flow cytometric residual disease monitoring in chronic lymphocytic leukaemia. Leukemia. 2007 May;21(5):956–964.
    1. Dohner H, Stilgenbauer S, Benner A, Leupolt E, Krober A, Bullinger L, Dohner K, Bentz M, Lichter P. Genomic aberrations and survival in chronic lymphocytic leukemia. N Engl J Med. 2000 Dec 28;343(26):1910–1916.
    1. Rassenti LZ, Jain S, Keating MJ, Wierda WG, Grever MR, Byrd JC, Kay NE, Brown JR, Gribben JG, Neuberg DS, He F, Greaves AW, Rai KR, Kipps TJ. Relative value of ZAP-70, CD38, and immunoglobulin mutation status in predicting aggressive disease in chronic lymphocytic leukemia. Blood. 2008 Sep 1;112(5):1923–1930.
    1. Rassenti LZ, Huynh L, Toy TL, Chen L, Keating MJ, Gribben JG, Neuberg DS, Flinn IW, Rai KR, Byrd JC, Kay NE, Greaves A, Weiss A, Kipps TJ. ZAP-70 compared with immunoglobulin heavy-chain gene mutation status as a predictor of disease progression in chronic lymphocytic leukemia. N Engl J Med. 2004 Aug 26;351(9):893–901.
    1. Kaplan EL, Meier P. Nonparametric estimation from incomplete observations. Journal of American Statistical Association. 1958;53:457–481.
    1. Peto R, Pike MC, Armitage P, Breslow NE, Cox DR, Howard SV, Mantel N, McPherson K, Peto J, Smith PG. Design and analysis of randomized clinical trials requiring prolonged observation of each patient. II. analysis and examples. Br J Cancer. 1977 Jan;35(1):1–39.
    1. Hillmen P, Skotnicki AB, Robak T, Jaksic B, Dmoszynska A, Wu J, Sirard C, Mayer J. Alemtuzumab compared with chlorambucil as first-line therapy for chronic lymphocytic leukemia. J Clin Oncol. 2007 Dec 10;25(35):5616–5623.
    1. Rai KR, Peterson BL, Appelbaum FR, Kolitz J, Elias L, Shepherd L, Hines J, Threatte GA, Larson RA, Cheson BD, Schiffer CA. Fludarabine compared with chlorambucil as primary therapy for chronic lymphocytic leukemia. N Engl J Med. 2000 Dec 14;343(24):1750–1757.
    1. Redaelli A, Laskin BL, Stephens JM, Botteman MF, Pashos CL. The clinical and epidemiological burden of chronic lymphocytic leukaemia. Eur J Cancer Care (Engl) 2004 Jul;13(3):279–287.
    1. Diehl LF, Karnell LH, Menck HR. The American College of Surgeons Commission on Cancer and the American Cancer Society. The National Cancer Data Base report on age, gender, treatment, and outcomes of patients with chronic lymphocytic leukemia. Cancer. 1999 Dec 15;86(12):2684–2692.
    1. Tam CS, O'Brien S, Wierda W, Kantarjian H, Wen S, Do KA, Thomas DA, Cortes J, Lerner S, Keating MJ. Long-term results of the fludarabine, cyclophosphamide, and rituximab regimen as initial therapy of chronic lymphocytic leukemia. Blood. 2008 Aug 15;112(4):975–980.
    1. Wendtner CM, Ritgen M, Schweighofer CD, Fingerle-Rowson G, Campe H, Jager G, Eichhorst B, Busch R, Diem H, Engert A, Stilgenbauer S, Dohner H, Kneba M, Emmerich B, Hallek M. Consolidation with alemtuzumab in patients with chronic lymphocytic leukemia (CLL) in first remission--experience on safety and efficacy within a randomized multicenter phase III trial of the German CLL Study Group (GCLLSG) Leukemia. 2004 Jun;18(6):1093–1101.
    1. O'Brien SM, Kantarjian HM, Thomas DA, Cortes J, Giles FJ, Wierda WG, Koller CA, Ferrajoli A, Browning M, Lerner S, Albitar M, Keating MJ. Alemtuzumab as treatment for residual disease after chemotherapy in patients with chronic lymphocytic leukemia. Cancer. 2003 Dec 15;98(12):2657–2663.
    1. Moreton P, Kennedy B, Lucas G, Leach M, Rassam SM, Haynes A, Tighe J, Oscier D, Fegan C, Rawstron A, Hillmen P. Eradication of minimal residual disease in B-cell chronic lymphocytic leukemia after alemtuzumab therapy is associated with prolonged survival. J Clin Oncol. 2005 May 1;23(13):2971–2979.
    1. O'Brien S, Kantarjian H, Beran M, Smith T, Koller C, Estey E, Robertson LE, Lerner S, Keating M. Results of fludarabine and prednisone therapy in 264 patients with chronic lymphocytic leukemia with multivariate analysis-derived prognostic model for response to treatment. Blood. 1993 Sep 15;82(6):1695–1700.
    1. Lin TDM, Lucas M, Byrd JC, Bengtson EM, Peterson BL, Larson RA. Consolidation therapy with subcutaneous alemtuzumab results in severe infectious toxicity in previously untreated CLL patients who achieve a complete response after fludarabine and rituximab induction therapy: Interim Safety Analysis of CALGB Study 10101. Blood. 2007;110 (Abstract 755)
    1. Montillo M, Tedeschi A, Miqueleiz S, Veronese S, Cairoli R, Intropido L, Ricci F, Colosimo A, Scarpati B, Montagna M, Nichelatti M, Regazzi M, Morra E. Alemtuzumab as consolidation after a response to fludarabine is effective in purging residual disease in patients with chronic lymphocytic leukemia. J Clin Oncol. 2006 May 20;24(15):2337–2342.
    1. Bowen DA, Call TG, Jenkins GD, Zent CS, Schwager SM, Van Dyke DL, Jelinek DF, Kay NE, Shanafelt TD. Methylprednisolone-rituximab is an effective salvage therapy for patients with relapsed chronic lymphocytic leukemia including those with unfavorable cytogenetic features. Leuk Lymphoma. 2007 Dec;48(12):2412–2417.
    1. Dungarwalla M, Evans SO, Riley U, Catovsky D, Dearden CE, Matutes E. High dose methylprednisolone and rituximab is an effective therapy in advanced refractory chronic lymphocytic leukemia resistant to fludarabine therapy. Haematologica. 2008 Mar;93(3):475–476.

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