160 results on '"Wijermans PW"'
Search Results
2. Induction therapy with vincristine, adriamycin, dexamethasone (VAD) and intermediate-dose melphalan (IDM) followed by autologous or allogeneic stem cell transplantation in newly diagnosed multiple myeloma
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Lokhorst, HM, Sonneveld, P, Cornelissen, JJ, Joosten, P, van Marwijk Kooy, M, Meinema, J, Nieuwenhuis, HK, van Oers, MHJ, Richel, DJ, Segeren, CN, Veth, G, Verdonck, LF, and Wijermans, PW
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- 1999
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3. Continuous infusion of low-dose 5-Aza-2′-deoxycytidine in elderly patients with high-risk myelodysplastic syndrome
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Wijermans, PW, Krulder, JWM, Huijgens, PC, and Neve, P
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- 1997
- Full Text
- View/download PDF
4. Clinical significance of complex karyotype at diagnosis in pediatric and adult patients with de novo acute promyelocytic leukemia treated with ATRA and chemotherapy
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Labrador, J, Luno, E, Vellenga, E, Brunet, S, Gonzalez-Campose, J, Chillon, MC, Holowiecka, A, Esteve, J, Bergua, J, Gonzalez-Sanmiguel, JD, Gil, C, Tormo, M, Salamero, O, Manso, F, Fernandez, I, de laSerna, J, Moreno, MJ, Perez-Encinas, M, Krsnik, I, Ribera, JM, Cervera, J, Calasanz, MJ, Boluda, B, Sobas, M, Lowenberg, B, Sanz, MA, Montesinos, P, Palmer, L, Ciarlo, S, Bezares, F, Rojas, F, Longoni, H, Gelemur, M, Fazio, P, Canepa, C, Saba, S, Balladares, G, Negri, P, Giunta, M, Milone, J, Prates, MV, Lafalse, D, Sossa, C, Jaramillo, F, Mayer, J, Protivankova, M, Scwarz, J, Holowiecka-Goral, A, Jakubas, B, Skret-Norwicz, A, Bizgalska-Skrzypek, P, Pluta, A, Becht, R, Kielbinski, M, Watek, M, Paluszewska, M, Gadomska, A, Rzenno, E, Piszcz, J, Ejduk, A, Dobrzanska, J, Calbecka, M, Kostyra, A, Malek, M, Grosicki, S, Knopinska, W, de Heredia, JMB, Hernandez, JM, Arias, J, Ramos, F, Roman, A, de la Serna, J, Negri, S, Rayon, C, Fernandez-Calvo, FJ, Diaz-Mediavilla, J, Olave, M, Amutio, E, Pedro, C, Gorosquieta, A, Viguria, M, Zudaire, M, Molero, T, Sayas, MJ, Guardia, R, Rivas, C, Esquembre, C, Garcia, R, Alcala, A, Lopez, JA, Rubio, V, Amigo, ML, Linares, M, San Miguel, JDG, Deben, G, Escoda, L, de la Camara, R, Molines, A, Loureiro, C, Allegue, MJ, Amador, L, Marti, JM, Madero, L, Lassaletta, A, Cabezudo, M, Garcia-Larana, J, Rojas, R, Ortega, F, Penarrubia, MJ, Puente, F, Lopez-Ibor, B, Bergua, JM, Ibanez, J, Sanchez, P, Novo, A, Font, LL, Guinea, JM, Montero, A, Gonzalez, M, Martin, G, Martinez, J, Verdeguer, A, Garcia, P, Conde, E, Garcia, J, Capote, FJ, Bueno, J, Bastida, P, Rubio, A, Fuster, JL, Gonzalez, J, Perez, I, Molina, J, Mateos, MC, Ardaiz, MA, Rodriguez-calvillo, M, Poderos, C, Arnan, M, Duarte, R, Hernandez, JA, Diaz-Morfa, M, Martin-Chacon, E, Calvo-Villas, JM, Garcia-Belmonte, D, Hernandez-Maraver, D, Ossenkoppele, GJ, van der Lelie, J, Sonneveld, P, Zijlmans, M, Maertens, J, de Valk, B, Wijermans, PW, de Groot, MR, Schouten, HC, Biesma, DH, Kooy, MV, and de Lisa, E
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relapse ,complex karyotype ,Acute promyelocytic leukemia ,ATRA ,chemotherapy ,prognostic - Abstract
Although additional cytogenetic abnormalities (ACA) do not affect the prognosis of patients with t(15;17) acute promyelocytic leukemia (APL), the role of a complex karyotype (CK) is yet to be clarified. We aimed to investigate the relationship of CK with relapse incidence in 1559 consecutive APL patients enrolled in three consecutive trials. Treatment consisted of AIDA induction followed by risk-adapted consolidation. A CK (CK) was defined as the presence of >= 2 ACA, and a very CK (CK+) as >= 3 ACA. Eighty-nine patients (8%) had a CK, of whom 41 (4%) had CK+. The 5-year cumulative incidence of relapse (CIR) in patients with CK was 18%, and 12% in those with
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- 2019
5. An analysis of the impact of CD56 expression in de novo acute promyelocytic leukemia patients treated with upfront all-trans retinoic acid and anthracycline-based regimens
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Sobas, M, Montesinos, P, Boluda, B, Bernal, T, Vellenga, E, Nomdedeu, J, Gonzalez-Campos, J, Chillon, M, Holowiecka, A, Esteve, J, Bergua, J, Gonzalez-Sanmiguel, JD, Gil-Cortes, C, Tormo, M, Salamero, O, Manso, F, Fernandez, I, de la Serna, J, Moreno, MJ, Perez-Encinas, M, Krsnik, I, Ribera, JM, Escoda, L, Lowenberg, B, Sanz, MA, de Heredia, JMB, Hernandez, JM, Arias, J, Ramos, F, Roman, A, Negri, S, Rayon, C, Fernandez-Calvo, FJ, Diaz-Mediavilla, J, Gil, C, Olave, M, Amutio, E, Pedro, C, Gorosquieta, A, Viguria, M, Zudaire, M, Molero, T, Sayas, MJ, Guardia, R, Esquembre, C, Garcia, R, Alcala, A, Lopez, JA, Rubio, V, Amigo, ML, Linares, M, San Miguel, JDG, Coruna, A, Deben, G, de la Camara, R, Molines, A, Loureiro, C, Allegue, MJ, Amador, L, Marti, JM, Madero, L, Lassaletta, A, Cabezudo, M, Garcia-Larana, J, Rojas, R, Ortega, F, Penarrubia, MJ, Puente, F, Lopez-Ibor, B, Brunet, S, Ibanez, J, Sanchez, P, Novo, A, Guinea, JM, Montero, A, Gonzalez, M, Martin, G, Martinez, J, Verdeguer, A, Garcia, P, Conde, E, Garcia, J, Capote, FJ, Bueno, J, Bastida, P, Rubio, A, Fuster, JL, Gonzalez, J, Perez, I, Molina, J, Mateos, MC, Ardaiz, MA, Rodriguez-calvillo, M, Poderos, C, Arnan, M, Duarte, R, Diaz-Morfa, M, Martin-Chacon, E, Calvo-Villas, JM, Garcia-Belmonte, D, Hernandez-Maraver, D, Ossenkoppele, GJ, van der Lelie, J, Sonneveld, P, Zijlmans, M, Maertens, J, de Valk, B, Wijermans, PW, de Groot, MR, Schouten, HC, Biesma, DH, van Marwijk, M, de Lisa, E, Golos, A, Ejduk, A, Armatys, A, Zarzycka, E, Knopinska, W, Miskiewicz, W, Jastrzab, B, Pluta, A, Paluszewska, M, Podhorecka, M, Gromek, T, Jakubas, B, Majcherek, M, Skret, A, Watek, M, Charlinski, G, Calbecka, M, Becht, R, Gadomska, A, Rzenno, E, Piszcz, J, Grosicki, S, Palmer, L, Ciarlo, S, Bezares, F, Rojas, F, Longoni, H, Gelemur, M, Fazio, P, Canepa, C, Saba, S, Balladares, G, Negri, P, Giunta, M, Milone, J, Lafalse, D, Sossa, C, Jaramillo, F, Mayer, J, Protivankova, M, and Scwarz, J
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relapse ,Acute promyelocytic leukemia ,CD56 ,ATRA ,chemotherapy ,prognostic - Abstract
Out of 956, there were 95 (10%) CD56+ APL patients treated with PETHEMA ATRA and chemotherapy. CD56+ expression was associated with high WBC, BCR3 isoform, and co-expression of CD2, CD34, CD7, HLA-DR, CD15, and CD117 antigens. CD56+ vs CD56- APL presented higher induction death rate (16% vs 8%, p = .02) and 5-years cumulative incidence of relapse (33% versus 10%, p = .006), irrespectively of the Sanz score (low-risk 47% versus 5%, p < .001; intermediate 23% versus 7%, p < .001; and high-risk 42% versus 21%, p = .007). In the multivariate analysis, CD56 + (p < .0001), higher relapse-risk score (p = .001), and male gender (p = .05) retained the independent predictive value. CD56+ APL also showed a greater risk of CNS relapse (6% versus 1%, p < .001) and lower 5-year OS (75% versus 83%, p = .003). The AIDA-based LPA2012 trial, with an intensified consolidation schedule for CD56+ APL, will elucidate whether an intensified consolidation schedule could mitigate the relapse rate in this setting.
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- 2019
6. Serum syndecan-1 in patients with newly diagnosed monoclonal proteinemia
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Schaar, CG, Vermeer, HJ, Wijermans, PW, Huisman, W, le Cessie, S, Kluin-Nelemans, HC, Damage and Repair in Cancer Development and Cancer Treatment (DARE), and Stem Cell Aging Leukemia and Lymphoma (SALL)
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hemic and lymphatic diseases ,MULTIPLE-MYELOMA ,PARAPROTEINEMIA ,SURVIVAL ,POPULATION-BASED REGISTRY - Abstract
Serum syndecan-1 was investigated in 189 patients with newly diagnosed monoclonal proteinemia [the diagnoses were multiple myeloma (66), monoclonal gammopathies of undetermined significance (MGUS; n=54), provisional MGUS (no bone marrow examination performed; n=69)] and 36 controls. Syndecan-1 levels ranged widely between all diagnostic categories and were of limited discriminatory value (sensitivity 68%, specificity 78%) in patients with newly diagnosed monoclonal proteinemia.
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- 2005
7. Cost analysis of common treatment options for indolent follicular non-Hodgkin's lymphoma
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van Agthoven, M (Michel), Kramer, MHH, Sonneveld, Pieter, van der Hem, KG, Huijgens, PC, Wijermans, PW, Kluin-Nelemans, HC, Schaafsma, MR, Biesma, DH, Mattijssen, V, Uyl - de Groot, Carin, Hagenbeek, A (Anton), Damage and Repair in Cancer Development and Cancer Treatment (DARE), Stem Cell Aging Leukemia and Lymphoma (SALL), Clinical Haematology, Erasmus School of Health Policy & Management, and Hematology
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non-Hodgkin's lymphoma ,antineoplastic combined chemotherapy protocols ,STEM-CELL TRANSPLANTATION ,economics ,cost and cost analysis ,BONE-MARROW-TRANSPLANTATION ,LOW-GRADE ,CLASSIFICATION ,STAGE-I ,follicular lymphoma ,RITUXIMAB ,FLUDARABINE ,health care economics and organizations ,HIGH-DOSE THERAPY ,TERM-FOLLOW-UP ,CLINICAL-TRIALS - Abstract
BACKGROUND AND OBJECTIVES: We assessed direct health care costs associated with the most commonly prescribed treatments for indolent follicular non-Hodgkin's lymphoma (FL). DESIGN AND METHODS: New and previously diagnosed FL patients (>or=18 years) known during 1997-1998 to 15 Dutch hospitals were selected for inclusion. Each patient was followed for 3 years, and resource use associated with each of the treatments, including watchful waiting, was recorded. The hospital perspective was adopted. Unit costs were based on 2003 price levels. RESULTS: Two hundred patients were included of whom 75% underwent one or more treatments during the 3-year data collection period [25% were not treated because of a watchful waiting strategy (10%) or complete remission (15%)]. Allogeneic and autologous stem cell transplantations were the most expensive treatments, with a mean (median) per patient cost of 45,326 euro(44,237; n=7) and 18,866 euro (16,532; n=9), respectively (up to discharge only). Intravenous fludarabine cost 10,651 euro (9,995; n=33), rituximab (10,628 euro; 10,124; n=7), and CHOP 7,547 euro (5,833; n=42). Classical FL treatments were found to be the least expensive treatments used with an estimated cost for cylophosphamide, vincristine and prednisone of 5,268 euro (2,644; n=58), for radiotherapy of 4,218 euro (4,313; n=52), and for chlorambucil of 2,476 euro (1,098; n=53). INTERPRETATION AND CONCLUSIONS: This study presents information on resource use and costs associated with the most commonly prescribed FL treatments. In addition to differences in effectiveness, commonly used treatments vary considerably in terms of resource use and overall cost. This information is of value for resource planning, given the high costs of new treatment modalities
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- 2005
8. A novel 7.9 kb deletion causing alpha+-thallasaemia in two independent families of Indian origin
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Harteveld, CL, van Delft, P, Wijermans, PW, Klunne, Mies, Weegenaar, J, Losekoot, M, Giordano, PC, and Hematology
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- 2003
9. Thalidomide als behandeling voor refractair multipel myeloom in een Nederlandse studie onder 72 patienten: een antitumoreffect bij 45%
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Wu, KL, Schaafsma, MR, Lokhorst, HM, Wijermans, PW, van der Holt, Ronnie, Sonneveld, Pieter, and Hematology
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- 2002
10. Response: Myelodysplastic syndromes standardized response criteria: further definition
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Cheson, BD, Bennett, JM, Kantarjian, H, Schiffer, CA, Nimer, SD, Lowenberg, B, Stone, RM, Mittelman, M, Sanz, GF, Wijermans, PW, and Greenberg, PL
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- 2001
11. Liposomal amphotericin B compared with amphotericin B deoxycholate in the treatment of documented and suspected neutropenia-associated invasive fungal infections
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Leenders, ACAP, Daenen, SMGJ, Jansen, RLH, Hop, Löwenberg, Bob, Wijermans, PW, Cornelissen, Jan, Herbrecht, R, Van Der Lelie, H, Hoogsteden, Henk, Verbrugh, Henri, de Marie, S (Siem), Faculteit Medische Wetenschappen/UMCG, Medical Microbiology & Infectious Diseases, Epidemiology, Hematology, and Pulmonary Medicine
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PHARMACOKINETICS ,AmBisome ,LIPID FORMULATIONS ,PULMONARY ASPERGILLOSIS ,randomized trial ,neutropenia ,aspergillosis ,FLUCONAZOLE ,liposomal amphotericin ,ITRACONAZOLE ,FUNGIZONE - Abstract
It has been suggested that a better outcome of neutropenia-associated invasive fungal infections can be achieved when high doses of lipid formulations of amphotericin B are used. We now report a randomized multicentre study comparing liposomal amphotericin B (AmBisome, 5 mg/kg/d) to amphotericin B deoxycholate (AmB, 1 mg/kg/d) in the treatment of these infections. Of 106 possible patients, 66 were enrolled and analysed for efficacy: nine had documented fungaemia, 17 had other invasive mould infections and 40 had suspected pulmonary aspergillosis. After completion of the course medication, in the AmBisome group (n = 32) 14 patients had achieved complete response, seven a partial response and 11 were failures as compared to 6, 13 and 15 patients (n = 34) treated with AmB (P = 0.09); P = 0.03 for complete responders. A favourable trend for AmBisome was found at day 14, in patients with documented infections and in patients with pulmonary aspergillosis (P = 0.05 and P = 0.096 respectively). Mortality rates were lower in patients treated with AmBisome (adjusted for malignancy status, P = 0.03). More patients on AmB had a >100% increase of their baseline serum creatinine (P
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- 1998
12. Treatment, patterns of failure, and survival of patients with stage 1 nodal and extranodal non-Hodgkin's lymphomas, according to data in the population-based registry of the Comprehensive Cancer Centre West
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Krol, AD, Hermans, J, Dawson, L, Snijder, S, Wijermans, PW, Kluin-Nelemans, JC, Kluin, PM, van Krieken, JHJM, Noordijk, EM, and Radiation Oncology
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SDG 3 - Good Health and Well-being - Published
- 1998
13. LONG-TERM TREATMENT WITH INTERFERON-ALPHA-2B FOR SEVERE PRURITUS IN PATIENTS WITH POLYCYTHEMIA-VERA
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MULLER, EW, DEWOLF, JTM, EGGER, R, WIJERMANS, PW, HUIJGENS, PC, HALIE, MR, VELLENGA, E, Guided Treatment in Optimal Selected Cancer Patients (GUTS), and Stem Cell Aging Leukemia and Lymphoma (SALL)
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POLYCYTHEMIA VERA ,ALPHA-INTERFERON ,PRURITUS ,INTRACTABLE PRURITUS ,INTERFERON-ALPHA ,PHLEBOTOMY ,POLYCYTHEMIA-VERA - Abstract
Pruritus is a major clinical problem in patients with polycythaemia vera (PV). Conventional symptomatic treatment is unsatisfactory. Recently, a favourable effect of interferon-alpha on pruritus in patients with PV has been reported. Also, interferon-alpha suppresses the increased haemopoiesis in PV. However, long-term treatment with interferon-alpha may be hampered by side-effects and the inconvenience of chronic subcutaneous injection therapy. We conducted a long-term study (median follow-up 13 months) of the efficacy and tolerability of interferon-alpha in 15 patients (mean age 68 years) with PV and severe pruritus. Six patients were evaluable after I year. Pruritus significantly improved in 12/15 patients. Haematological control improved, as evidenced by a decreased number of phlebotomies from a mean of 4.3 in the year before the study to 1.8 while on interferon-alpha. Leucocyte and platelet numbers also decreased significantly. Five patients (33%) did not tolerate interferon-alpha. The effects of interferon-alpha could not be ascribed to an inhibitive effect on histamine production or to the disappearance of the abnormal erythroid progenitor clone, because erythropoietin-independent erythroid colony formation persisted during interferon-alpha treatment. We conclude that long-term interferon-alpha treatment is feasible and effectively relieves pruritus in patients with PV, but side-effects are an important concern. The optimal dose regimen that is well tolerated, relieves pruritus, and offers satisfactory haematological control at the same time remains to be established.
- Published
- 1995
14. B152 First Analysis of HOVON-65/GMMG-HD4 Randomized Phase III Trial Comparing Bortezomib, Doxorubicin, Dexamethasone (PAD) vs. VAD as Induction Treatment Prior to High-dose Melphalan (HDM) in Patients with Newly Diagnosed Multiple Myeloma (MM)
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Sonneveld, P, primary, Eljarari, L, additional, Salwender, H, additional, Zweegman, S, additional, Vellenga, E, additional, Van Der Holt, B, additional, Schmidt-Wolf, IGH, additional, Bertsch, U, additional, Schubert, J, additional, Blau, IW, additional, Jie, GSK, additional, Beverloo, B, additional, Jauch, A, additional, Hose, D, additional, Schaafsma, R, additional, Kersten, MJ, additional, Delforge, M, additional, De Weerdt, O, additional, Van Der Griend, R, additional, Wijermans, PW, additional, Martin, H, additional, Van Der Velde, H, additional, Lokhorst, HM, additional, and Goldschmidt, H, additional
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- 2009
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15. A116 MP versus MPT in Elderly Myeloma Patients: The Final Outcome of the HOVON-49 Study
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Wijermans, PW, primary, Zweegman, S, additional, Van Marwijk Kooy, M, additional, Van der Griend, R, additional, Lokhorst, H, additional, Schaafsma, M, additional, Van Norden, Y, additional, Ammerlaan, M, additional, Wittebol, S, additional, Sinnegen, H, additional, and Sonneveld, P, additional
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- 2009
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16. Serum neural cell adhesion molecule differentiates multiple myeloma from paraproteinemias due to other causes
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Ong, F, primary, Kaiser, U, additional, Seelen, PJ, additional, Hermans, J, additional, Wijermans, PW, additional, de Kieviet, W, additional, Jaques, G, additional, and Kluin-Nelemans, JC, additional
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- 1996
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17. International Prognostic Index for aggressive non-Hodgkin's lymphoma is valid for all malignancy grades
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Hermans, J, primary, Krol, AD, additional, van Groningen, K, additional, Kluin, PM, additional, Kluin-Nelemans, JC, additional, Kramer, MH, additional, Noordijk, EM, additional, Ong, F, additional, and Wijermans, PW, additional
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- 1995
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18. Comparative analysis of the value of allogeneic hematopoietic stem-cell transplantation in acute myeloid leukemia with monosomal karyotype versus other cytogenetic risk categories.
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Cornelissen JJ, Breems D, van Putten WL, Gratwohl AA, Passweg JR, Pabst T, Maertens J, Beverloo HB, van Marwijk Kooy M, Wijermans PW, Biemond BJ, Vellenga E, Verdonck LF, Ossenkoppele GJ, and Löwenberg B
- Published
- 2012
19. Combined procoagulant activity and proteolytic activity of acute promyelocytic leukemic cells: reversal of the bleeding disorder by cell differentiation
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Wijermans, PW, Rebel, VI, Ossenkoppele, GJ, Huijgens, PC, and Langenhuijsen, MM
- Abstract
In the human promyelocytic cell line HL60, we observed both a strong procoagulant activity (PCA) on the cell membrane and proteolytic activity in the lysate of these cells. Because these cell-line cells are susceptible to differentiation to either a more mature granulocytic or monocytic form, we were able to study the hypothesis that the combination of PCA and proteolytic activity is confined to the promyelocyte. This may explain the severe coagulopathy seen in patients with acute promyelocytic leukemia. Cell differentiation in a myeloid direction induced by retinoic acid or DMSO led to a diminished PCA, while not affecting the fibrinolytic activity. On the other hand, monocytic differentiation obtained by culturing the cells in the presence of 1; 25 dihydroxy vitamin D3 led to the complete disappearance of the proteolytic activity of the cell lysate, although the procoagulant activity was still present. Furthermore, we found that the elastase activity almost disappeared after monocytic differentiation. We also studied the PCA, proteolytic activity, and elastase activity of blast cells of patients with acute myeloid leukemia. Only in patients with acute promyelocytic leukemia did we observe both a strong PCA and fibrinolytic activity. This supports our hypothesis that the combination of these activities is unique to the promyelocyte and may explain the observed bleeding complications in patients with acute promyelocytic leukemia.
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- 1989
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20. Decitabine in older patients with AML: quality of life results of the EORTC-GIMEMA-GMDS-SG randomized phase 3 trial.
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Efficace F, Kicinski M, Coens C, Suciu S, van der Velden WJFM, Noppeney R, Chantepie S, Griskevicius L, Neubauer A, Audisio E, Luppi M, Fuhrmann S, Foà R, Crysandt M, Gaidano G, Vrhovac R, Venditti A, Posthuma EFM, Candoni A, Baron F, Legrand O, Mengarelli A, Fazi P, Vignetti M, Giraut A, Wijermans PW, Huls G, and Lübbert M
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- Humans, Aged, Male, Female, Middle Aged, Aged, 80 and over, Hematopoietic Stem Cell Transplantation, Azacitidine therapeutic use, Surveys and Questionnaires, Antineoplastic Combined Chemotherapy Protocols therapeutic use, Antineoplastic Combined Chemotherapy Protocols adverse effects, Quality of Life, Leukemia, Myeloid, Acute drug therapy, Decitabine therapeutic use, Decitabine administration & dosage, Antimetabolites, Antineoplastic therapeutic use
- Abstract
Abstract: We hypothesized that fit older patients with acute myeloid leukemia (AML) treated with decitabine (DEC) would report better health-related quality of life (HRQoL) outcomes than those receiving intensive chemotherapy (IC). We conducted a phase 3 randomized trial to compare DEC (10-day schedule) with IC (3+7) in older fit patients with AML. HRQoL was a secondary end point, and it was assessed with the European Organisation for Research and Treatment of Cancer Quality of Life Questionnaire Core 30 (EORTC QLQ-C30) in conjunction with its elderly module (EORTC QLQ-ELD14). The following scales were a priori selected for defining the primary end point: physical and role functioning, fatigue, pain, and burden of illness. HRQoL was assessed at baseline, at regeneration from cycle 2, and at 6 and 12 months after randomization, and also before allogeneic hematopoietic stem cell transplantation (allo-HSCT) and 100 days after transplantation. Overall, 606 patients underwent randomization. At 2 months, the risk of HRQoL deterioration was lower in the DEC arm than in the 3+7 arm; 76% (95% confidence interval [CI], 69-82) vs 88% (95% CI, 82-93); odds ratio, 0.43 (95% CI, 0.24-0.76; P = .003). No statistically significant HRQoL differences were observed between treatment arms at the long-term evaluation combining assessments at 6 and 12 months. HRQoL deteriorations between baseline and after allo-HSCT were observed in both arms. However, these deteriorations were not clinically meaningful in patients randomized to DEC, whereas this was the case for those in the 3+7 arm, in 4 of 5 primary HRQoL scales. Our HRQoL findings suggest that lower-intensity treatment with DEC may be preferable to current standard IC (3+7) in fit older patients with AML. This trial was registered at www.clinicaltrials.gov as #NCT02172872., (© 2024 American Society of Hematology. Published by Elsevier Inc. All rights are reserved, including those for text and data mining, AI training, and similar technologies.)
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- 2024
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21. Determinants of lenalidomide response with or without erythropoiesis-stimulating agents in myelodysplastic syndromes: the HOVON89 trial.
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van de Loosdrecht AA, Cremers EMP, Alhan C, Duetz C, In 't Hout FEM, Visser-Wisselaar HA, Chitu DA, Verbrugge A, Cunha SM, Ossenkoppele GJ, Janssen JJWM, Klein SK, Vellenga E, Huls GA, Muus P, Langemeijer SMC, de Greef GE, Te Boekhorst PAW, Raaijmakers MHG, van Marwijk Kooy M, Legdeur MC, Wegman JJ, Deenik W, de Weerdt O, van Maanen-Lamme TM, Jobse P, van Kampen RJW, Beeker A, Wijermans PW, Biemond BJ, Tanis BC, van Esser JWJ, Schaar CG, Noordzij-Nooteboom HS, Jacobs EMG, de Graaf AO, Jongen-Lavrencic M, Stevens-Kroef MJPL, Westers TM, and Jansen JH
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- Humans, Lenalidomide pharmacology, Erythropoiesis, Granulocyte Colony-Stimulating Factor pharmacology, Chromosome Deletion, Chromosomes, Human, Pair 5 genetics, Treatment Outcome, Hematinics pharmacology, Myelodysplastic Syndromes drug therapy, Myelodysplastic Syndromes genetics
- Abstract
A randomized phase-II study was performed in low/int-1 risk MDS (IPSS) to study efficacy and safety of lenalidomide without (arm A) or with (arm B) ESA/G-CSF. In arm B, patients without erythroid response (HI-E) after 4 cycles received ESA; G-CSF was added if no HI-E was obtained by cycle 9. HI-E served as primary endpoint. Flow cytometry and next-generation sequencing were performed to identify predictors of response. The final evaluation comprised 184 patients; 84% non-del(5q), 16% isolated del(5q); median follow-up: 70.7 months. In arm A and B, 39 and 41% of patients achieved HI-E; median time-to-HI-E: 3.2 months for both arms, median duration of-HI-E: 9.8 months. HI-E was significantly lower in non-del(5q) vs. del(5q): 32% vs. 80%. The same accounted for transfusion independency-at-week 24 (16% vs. 67%), but similar in both arms. Apart from presence of del(5q), high percentages of bone marrow lymphocytes and progenitor B-cells, a low number of mutations, absence of ring sideroblasts, and SF3B1 mutations predicted HI-E. In conclusion, lenalidomide induced HI-E in patients with non-del(5q) and del(5q) MDS without additional effect of ESA/G-CSF. The identified predictors of response may guide application of lenalidomide in lower-risk MDS in the era of precision medicine. (EudraCT 2008-002195-10)., (© 2024. The Author(s).)
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- 2024
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22. 10-day decitabine versus 3 + 7 chemotherapy followed by allografting in older patients with acute myeloid leukaemia: an open-label, randomised, controlled, phase 3 trial.
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Lübbert M, Wijermans PW, Kicinski M, Chantepie S, Van der Velden WJFM, Noppeney R, Griškevičius L, Neubauer A, Crysandt M, Vrhovac R, Luppi M, Fuhrmann S, Audisio E, Candoni A, Legrand O, Foà R, Gaidano G, van Lammeren-Venema D, Posthuma EFM, Hoogendoorn M, Giraut A, Stevens-Kroef M, Jansen JH, de Graaf AO, Efficace F, Ammatuna E, Vilque JP, Wäsch R, Becker H, Blijlevens N, Dührsen U, Baron F, Suciu S, Amadori S, Venditti A, and Huls G
- Subjects
- Humans, Middle Aged, Aged, Decitabine therapeutic use, Cytarabine therapeutic use, Daunorubicin therapeutic use, Transplantation, Homologous, Antineoplastic Combined Chemotherapy Protocols adverse effects, Leukemia, Myeloid, Acute drug therapy, Leukemia, Myeloid, Acute diagnosis
- Abstract
Background: Many older patients with acute myeloid leukaemia die or cannot undergo allogeneic haematopoietic stem-cell transplantation (HSCT) due to toxicity caused by intensive chemotherapy. We hypothesised that replacing intensive chemotherapy with decitabine monotherapy could improve outcomes., Methods: This open-label, randomised, controlled, phase 3 trial was conducted at 54 hospitals in nine European countries. Patients aged 60 years and older who were newly diagnosed with acute myeloid leukaemia and had not yet been treated were enrolled if they had an Eastern Cooperative Oncology Group performance status of 2 or less and were eligible for intensive chemotherapy. Patients were randomly assigned (1:1) to receive decitabine or standard chemotherapy (known as 3 + 7). For the decitabine group, decitabine (20 mg/m
2 ) was administered for the first 10 days in the first 28-day cycle, followed by 28-day cycles consisting of 5 days or 10 days of decitabine. For the 3 + 7 group, daunorubicin (60 mg/m2 ) was administered over the first 3 days and cytarabine (200 mg/m2 ) over the first 7 days, followed by 1-3 additional chemotherapy cycles. Allogeneic HSCT was strongly encouraged. Overall survival in the intention-to-treat population was the primary endpoint. Safety was assessed in all patients who received the allocated treatment. This trial is registered at ClinicalTrials.gov, NCT02172872, and is closed to new participants., Findings: Between Dec 1, 2014, and Aug 20, 2019, 606 patients were randomly assigned to the decitabine (n=303) or 3 + 7 (n=303) group. Following an interim analysis which showed futility, the IDMC recommended on May 22, 2019, that the study continued as planned considering the risks and benefits for the patients participating in the study. The cutoff date for the final analysis presented here was June 30, 2021. At a median follow-up of 4·0 years (IQR 2·9-4·8), 4-year overall survival was 26% (95% CI 21-32) in the decitabine group versus 30% (24-35) in the 3 + 7 group (hazard ratio for death 1·04 [95% CI 0·86-1·26]; p=0·68). Rates of on-protocol allogeneic HSCT were similar between groups (122 [40%] of 303 patients for decitabine and 118 [39%] of 303 patients for 3+7). Rates of grade 3-5 adverse events were 254 (84%) of 302 patients in the decitabine group and 279 (94%) of 298 patients in the 3 + 7 group. The rates of grade 3-5 infections (41% [125 of 302] vs 53% [158 of 298]), oral mucositis (2% [seven of 302] vs 10% [31 of 298]) and diarrhoea (1% [three of 302] vs 8% [24 of 298]) were lower in the decitabine group than in the 3 + 7 group. Treatment-related deaths were reported for 12% (35 of 302) of patients in the decitabine group and 14% (41 of 298) in the 3 + 7 group., Interpretation: 10-day decitabine did not improve overall survival but showed a better safety profile compared with 3 + 7 chemotherapy in older patients with acute myeloid leukaemia eligible for intensive chemotherapy. Decitabine could be considered a better-tolerated and sufficiently efficacious alternative to 3 + 7 induction in fit older patients with acute myeloid leukaemia without favourable genetics., Funding: Janssen Pharmaceuticals., Competing Interests: Declaration of interests MLü received research support to his institution from Janssen and European Organisation for Research and Treatment of Cancer (EORTC); is on the advisory boards for AbbVie, Astex, Janssen-Cilag, Otsuka, and Syros; and is currently working in an ongoing trial with a study drug provided by Cheplapharm. MK received research funding from Merck, Bristol Myers Squibb (BMS), Pierre Fabre, Janssen, and Immunocore. SF received personal funding by BMS and Celgene. AG received a grant for study conduct, and drug supply for Dacogen from Janssen Pharma Educational. JHJ received support for molecular analysis from Janssen and EORTC. FE received personal funding from AbbVie, Incyte, Janssen, Novartis, and Syros. RW received consulting fees from Amgen, BMS, Celgene, Janssen, Kite, Gilead, Novartis, Pfizer, and Sanofi; payment from AbbVie, Amgen, BMS, Celgene, Janssen, Kite, Gilead, Pfizer, and Sanofi; and support for attending meetings or travel from Janssen. HB is secretary of EORTC Leukemia Group; received research funding by the German Jose Carreras Leukemia Foundation and German Research Foundation; and honoraria from AbbVie, BMS, Celgene, Merck, Novartis, and Servier. UD received personal honoraria for participation in a data safety monitoring board from Avencell Europe and data safety monitoring board for an acute myeloid leukaemia CAR-T cell trial from Avencell Europe. FB received payments to his institution from Incyte Biosciences, Takeda, ExCellThera, and MaaT Pharma. SS received funding to his institution from Janssen Pharmaceuticals. All other authors declare no competing interests., (Copyright © 2023 Elsevier Ltd. All rights reserved.)- Published
- 2023
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23. Monosomal karyotype and chromosome 17p loss or TP53 mutations in decitabine-treated patients with acute myeloid leukemia.
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Becker H, Pfeifer D, Ihorst G, Pantic M, Wehrle J, Rüter BH, Bullinger L, Hackanson B, Germing U, Kuendgen A, Platzbecker U, Döhner K, Ganser A, Hagemeijer A, Wijermans PW, Döhner H, Duyster J, and Lübbert M
- Subjects
- Aged, Aged, 80 and over, Chromosomes, Human, Pair 17 genetics, Clonal Evolution drug effects, Clonal Evolution genetics, DNA Mutational Analysis, Female, Germany epidemiology, Humans, Karyotype, Karyotyping, Leukemia, Myeloid, Acute epidemiology, Leukemia, Myeloid, Acute pathology, Male, Middle Aged, Mutation, Survival Analysis, Chromosome Deletion, Decitabine therapeutic use, Leukemia, Myeloid, Acute drug therapy, Leukemia, Myeloid, Acute genetics, Monosomy diagnosis, Monosomy genetics, Smith-Magenis Syndrome diagnosis, Smith-Magenis Syndrome epidemiology, Smith-Magenis Syndrome genetics, Tumor Suppressor Protein p53 genetics
- Abstract
TP53 aberrations reportedly predict favorable responses to decitabine (DAC) in acute myeloid leukemia (AML). We evaluated clinical features and outcomes associated with chromosome 17p loss or TP53 gene mutations in older, unfit DAC-treated AML patients in a phase II trial. Of 178 patients, 25 had loss of 17p in metaphase cytogenetics; 24 of these had a complex (CK+) and 21 a monosomal karyotype (MK+). In analyses in all patients and restricted to CK+ and MK+ patients, 17p loss tended to associate with higher rates of complete remission (CR), partial remission (PR), or antileukemic effect (ALE). Despite favorable response rates, there was no significant OS difference between patients with or without loss of 17p in the entire cohort or in the CK+ and MK+ cohort. TP53 mutations were identified in eight of 45 patients with material available. Five of the eight TP53-mutated patients had 17p loss. TP53-mutated patients had similar rates of CR/PR/ALE but shorter OS than those with TP53 wild type (P = 0.036). Moreover, patients with a subclone based on mutation data had shorter OS than those without (P = 0.05); only one patient with TP53-mutated AML had a subclone. In conclusion, 17p loss conferred a favorable impact on response rates, even among CK+ and MK+ patients that however could not be maintained. The effect of TP53 mutations appeared to be different; however, patient numbers were low. Future research needs to further dissect the impact of the various TP53 aberrations in HMA-based combination therapies. The limited duration of favorable responses to HMA treatment in adverse-risk genetics AML should prompt physicians to advance allografting for eligible patients in a timely fashion.
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- 2020
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24. Distinct bone marrow morphologic features discriminate myelodysplastic syndromes patients with and without an early platelet response to decitabine.
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May AM, Stomper J, Joeckel TE, Bronsert P, Wijermans PW, Werner M, and Lübbert M
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- Biopsy, Humans, Megakaryocytes pathology, Myelodysplastic Syndromes pathology, Platelet Count, Time Factors, Treatment Outcome, Antimetabolites therapeutic use, Bone Marrow pathology, Decitabine therapeutic use, Myelodysplastic Syndromes drug therapy
- Published
- 2020
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25. Fetal hemoglobin induction during decitabine treatment of elderly patients with high-risk myelodysplastic syndrome or acute myeloid leukemia: a potential dynamic biomarker of outcome.
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Stomper J, Ihorst G, Suciu S, Sander PN, Becker H, Wijermans PW, Plass C, Weichenhan D, Bissé E, Claus R, and Lübbert M
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- Aged, Female, Humans, K562 Cells, Leukemia, Myeloid, Acute blood, Leukemia, Myeloid, Acute drug therapy, Male, Middle Aged, Biomarkers, Tumor blood, Decitabine administration & dosage, Fetal Hemoglobin metabolism, Myelodysplastic Syndromes blood, Myelodysplastic Syndromes drug therapy, Neoplasm Proteins blood
- Abstract
Hematologic responses to hypomethylating agents are often delayed in patients with myelodysplastic syndrome or acute myeloid leukemia. Fetal hemoglobin is a potential novel bio-marker of response: recently, we demonstrated that a high fetal hemoglobin level prior to decitabine treatment was associated with superior outcome. Here we investigated whether early fetal hemoglobin induction during decitabine treatment also had prognostic value, and studied the potential of decitabine to induce erythroid differentiation and fetal hemoglobin expression in vitro Fetal hemoglobin levels were measured by high-performance liquid chromatography in patients with higher-risk myelodysplastic syndrome (n=16) and acute myeloid leukemia (n=37) before treatment and after each course of decitabine. Levels above 1.0% were considered induced. Patients achieving complete or partial remission as best response had attained a median fetal hemoglobin of 1.9% after two courses of treatment, whereas the median value in patients who did not reach complete or partial remission was 0.8% ( P =0.015). Fetal hemoglobin induction after two courses of decitabine treatment was associated with early platelet doubling ( P =0.006), and its subsequent decrease with hematologic relapse. In patients with myelodysplastic syndrome, induction of fetal hemoglobin after course 2 of treatment was associated with longer overall survival: median of 22.9 versus 7.3 months in patients with or without induction of fetal hemoglobin, respectively [hazard ratio=0.2 (95% confidence interval: 0.1-0.9); P =0.03]. In vitro decitabine treatment of two bi-potential myeloid leukemia cell lines (K562 and HEL) resulted in induction of an erythroid (not megakaryocytic) differentiation program, and of fetal hemoglobin mRNA and protein, associated with GATA1 gene demethylation and upregulation. In conclusion, fetal hemoglobin may provide a useful dynamic biomarker during hypomethylating agent therapy in patients with myelodysplastic syndrome or acute myeloid leukemia., (Copyright© 2019 Ferrata Storti Foundation.)
- Published
- 2019
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26. Graft-Versus-Leukemia Effect of Allogeneic Stem-Cell Transplantation and Minimal Residual Disease in Patients With Acute Myeloid Leukemia in First Complete Remission.
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Versluis J, Kalin B, Zeijlemaker W, Passweg J, Graux C, Manz MG, Vekemans MC, Biemond BJ, Legdeur MJC, Kooy MVM, de Weerdt O, Wijermans PW, Hoogendoorn M, Bargetzi MJ, Kuball J, Schouten HC, van der Velden VHJ, Janssen JJWM, Pabst T, Lowenberg B, Jongen-Lavrencic M, Schuurhuis GJ, Ossenkoppele G, and Cornelissen JJ
- Abstract
Purpose: The detection of minimal residual disease (MRD) in patients with acute myeloid leukemia (AML) may improve future risk-adapted treatment strategies. We assessed whether MRD-positive and MRD-negative patients with AML benefit differently from the graft-versus-leukemia effect of allogeneic hematopoietic stem-cell transplantation (alloHSCT)., Methods: A total of 1,511 patients were treated in subsequent Dutch-Belgian Hemato-Oncology Cooperative Group and the Swiss Group for Clinical Cancer Research AML trials, of whom 547 obtained a first complete remission, received postremission treatment (PRT), and had available flow cytometric MRD before PRT. MRD positivity was defined as more than 0.1% cells with a leukemia-associated immunophenotype within the WBC compartment. PRT consisted of alloHSCT (n = 282), conventional PRT by a third cycle of chemotherapy (n = 160), or autologous hematopoietic stem-cell transplantation (n = 105)., Results: MRD was positive in 129 patients (24%) after induction chemotherapy before proceeding to PRT. Overall survival and relapse-free survival were significantly better in patients without MRD before PRT compared with MRD-positive patients (65% ± 2% v 50% ± 5% at 4 years; P = .002; and 58% ± 3% v 38% ± 4%; P < .001, respectively), which was mainly because of a lower cumulative incidence of relapse (32% ± 2% compared with 54% ± 4%; P < .001, respectively). Multivariable analysis with adjustment for covariables showed that the incidence of relapse was significantly reduced after alloHSCT compared with chemotherapy or autologous hematopoietic stem cell transplantation (hazard ratio [HR], 0.36; P < .001), which was similarly exerted in both MRD-negative and MRD-positive patients (HR, 0.38; P < .001; and HR, 0.35; P < .001, respectively)., Conclusion: The graft-versus-leukemia effect of alloHSCT is equally present in MRD-positive and MRD-negative patients, which advocates a personalized application of alloHSCT, taking into account the risk of relapse determined by AML risk group and MRD status, as well as the counterbalancing risk of nonrelapse mortality.
- Published
- 2017
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27. Implementation of erythroid lineage analysis by flow cytometry in diagnostic models for myelodysplastic syndromes.
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Cremers EM, Westers TM, Alhan C, Cali C, Visser-Wisselaar HA, Chitu DA, van der Velden VH, Te Marvelde JG, Klein SK, Muus P, Vellenga E, de Greef GE, Legdeur MC, Wijermans PW, Stevens-Kroef MJ, Silva-Coelho PD, Jansen JH, Ossenkoppele GJ, and van de Loosdrecht AA
- Subjects
- Adult, Aged, Aged, 80 and over, Biomarkers, Case-Control Studies, Female, Humans, Immunophenotyping, Male, Middle Aged, Cell Lineage, Erythroid Cells metabolism, Flow Cytometry, Myelodysplastic Syndromes diagnosis, Myelodysplastic Syndromes metabolism
- Abstract
Flow cytometric analysis is a recommended tool in the diagnosis of myelodysplastic syndromes. Current flow cytometric approaches evaluate the (im)mature myelo-/monocytic lineage with a median sensitivity and specificity of ~71% and ~93%, respectively. We hypothesized that the addition of erythroid lineage analysis could increase the sensitivity of flow cytometry. Hereto, we validated the analysis of erythroid lineage parameters recommended by the International/European LeukemiaNet Working Group for Flow Cytometry in Myelodysplastic Syndromes, and incorporated this evaluation in currently applied flow cytometric models. One hundred and sixty-seven bone marrow aspirates were analyzed; 106 patients with myelodysplastic syndromes, and 61 cytopenic controls. There was a strong correlation between presence of erythroid aberrancies assessed by flow cytometry and the diagnosis of myelodysplastic syndromes when validating the previously described erythroid evaluation. Furthermore, addition of erythroid aberrancies to two different flow cytometric models led to an increased sensitivity in detecting myelodysplastic syndromes: from 74% to 86% for the addition to the diagnostic score designed by Ogata and colleagues, and from 69% to 80% for the addition to the integrated flow cytometric score for myelodysplastic syndromes, designed by our group. In both models the specificity was unaffected. The high sensitivity and specificity of flow cytometry in the detection of myelodysplastic syndromes illustrates the important value of flow cytometry in a standardized diagnostic approach. The trial is registered at www.trialregister.nl as NTR1825; EudraCT n.: 2008-002195-10., (Copyright© Ferrata Storti Foundation.)
- Published
- 2017
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28. Elevated fetal haemoglobin is a predictor of better outcome in MDS/AML patients receiving 5-aza-2'-deoxycytidine (Decitabine).
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Lübbert M, Ihorst G, Sander PN, Bogatyreva L, Becker H, Wijermans PW, Suciu S, Bissé E, and Claus R
- Subjects
- Aged, Aged, 80 and over, Antimetabolites, Antineoplastic therapeutic use, Azacitidine administration & dosage, Azacitidine pharmacology, Azacitidine therapeutic use, Biomarkers analysis, DNA Methylation drug effects, Decitabine, Disease-Free Survival, Female, Fetal Hemoglobin drug effects, Humans, Leukemia, Myeloid, Acute mortality, Male, Middle Aged, Myelodysplastic Syndromes mortality, Prognosis, Survival Analysis, Azacitidine analogs & derivatives, Fetal Hemoglobin analysis, Leukemia, Myeloid, Acute drug therapy, Myelodysplastic Syndromes drug therapy
- Abstract
Although azanucleoside DNA-hypomethylating agents (HMAs) are routinely used for the treatment of myelodysplastic syndrome/acute myeloid leukaemia (MDS/AML), very few outcome predictors have been established. Expression of the β-like globin gene locus is tightly regulated by DNA methylation, is HMA-sensitive in vitro, and fetal haemoglobin (HbF) expression is under study as a potential biomarker for response of MDS patients to azacitidine. We determined HbF expression in 16 MDS and 36 AML patients receiving decitabine (DAC). Pre-treatment HbF was already elevated (>1·0% of total haemoglobin) in 7/16 and 12/36 patients, and HbF was induced by DAC in 81%/54% of MDS/AML patients, respectively. Elevated pre-treatment HbF was associated with longer median overall survival (OS): 26·6 vs. 8·6 months for MDS (hazard ratio [HR] 8·56, 95% confidence interval [CI] 1·74-42·49, P = 0·008, with similarly longer progression-free and AML-free survival), and 10·0 vs. 2·9 months OS for AML (HR 3·01, 95% CI 1·26-7·22, P = 0·014). In a multivariate analysis, the prognostic value of HbF was retained. Time-dependent Cox models revealed that the prognostic value of treatment-induced HbF induction was inferior to that of pre-treatment HbF. In conclusion, we provide first evidence for in vivo HbF induction by DAC in MDS/AML, and demonstrate prognostic value of elevated pre-treatment HbF, warranting prospective, randomized studies., (© 2016 John Wiley & Sons Ltd.)
- Published
- 2017
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29. Phase I/II trial of weekly bortezomib with lenalidomide and dexamethasone in first relapse or primary refractory myeloma.
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Broijl A, Kersten MJ, Alemayehu WG, Levin MD, de Weerdt O, Vellenga E, Meijer E, Wittebol S, Tanis BC, Cornelisse PB, Stevens-Kroef M, Bos GM, Wijermans PW, Lokhorst H, and Sonneveld P
- Subjects
- Aged, Aged, 80 and over, Drug Administration Schedule, Drug Dosage Calculations, Female, Humans, Lenalidomide, Logistic Models, Male, Maximum Tolerated Dose, Middle Aged, Multiple Myeloma complications, Multiple Myeloma mortality, Multiple Myeloma pathology, Neoplasms, Second Primary complications, Neoplasms, Second Primary mortality, Neoplasms, Second Primary pathology, Recurrence, Survival Analysis, Thalidomide therapeutic use, Treatment Outcome, Antineoplastic Combined Chemotherapy Protocols therapeutic use, Bortezomib therapeutic use, Dexamethasone therapeutic use, Multiple Myeloma drug therapy, Neoplasms, Second Primary drug therapy, Thalidomide analogs & derivatives
- Published
- 2016
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30. Decitabine improves progression-free survival in older high-risk MDS patients with multiple autosomal monosomies: results of a subgroup analysis of the randomized phase III study 06011 of the EORTC Leukemia Cooperative Group and German MDS Study Group.
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Lübbert M, Suciu S, Hagemeijer A, Rüter B, Platzbecker U, Giagounidis A, Selleslag D, Labar B, Germing U, Salih HR, Muus P, Pflüger KH, Schaefer HE, Bogatyreva L, Aul C, de Witte T, Ganser A, Becker H, Huls G, van der Helm L, Vellenga E, Baron F, Marie JP, and Wijermans PW
- Subjects
- Aged, Aged, 80 and over, Azacitidine therapeutic use, Decitabine, Disease-Free Survival, Female, Germany epidemiology, Humans, Leukemia diagnosis, Leukemia drug therapy, Leukemia genetics, Male, Middle Aged, Myelodysplastic Syndromes diagnosis, Risk Factors, Antimetabolites, Antineoplastic therapeutic use, Azacitidine analogs & derivatives, Disease Progression, Monosomy genetics, Myelodysplastic Syndromes drug therapy, Myelodysplastic Syndromes genetics
- Abstract
In a study of elderly AML patients treated with the hypomethylating agent decitabine (DAC), we noted a surprisingly favorable outcome in the (usually very unfavorable) subgroup with two or more autosomal monosomies (MK2+) within a complex karyotype (Lübbert et al., Haematologica 97:393-401, 2012). We now analyzed 206 myelodysplastic syndrome (MDS) patients (88 % of 233 patients randomized in the EORTC/GMDSSG phase III trial 06011, 61 of them with RAEBt, i.e. AML by WHO) with cytogenetics informative for MK status.. Endpoints are the following: complete/partial (CR/PR) and overall response rate (ORR) and progression-free (PFS) and overall survival (OS). Cytogenetic subgroups are the following: 63 cytogenetically normal (CN) patients, 143 with cytogenetic abnormalities, 73 of them MK-negative (MK-), and 70 MK-positive (MK+). These MK+ patients could be divided into 17 with a single autosomal monosomy (MK1) and 53 with at least two monosomies (MK2+). ORR with DAC in CN patients: 36.1 %, in MK- patients: 16.7 %, in MK+ patients: 43.6 % (MK1: 44.4 %, MK2+ 43.3 %). PFS was prolonged by DAC compared to best supportive care (BSC) in the CN (hazard ratio (HR) 0.55, 99 % confidence interval (CI), 0.26; 1.15, p = 0.03) and MK2+ (HR 0.50; 99 % CI, 0.23; 1.06, p = 0.016) but not in the MK-, MK+, and MK1 subgroups. OS was not improved by DAC in any subgroup. In conclusion, we demonstrate for the first time in a randomized phase III trial that high-risk MDS patients with complex karyotypes harboring two or more autosomal monosomies attain encouraging responses and have improved PFS with DAC treatment compared to BSC.
- Published
- 2016
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31. Quality of life of patients with chronic lymphocytic leukaemia in the Netherlands: results of a longitudinal multicentre study.
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Holtzer-Goor KM, Schaafsma MR, Joosten P, Posthuma EF, Wittebol S, Huijgens PC, Mattijssen EJ, Vreugdenhil G, Visser H, Peters WG, Erjavec Z, Wijermans PW, Daenen SM, van der Hem KG, van Oers MH, and Uyl-de Groot CA
- Subjects
- Adult, Aged, Chlorambucil adverse effects, Chlorambucil therapeutic use, Dyspnea psychology, Fatigue psychology, Female, Humans, Leukemia, Lymphocytic, Chronic, B-Cell drug therapy, Longitudinal Studies, Male, Middle Aged, Netherlands, Sleep Wake Disorders psychology, Surveys and Questionnaires, Health Status, Leukemia, Lymphocytic, Chronic, B-Cell psychology, Quality of Life
- Abstract
Purpose: To describe the health-related quality of life (HRQoL) of an unselected population of patients with chronic lymphocytic leukaemia (CLL) including untreated patients., Methods: HRQoL was measured by the EORTC QLQ-C30 including the CLL16 module, EQ-5D, and VAS in an observational study over multiple years. All HRQoL measurements per patient were connected and analysed using area under the curve analysis over the entire study duration. The total patient group was compared with the general population, and three groups of CLL patients were described separately, i.e. patients without any active treatment ("watch and wait"), chlorambucil treatment only, and patients with other treatment(s)., Results: HRQoL in the total group of CLL patients was compromised when compared with age- and gender-matched norm scores of the general population. CLL patients scored statistically worse on the VAS and utility score of the EQ-5D, all functioning scales of the EORTC QLQ-C30, and the symptoms of fatigue, dyspnoea, sleeping disturbance, appetite loss, and financial difficulties. In untreated patients, the HRQoL was slightly reduced. In all treatment stages, HRQoL was compromised considerably. Patients treated with chlorambucil only scored worse on the EORTC QLQ-C30 than patients who were treated with other treatments with regard to emotional functioning, cognitive functioning, bruises, uncomfortable stomach, and apathy., Conclusions: CLL patients differ most from the general population on role functioning, fatigue, concerns about future health, and having not enough energy. Once treatment is indicated, HRQoL becomes considerably compromised. This applies to all treatments, including chlorambucil, which is considered to be a mild treatment.
- Published
- 2015
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32. Decitabine versus best supportive care in older patients with refractory anemia with excess blasts in transformation (RAEBt) - results of a subgroup analysis of the randomized phase III study 06011 of the EORTC Leukemia Cooperative Group and German MDS Study Group (GMDSSG).
- Author
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Becker H, Suciu S, Rüter BH, Platzbecker U, Giagounidis A, Selleslag D, Labar B, Germing U, Salih HR, Muus P, Pflüger KH, Hagemeijer A, Schaefer HE, Fiaccadori V, Baron F, Ganser A, Aul C, de Witte T, Wijermans PW, and Lübbert M
- Subjects
- Aged, Aged, 80 and over, Azacitidine administration & dosage, Decitabine, Disease-Free Survival, Female, Humans, Male, Middle Aged, Survival Rate, Anemia, Refractory, with Excess of Blasts mortality, Anemia, Refractory, with Excess of Blasts therapy, Antimetabolites, Antineoplastic administration & dosage, Azacitidine analogs & derivatives, Blast Crisis mortality, Blast Crisis therapy
- Abstract
In the European Organisation for Research and Treatment of Cancer (EORTC)/GMDSSG phase III trial 06011, we compared decitabine (15 mg/m(2) every 8 h for 3 days) with best supportive care (BSC) in patients ≥60 years with myelodysplastic syndromes (MDS) by French-American-British (FAB) criteria. Here, we reinvestigate trial 06011 for the activity and efficacy specifically in patients with refractory anemia with excess blasts in transformation (RAEBt). Response rates in the decitabine arm (N = 40) were as follows: complete or partial remission, 15 %; hematologic improvement, 15 %; resistant disease, 30 %. RAEBt patients in the decitabine arm had longer progression-free survival (PFS; hazard ratio (HR) 0.30, 95 % confidence interval (CI) 0.18-0.51; median, 6.2 vs 2.8 months) and overall survival (OS; HR 0.68, 95 % CI 0.42-1.11; median, 8.0 vs 6.0 months) than in the BSC arm (N = 35). Censoring at allogeneic hematopoietic stem cell transplantation, the OS difference between the treatment groups increased, particularly among patients aged 60-74 years (HR 0.48, 95 % CI 0.26-0.89). After regrouping the study cohort according to World Health Organization (WHO) criteria, patients with acute myeloid leukemia (AML) (i.e., ≥20 % blasts) in the decitabine arm (N = 27) also had longer PFS than in the BSC arm (N = 23) (HR 0.46, 95 % CI 0.26-0.83; median, 6.2 vs 2.8 months). In conclusion, 3-day decitabine displays clinical activity and efficacy in MDS and/or AML with 5-30 % blood or 20-30 % marrow blasts.
- Published
- 2015
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33. Comparative therapeutic value of post-remission approaches in patients with acute myeloid leukemia aged 40-60 years.
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Cornelissen JJ, Versluis J, Passweg JR, van Putten WL, Manz MG, Maertens J, Beverloo HB, Valk PJ, van Marwijk Kooy M, Wijermans PW, Schaafsma MR, Biemond BJ, Vekemans MC, Breems DA, Verdonck LF, Fey MF, Jongen-Lavrencic M, Janssen JJ, Huls G, Kuball J, Pabst T, Graux C, Schouten HC, Gratwohl A, Vellenga E, Ossenkoppele G, and Löwenberg B
- Subjects
- Adult, Antineoplastic Agents chemistry, Disease-Free Survival, Female, Hematopoietic Stem Cell Transplantation, Humans, Leukemia, Myeloid, Acute mortality, Male, Middle Aged, Multivariate Analysis, Proportional Hazards Models, Remission Induction, Risk, Time Factors, Transplantation Conditioning methods, Transplantation, Homologous, Treatment Outcome, Leukemia, Myeloid, Acute therapy
- Abstract
The preferred type of post-remission therapy (PRT) in patients with acute myeloid leukemia (AML) in first complete remission (CR1) is a subject of continued debate, especially in patients at higher risk of nonrelapse mortality (NRM), including patients >40 years of age. We report results of a time-dependent multivariable analysis of allogenic hematopoietic stem cell transplantation (alloHSCT) (n=337) versus chemotherapy (n=271) or autologous HSCT (autoHSCT) (n=152) in 760 patients aged 40-60 years with AML in CR1. Patients receiving alloHSCT showed improved overall survival (OS) as compared with chemotherapy (respectively, 57±3% vs 40±3% at 5 years, P<0.001). Comparable OS was observed following alloHSCT and autoHSCT in patients with intermediate-risk AML (60±4 vs 54±5%). However, alloHSCT was associated with less relapse (hazard ratio (HR) 0.51, P<0.001) and better relapse-free survival (RFS) (HR 0.74, P=0.029) as compared with autoHSCT in intermediate-risk AMLs. AlloHSCT was applied following myeloablative conditioning (n=157) or reduced intensity conditioning (n=180), resulting in less NRM, but comparable outcome with respect to OS, RFS and relapse. Collectively, these results show that alloHSCT is to be preferred over chemotherapy as PRT in patients with intermediate- and poor-risk AML aged 40-60 years, whereas autoHSCT remains a treatment option to be considered in patients with intermediate-risk AML.
- Published
- 2015
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34. Extended follow up of high-dose melphalan and autologous stem cell transplantation after vincristine, doxorubicin, dexamethasone induction in amyloid light chain amyloidosis of the prospective phase II HOVON-41 study by the Dutch-Belgian Co-operative Trial Group for Hematology Oncology.
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Hazenberg BP, Croockewit A, van der Holt B, Zweegman S, Bos GM, Delforge M, Raymakers RA, Sonneveld P, Vellenga E, Wijermans PW, von dem Borne PA, van Oers MH, de Weerdt O, Spoelstra FM, and Lokhorst HM
- Subjects
- Adult, Aged, Amyloidosis diagnosis, Amyloidosis etiology, Amyloidosis mortality, Antineoplastic Combined Chemotherapy Protocols adverse effects, Combined Modality Therapy, Dexamethasone administration & dosage, Doxorubicin administration & dosage, Female, Follow-Up Studies, Humans, Kaplan-Meier Estimate, Male, Middle Aged, Remission Induction, Transplantation, Autologous, Treatment Outcome, Vincristine administration & dosage, Amyloidosis therapy, Antineoplastic Combined Chemotherapy Protocols therapeutic use, Hematopoietic Stem Cell Transplantation adverse effects, Melphalan administration & dosage
- Abstract
In a prospective multicenter phase II study, we evaluated the effect of three courses of vincristine, doxorubicin and dexamethasone followed by high-dose melphalan and autologous stem cell transplantation on an intention-to-treat basis. Sixty-nine newly diagnosed patients with amyloid light chain amyloidosis were included between November 2000 and January 2006: 37 men and 32 women with a median age of 56 years, including 46% of patients with cardiac and 22% of patients with involvement of 3 or 4 organs. Initial results presented in 2008 showed a 4-year overall survival rate of 62% among all the patients, while the 4-year survival rate after transplantation was 78%. Here we report the long-term follow-up data after a median follow up of 115 months of the patients still alive. Median survival of all patients was 96 months from registration and for the transplanted patients ten years from the date of transplantation. Twelve (12%) patients died during induction therapy with vincristine, doxorubicin and dexamethasone, including 8 patients (12%) due to treatment-related mortality. Two patients died within one month following high-dose melphalan. We conclude that vincristine, doxorubicin and dexamethasone should not be applied as induction therapy for intensification in amyloid light chain amyloidosis. However, a 2-step approach consisting of a non-intensive less toxic induction therapy followed by high-dose melphalan and autologous stem cell transplantation may result in extended survival in newly diagnosed patients with amyloid light chain amyloidosis (clinicaltrials.gov identifier: 01207094)., (Copyright© Ferrata Storti Foundation.)
- Published
- 2015
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35. The efficiency of therapeutic erythrocytapheresis compared to phlebotomy: a mathematical tool for predicting response in hereditary hemochromatosis, polycythemia vera, and secondary erythrocytosis.
- Author
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Evers D, Kerkhoffs JL, Van Egmond L, Schipperus MR, and Wijermans PW
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- Adult, Aged, Aged, 80 and over, Blood Volume, Cytapheresis statistics & numerical data, Female, Hematocrit, Hemochromatosis blood, Hemochromatosis physiopathology, Humans, Male, Mathematical Concepts, Middle Aged, Models, Theoretical, Phlebotomy statistics & numerical data, Polycythemia blood, Polycythemia physiopathology, Polycythemia Vera blood, Polycythemia Vera physiopathology, Retrospective Studies, Treatment Outcome, Young Adult, Cytapheresis methods, Hemochromatosis therapy, Phlebotomy methods, Polycythemia therapy, Polycythemia Vera therapy
- Abstract
Recently, therapeutic erythrocytapheresis (TE) was suggested to be more efficient in depletion of red blood cells (RBC) compared to manual phlebotomy in the treatment of hereditary hemochromatosis (HH), polycythemia vera (PV), and secondary erythrocytosis (SE). The efficiency rate (ER) of TE, that is, the increase in RBC depletion achieved with one TE cycle compared to one phlebotomy procedure, can be calculated based on estimated blood volume (BV), preprocedural hematocrit (Hct(B)), and delta-hematocrit (ΔHct). In a retrospective evaluation of 843 TE procedures (in 45 HH, 33 PV, and 40 SE patients) the mean ER was 1.86 ± 0.62 with the highest rates achieved in HH patients. An ER of 1.5 was not reached in 37.9% of all procedures mainly concerning patients with a BV below 4,500 ml. In 12 newly diagnosed homozygous HH patients, the induction phase duration was medially 38.4 weeks (medially 10.5 procedures). During the maintenance treatment of HH, PV, and SE, the interval between TE procedures was medially 13.4 weeks. This mathematical model can help select the proper treatment modality for the individual patient. Especially for patients with a large BV and high achievable ΔHct, TE appears to be more efficient than manual phlebotomy in RBC depletion thereby potentially reducing the numbers of procedures and expanding the interprocedural time period for HH, PV, and SE., (© 2013 Wiley Periodicals, Inc.)
- Published
- 2014
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36. Real-world costs of chronic lymphocytic leukaemia in the Netherlands.
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Holtzer-Goor KM, Bouwmans-Frijters CA, Schaafsma MR, de Weerdt O, Joosten P, Posthuma EF, Wittebol S, Huijgens PC, Mattijssen EJ, Vreugdenhil G, Visser H, Peters WG, Erjavec Z, Wijermans PW, Daenen SM, van der Hem KG, van Oers MH, and Groot CA
- Subjects
- Adult, Aged, Aged, 80 and over, Cost-Benefit Analysis, Costs and Cost Analysis, Diagnostic Tests, Routine methods, Drug Therapy methods, Female, Humans, Male, Middle Aged, Netherlands, Stem Cell Transplantation methods, Diagnostic Tests, Routine economics, Drug Therapy economics, Leukemia, Lymphocytic, Chronic, B-Cell diagnosis, Leukemia, Lymphocytic, Chronic, B-Cell therapy, Stem Cell Transplantation economics
- Abstract
We performed a comprehensive cost calculation identifying the main cost drivers of treatment of chronic lymphocytic leukaemia in daily practice. In our observational study 160 patient charts were reviewed repeatedly to assess the treatment strategies from diagnosis till the study end. Ninety-seven patients (61%) received ≥1 treatment lines during an average follow-up time of 6.4 years. The average total costs per patient were €41,417 (€539 per month). The costs varied considerably between treatment groups and between treatment lines. Although patients were treated with expensive chemo(immuno-)therapy, the main cost driver was inpatient days for other reasons than administration of chemo(immuno-)therapy., (Copyright © 2013 Elsevier Ltd. All rights reserved.)
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- 2014
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37. A phase 2 multicentre study of siltuximab, an anti-interleukin-6 monoclonal antibody, in patients with relapsed or refractory multiple myeloma.
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Voorhees PM, Manges RF, Sonneveld P, Jagannath S, Somlo G, Krishnan A, Lentzsch S, Frank RC, Zweegman S, Wijermans PW, Orlowski RZ, Kranenburg B, Hall B, Casneuf T, Qin X, van de Velde H, Xie H, and Thomas SK
- Subjects
- Adrenal Cortex Hormones administration & dosage, Adrenal Cortex Hormones pharmacology, Adult, Aged, Aged, 80 and over, Antibodies, Anti-Idiotypic biosynthesis, Antibodies, Monoclonal administration & dosage, Antibodies, Monoclonal adverse effects, Antibodies, Monoclonal immunology, Antineoplastic Agents adverse effects, Antineoplastic Agents pharmacology, Boronic Acids administration & dosage, Boronic Acids pharmacology, Bortezomib, C-Reactive Protein analysis, Dexamethasone administration & dosage, Disease Progression, Drug Administration Schedule, Drug Resistance, Neoplasm, Female, Hematologic Diseases chemically induced, Humans, Infection Control, Interleukin-6 immunology, Kaplan-Meier Estimate, Male, Middle Aged, Multiple Myeloma blood, Pyrazines administration & dosage, Pyrazines pharmacology, Salvage Therapy, Antibodies, Monoclonal therapeutic use, Antineoplastic Agents therapeutic use, Antineoplastic Combined Chemotherapy Protocols therapeutic use, Interleukin-6 antagonists & inhibitors, Multiple Myeloma drug therapy
- Abstract
Interleukin-6 (IL6) plays a central role in multiple myeloma pathogenesis and confers resistance to corticosteroid-induced apoptosis. We therefore evaluated the efficacy and safety of siltuximab, an anti-IL6 monoclonal antibody, alone and in combination with dexamethasone, for patients with relapsed or refractory multiple myeloma who had ≥ 2 prior lines of therapy, one of which had to be bortezomib-based. Fourteen initial patients received siltuximab alone, 10 of whom had dexamethasone added for suboptimal response; 39 subsequent patients were treated with concurrent siltuximab and dexamethasone. Patients received a median of four prior lines of therapy, 83% were relapsed and refractory, and 70% refractory to their last dexamethasone-containing regimen. Suppression of serum C-reactive protein levels, a surrogate marker of IL6 inhibition, was demonstrated. There were no responses to siltuximab but combination therapy yielded a partial (17%) + minimal (6%) response rate of 23%, with responses seen in dexamethasone-refractory disease. The median time to progression, progression-free survival and overall survival for combination therapy was 4.4, 3.7 and 20.4 months respectively. Haematological toxicity was common but manageable. Infections occurred in 57% of combination-treated patients, including ≥ grade 3 infections in 18%. Further study of siltuximab in modern corticosteroid-containing myeloma regimens is warranted, with special attention to infection-related toxicity., (© 2013 Blackwell Publishing Ltd.)
- Published
- 2013
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38. The efficiency of therapeutic erythrocytapheresis compared to phlebotomy in relation to blood volume and delta-hematocrit: an evaluation in hereditary hemochromatosis polycythemia vera and secondary erythrocytosis.
- Author
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Evers D, Kerkhoffs JL, Van Egmond L, and Wijermans PW
- Subjects
- Female, Hematocrit, Humans, Male, Blood Volume, Cytapheresis, Hemochromatosis physiopathology, Hemochromatosis therapy, Models, Biological, Phlebotomy, Polycythemia physiopathology, Polycythemia therapy, Polycythemia Vera physiopathology, Polycythemia Vera therapy
- Published
- 2013
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39. Guideline for diagnosis and treatment of Waldenström's macroglobulinaemia.
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Vos JM, Minnema MC, Wijermans PW, Croockewit S, Chamuleau ME, Pals ST, Klein SK, Delforge M, van Imhoff GW, and Kersten MJ
- Subjects
- Bone Marrow pathology, Humans, Monoclonal Gammopathy of Undetermined Significance diagnosis, Monoclonal Gammopathy of Undetermined Significance therapy, Plasmapheresis, Waldenstrom Macroglobulinemia therapy, Antineoplastic Combined Chemotherapy Protocols therapeutic use, Immunologic Factors therapeutic use, Waldenstrom Macroglobulinemia diagnosis
- Abstract
On behalf of the lymphoma and multiple myeloma working parties of the Dutch/Belgian Haemato-Oncology Foundation for Adults in The Netherlands (HOVON), we present a guideline for diagnosis and management of Waldenström's macroglobulinemia (WM). Considering the indolent behaviour and heterogeneous clinical presentation of WM, it is crucial to determine the right indications for treatment, as well as to individualise therapeutic options. There are significant differences from the approach to multiple myeloma or the treatment of other indolent non-Hodkgin lymphomas, and these results cannot always be extrapolated. There is a lack of large clinical trials due to the low incidence of WM. Based on the available data, we provide a practical diagnostic classification, as well as recommendations for first-line therapy and options for treating relapsed disease. Some typical clinical features of WM, such as autoimmune phenomena and 'IgM flare' after rituximab treatment, are highlighted. A more elaborate version of this guideline was published in the 'Nederlands Tijdschrift voor Hematologie' (Dutch Journal for Hematology) September 2012.
- Published
- 2013
40. Bortezomib induction and maintenance treatment in patients with newly diagnosed multiple myeloma: results of the randomized phase III HOVON-65/ GMMG-HD4 trial.
- Author
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Sonneveld P, Schmidt-Wolf IG, van der Holt B, El Jarari L, Bertsch U, Salwender H, Zweegman S, Vellenga E, Broyl A, Blau IW, Weisel KC, Wittebol S, Bos GM, Stevens-Kroef M, Scheid C, Pfreundschuh M, Hose D, Jauch A, van der Velde H, Raymakers R, Schaafsma MR, Kersten MJ, van Marwijk-Kooy M, Duehrsen U, Lindemann W, Wijermans PW, Lokhorst HM, and Goldschmidt HM
- Subjects
- Adult, Aged, Antineoplastic Combined Chemotherapy Protocols therapeutic use, Bortezomib, Dexamethasone administration & dosage, Dexamethasone therapeutic use, Disease-Free Survival, Doxorubicin administration & dosage, Doxorubicin therapeutic use, Drug Administration Schedule, Female, Humans, Maintenance Chemotherapy, Male, Middle Aged, Remission Induction, Thalidomide administration & dosage, Vincristine therapeutic use, Boronic Acids administration & dosage, Multiple Myeloma drug therapy, Pyrazines administration & dosage
- Abstract
Purpose: We investigated whether bortezomib during induction and maintenance improves survival in newly diagnosed multiple myeloma (MM)., Patients and Methods: In all, 827 eligible patients with newly diagnosed symptomatic MM were randomly assigned to receive induction therapy with vincristine, doxorubicin, and dexamethasone (VAD) or bortezomib, doxorubicin, and dexamethasone (PAD) followed by high-dose melphalan and autologous stem-cell transplantation. Maintenance consisted of thalidomide 50 mg (VAD) once per day or bortezomib 1.3 mg/m(2) (PAD) once every 2 weeks for 2 years. The primary analysis was progression-free survival (PFS) adjusted for International Staging System (ISS) stage., Results: Complete response (CR), including near CR, was superior after PAD induction (15% v 31%; P < .001) and bortezomib maintenance (34% v 49%; P < .001). After a median follow-up of 41 months, PFS was superior in the PAD arm (median of 28 months v 35 months; hazard ratio [HR], 0.75; 95% CI, 0.62 to 0.90; P = .002). In multivariate analysis, overall survival (OS) was better in the PAD arm (HR, 0.77; 95% CI, 0.60 to 1.00; P = .049). In high-risk patients presenting with increased creatinine more than 2 mg/dL, bortezomib significantly improved PFS from a median of 13 months to 30 months (HR, 0.45; 95% CI, 0.26 to 0.78; P = .004) and OS from a median of 21 months to 54 months (HR, 0.33; 95% CI, 0.16 to 0.65; P < .001). A benefit was also observed in patients with deletion 17p13 (median PFS, 12 v 22 months; HR, 0.47; 95% CI, 0.26 to 0.86; P = .01; median OS, 24 months v not reached at 54 months; HR, 0.36; 95% CI, 0.18 to 0.74; P = .003)., Conclusion: Bortezomib during induction and maintenance improves CR and achieves superior PFS and OS.
- Published
- 2012
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41. Intensive chemotherapy to improve outcome in patients with acute lymphoblastic leukemia over the age of 40: a phase II study for efficacy and feasibility by HOVON.
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Daenen S, van der Holt B, Dekker AW, Willemze R, Rijneveld AW, Biemond BJ, Muus P, van de Loosdrecht AA, Schouten HC, van Marwijk Kooy M, Breems DA, Demuynck H, Maertens J, Wijermans PW, Wittebol S, de Klerk EW, and Cornelissen JJ
- Subjects
- Adult, Aged, Feasibility Studies, Female, Humans, Male, Middle Aged, Prognosis, Prospective Studies, Survival Rate, Antineoplastic Combined Chemotherapy Protocols therapeutic use, Neoplasm Recurrence, Local drug therapy, Neoplasm Recurrence, Local mortality, Precursor Cell Lymphoblastic Leukemia-Lymphoma drug therapy, Precursor Cell Lymphoblastic Leukemia-Lymphoma mortality
- Published
- 2012
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42. Decitabine triphosphate levels in peripheral blood mononuclear cells from patients receiving prolonged low-dose decitabine administration: a pilot study.
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Jansen RS, Rosing H, Wijermans PW, Keizer RJ, Schellens JH, and Beijnen JH
- Subjects
- Azacitidine administration & dosage, Azacitidine metabolism, Chromatography, Liquid, Decitabine, Humans, Myelodysplastic Syndromes metabolism, Pilot Projects, Tandem Mass Spectrometry, Antimetabolites, Antineoplastic metabolism, Azacitidine analogs & derivatives, Leukocytes, Mononuclear metabolism, Myelodysplastic Syndromes drug therapy
- Abstract
Purpose: Decitabine is a nucleoside analog used in the treatment for myelodysplastic syndrome. The compound requires intracellular conversion to its triphosphate to become active. Decitabine triphosphate has, however, never been quantified in peripheral blood mononuclear cells (PBMCs) from patients., Method: This article describes a method for the quantitative determination of decitabine triphosphate in PBMCs using liquid chromatography coupled to tandem mass spectrometry. The method was applied to ex vivo incubated whole blood samples and samples from three patients receiving prolonged low-dose decitabine treatment., Results: We successfully quantitated decitabine triphosphate in PBMCs. Considerable levels were detected in PBMCs from two patients that responded well to therapy, whereas only low levels were present in a non-responding patient. Moreover, the data show that, in contrast to plasma decitabine, intracellular decitabine triphosphate accumulates during a treatment cycle of nine infusions at a dose of 15 mg/m(2)., Conclusions: The results suggest a relationship between decitabine triphosphate levels and response to therapy. Based on the observed accumulation of decitabine triphosphate during a treatment cycle, a less intensive dose scheme could be feasible.
- Published
- 2012
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43. A multicenter phase II trial of decitabine as first-line treatment for older patients with acute myeloid leukemia judged unfit for induction chemotherapy.
- Author
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Lübbert M, Rüter BH, Claus R, Schmoor C, Schmid M, Germing U, Kuendgen A, Rethwisch V, Ganser A, Platzbecker U, Galm O, Brugger W, Heil G, Hackanson B, Deschler B, Döhner K, Hagemeijer A, Wijermans PW, and Döhner H
- Subjects
- Aged, Aged, 80 and over, Antimetabolites, Antineoplastic administration & dosage, Antimetabolites, Antineoplastic adverse effects, Azacitidine administration & dosage, Azacitidine adverse effects, Azacitidine therapeutic use, Comorbidity, Decitabine, Female, Humans, Leukemia, Myeloid, Acute diagnosis, Leukemia, Myeloid, Acute epidemiology, Male, Middle Aged, Prevalence, Treatment Outcome, Antimetabolites, Antineoplastic therapeutic use, Azacitidine analogs & derivatives, Leukemia, Myeloid, Acute drug therapy
- Abstract
Background: The treatment of acute myeloid leukemia of older, medically non-fit patients still poses a highly unmet clinical need, and only few large, prospective studies have been performed in this setting. Given the established activity of hypomethylating agents such as 5-aza-2'-deoxycytidine (decitabine) in myelodysplastic syndromes and acute myeloid leukemia with 20-30% bone marrow blasts, we investigated whether this drug is also active in patients with more than 30% blasts., Design and Methods: To evaluate the efficacy and toxicity of decitabine in patients over 60 years old with untreated acute myeloid leukemia ineligible for induction chemotherapy, 227 patients (median age, 72 years), many with comorbidities, adverse cytogenetics and/or preceding myelodysplastic syndrome were treated with this hypomethylating agent. During the initial decitabine treatment (135 mg/m(2) total dose infused intravenously over 72 hours every 6 weeks), a median of two cycles was administered (range, 1-4). All-trans retinoic acid was administered to 100 patients during course 2. Fifty-two patients who completed four cycles of treatment subsequently received a median of five maintenance courses (range, 1-19) with a lower dose of decitabine (20 mg/m(2)) infused over 1 hour on 3 consecutive days every 4-6 weeks., Results: The complete and partial remission rate was 26%, 95% CI (20%, 32%), and an antileukemic effect was noted in 26% of patients. Response rates did not differ between patients with or without adverse cytogenetics; patients with monosomal karyotypes also responded. The median overall survival from the start of decitabine treatment was 5.5 months (range, 0-57.5+) and the 1-year survival rate was 28%, 95%CI (22%,34%). Toxicities were predominantly hematologic., Conclusions: Decitabine is well tolerated by older, medically non-fit patients with acute myeloid leukemia; myelosuppression is the major toxicity. The response rate and overall survival were not adversely influenced by poor-risk cytogenetics or myelodysplastic syndrome. Because of these encouraging results, randomized studies evaluating single-agent decitabine versus conventional treatment are warranted. The study is registered with the German Clinical Trials Registry, number DRKS00000069.
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- 2012
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44. [Demethylating medication in myelodysplastic syndrome].
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Manson ML, Derissen EJ, Wijermans PW, Schellens JH, and Beijnen JH
- Subjects
- Age Factors, Azacitidine analogs & derivatives, DNA Modification Methylases antagonists & inhibitors, Decitabine, Humans, Treatment Outcome, Antimetabolites, Antineoplastic therapeutic use, Azacitidine therapeutic use, DNA Methylation drug effects, Myelodysplastic Syndromes drug therapy
- Abstract
Myelodysplastic syndrome, a disorder of haematopoiesis, is associated with anaemia and an increased risk of infections, bleeding and the development of acute myeloid leukaemia. The disorder occurs mainly in later life. Until recently the only therapy that could induce sustained remission was allogeneic stem cell transplantation. However in elderly patients caution is needed with this therapy. Increasing awareness of the role of epigenetic changes in cancer development has led to the rediscovery of the cytidine analogues azacitidine and decitabine. At low doses these drugs inhibit DNA methylation. The efficacy of these drugs was demonstrated in the treatment of patients with myelodysplastic syndrome. These drugs showed low toxicity and were relatively well-tolerated in elderly patients. The results with azacitidine and decitabine have demonstrated that manipulation of the epigenetic process offers new antineoplastic treatment options.
- Published
- 2012
45. Autologous stem-cell transplantation in patients with mantle cell lymphoma beyond 65 years of age: a study from the European Group for Blood and Marrow Transplantation (EBMT).
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Jantunen E, Canals C, Attal M, Thomson K, Milpied N, Buzyn A, Ferrant A, Biron P, Crawley C, Schattenberg A, Luan JJ, Tilly H, Rio B, Wijermans PW, Dreger P, and Sureda A
- Subjects
- Adult, Age Distribution, Aged, Disease-Free Survival, Female, Humans, Kaplan-Meier Estimate, Male, Middle Aged, Proportional Hazards Models, Transplantation, Autologous, Lymphoma, Mantle-Cell mortality, Lymphoma, Mantle-Cell surgery, Stem Cell Transplantation mortality
- Abstract
Background: Limited experience is available on the feasibility and efficacy of autologous stem-cell transplantation (ASCT) in patients with mantle cell lymphoma (MCL) beyond 65 years., Design and Methods: We analysed 712 patients with MCL treated with ASCT from 2000 to 2007 and reported to the European Group for Blood and Marrow Transplantation registry. Patients>65 years were compared with patients<65 years for the end points non-relapse mortality (NRM), relapse incidence, progression-free survival (PFS), and overall survival (OS)., Results: Seventy-nine patients were ≥65 years old. Median time from diagnosis to ASCT was longer in the elderly patients (11 versus 9 months, P=0.005); they had more commonly received at least two treatment lines (62.0% versus 47.9%, P=0.02) and were less commonly in first complete remission at ASCT (35.4% versus 51.2%, P=0.002). Median follow-up after ASCT was 19 and 25 months, respectively. NRM was comparable at 3 months (3.8% versus 2.5%) and at 5 years (5.6% versus 5.0%). There were no differences in relapse rate (66% versus 55% at 5 years), PFS (29% versus 40%) and OS (61% versus 67%) between both populations of patients., Conclusion: ASCT beyond 65 years of age is feasible in selected patients with MCL and results in similar disease control and survival as in younger patients.
- Published
- 2012
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46. Effect of thalidomide with melphalan and prednisone on health-related quality of life (HRQoL) in elderly patients with newly diagnosed multiple myeloma: a prospective analysis in a randomized trial.
- Author
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Verelst SG, Termorshuizen F, Uyl-de Groot CA, Schaafsma MR, Ammerlaan AH, Wittebol S, Sinnige HA, Zweegman S, van Marwijk Kooy M, van der Griend R, Lokhorst HM, Sonneveld P, and Wijermans PW
- Subjects
- Aged, Aged, 80 and over, Antineoplastic Agents, Alkylating therapeutic use, Female, Glucocorticoids therapeutic use, Humans, Immunosuppressive Agents therapeutic use, Male, Middle Aged, Models, Statistical, Multiple Myeloma physiopathology, Prospective Studies, Surveys and Questionnaires, Treatment Outcome, Melphalan therapeutic use, Multiple Myeloma drug therapy, Prednisone therapeutic use, Quality of Life, Thalidomide therapeutic use
- Abstract
Thalidomide with melphalan/prednisone (MPT) was defined as standard treatment in elderly patients with multiple myeloma (MM) based on five randomized trials. In one of these trials, HOVON49, a prospective health-related quality-of-life (HRQoL) study was initiated in order to assess the impact of thalidomide on QoL. Patients aged >65 years with newly diagnosed MM were randomized to receive melphalan plus prednisone (MP) or MPT, followed by thalidomide maintenance in the MPT arm. Two hundred eighty-four patients were included in this side study (MP, n=149; MPT n=135). HRQoL was assessed with the EORTC Core QoL Questionnaire (QLQ-C30) and the myeloma-specific module (QLQ-MY24) at baseline and at predetermined intervals during treatment. The QLQ-C30 subscales physical function (P=0.044) and constipation (P<0.001) showed an improvement during induction in favour of the MP arm. During thalidomide maintenance, the scores for the QLQ-MY24 paraesthesia became significantly higher in the MPT arm (P<0.001). The QLQ-C30 subscales pain (P=0.12), insomnia (P=0.068), appetite loss (P=0.074) and the QLQ-MY24 item sick (P=0.086) scored marginally better during thalidomide maintenance. The overall QoL-scale QLQ-C30-HRQoL showed a significant time trend towards more favourable mean values during protocol treatment without differences between MP and MPT. For the QLQ-C30 subscales emotional function and future perspectives, difference in favour of the MPT arm from the start of treatment was observed (P=0.018 and P=0.045, respectively) with no significant 'time × arm' interaction, indicating a persistent better patient perspective with MPT treatment. This study shows that the higher frequency of toxicity associated with MPT does not translate into a negative effect on HRQoL and that MPT holds a better patient perspective.
- Published
- 2011
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47. Platelet doubling after the first azacitidine cycle is a promising predictor for response in myelodysplastic syndromes (MDS), chronic myelomonocytic leukaemia (CMML) and acute myeloid leukaemia (AML) patients in the Dutch azacitidine compassionate named patient programme.
- Author
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van der Helm LH, Alhan C, Wijermans PW, van Marwijk Kooy M, Schaafsma R, Biemond BJ, Beeker A, Hoogendoorn M, van Rees BP, de Weerdt O, Wegman J, Libourel WJ, Luykx-de Bakker SA, Minnema MC, Brouwer RE, Croon-de Boer F, Eefting M, Jie KS, van de Loosdrecht AA, Koedam J, Veeger NJ, Vellenga E, and Huls G
- Subjects
- Adult, Aged, Aged, 80 and over, Cohort Studies, Female, Humans, Leukemia, Myeloid, Acute drug therapy, Leukemia, Myelomonocytic, Chronic drug therapy, Male, Middle Aged, Myelodysplastic Syndromes drug therapy, Netherlands, Retrospective Studies, Survival Analysis, Treatment Outcome, Antimetabolites, Antineoplastic therapeutic use, Azacitidine therapeutic use, Blood Platelets drug effects, Compassionate Use Trials, Leukemia, Myeloid, Acute blood, Leukemia, Myelomonocytic, Chronic blood, Myelodysplastic Syndromes blood
- Abstract
The efficacy of azacitidine in the treatment of high-risk myelodysplastic syndromes (MDS), chronic myelomonocytic leukaemia (CMML) and acute myeloid leukaemia (AML) (20-30% blasts) has been demonstrated. To investigate the efficacy of azacitidine in daily clinical practice and to identify predictors for response, we analysed a cohort of 90 MDS, CMML and AML patients who have been treated in a Dutch compassionate named patient programme. Patients received azacitidine for a median of five cycles (range 1-19). The overall response rate (complete/partial/haematological improvement) was 57% in low risk MDS, 53% in high risk MDS, 50% in CMML, and 39% in AML patients. Median overall survival (OS) was 13·0 (9·8-16·2) months. Multivariate analysis confirmed circulating blasts [Hazard Ratio (HR) 0·48, 95% confidence interval (CI) 0·24-0·99; P = 0·05] and poor risk cytogenetics (HR 0·45, 95% CI 0·22-0·91; P = 0·03) as independent predictors for OS. Interestingly, this analysis also identified platelet doubling after the first cycle of azacitidine as a simple and independent positive predictor for OS (HR 5·4, 95% CI 0·73-39·9; P = 0·10). In conclusion, routine administration of azacitidine to patients with variable risk groups of MDS, CMML and AML is feasible, and subgroups with distinct efficacy of azacitidine treatment can be identified., (© 2011 Blackwell Publishing Ltd.)
- Published
- 2011
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48. Intensified chemotherapy inspired by a pediatric regimen combined with allogeneic transplantation in adult patients with acute lymphoblastic leukemia up to the age of 40.
- Author
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Rijneveld AW, van der Holt B, Daenen SM, Biemond BJ, de Weerdt O, Muus P, Maertens J, Mattijssen V, Demuynck H, Legdeur MC, Wijermans PW, Wittebol S, Spoelstra FM, Dekker AW, Ossenkoppele GJ, Willemze R, and Cornelissen JJ
- Subjects
- Adolescent, Adult, Combined Modality Therapy, Feasibility Studies, Female, Humans, Male, Middle Aged, Remission Induction, Young Adult, Antineoplastic Combined Chemotherapy Protocols therapeutic use, Bone Marrow Transplantation, Precursor Cell Lymphoblastic Leukemia-Lymphoma drug therapy, Precursor Cell Lymphoblastic Leukemia-Lymphoma surgery
- Abstract
Event-free survival (EFS) at 5 years in pediatric acute lymphoblastic leukemia (ALL) is >80%. Outcome in adult ALL is still unsatisfactory, which is due to less cumulative dosing of chemotherapy and less strict adherence to timing of successive cycles. In the present phase II trial, we evaluated a pediatric regimen in adult patients with ALL under the age of 40. Treatment was according to the pediatric FRALLE approach for high-risk ALL patients and characterized by increased dosages of asparaginase, steroids, methotrexate and vincristin. However, allogeneic stem cell transplantation was offered to standard risk patients with a sibling donor and to all high-risk patients in contrast to the pediatric protocol. Feasibility was defined by achieving complete remission (CR) and completion of treatment within a strict timeframe in at least 60% of patients. In all, 54 patients were included with a median age of 26. CR was achieved in 49 patients (91%), of whom 33 completed treatment as scheduled (61%). Side effects primarily consisted of infections and occurred in 40% of patients. With a median follow-up of 32 months, EFS estimated 66% at 24 months and overall survival 72%. These data show that a dose-intensive pediatric regimen is feasible in adult ALL patients up to the age of 40.
- Published
- 2011
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49. Regression of HIV-associated grade IV T cell lymphoma with combined antiretroviral therapy only.
- Author
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Teng YKO, Schippers EF, and Wijermans PW
- Subjects
- Antiretroviral Therapy, Highly Active, Bone and Bones pathology, CD4 Lymphocyte Count, HIV Infections complications, Humans, Lymphoma, AIDS-Related diagnosis, Lymphoma, T-Cell diagnosis, Male, Middle Aged, Neoplasm Staging, Positron-Emission Tomography, Tomography, X-Ray Computed, Treatment Outcome, Viral Load, Anti-HIV Agents therapeutic use, Lymphoma, AIDS-Related drug therapy, Lymphoma, AIDS-Related pathology, Lymphoma, T-Cell drug therapy, Lymphoma, T-Cell pathology
- Abstract
The present report describes repeated long-term remissions of a high-grade T cell lymphoma in an HIV-positive patient upon cART only, without additional chemotherapy. A review of cases from the literature further illustrates the anti-tumor effects of cART through the induction of a strong immune reconstitution in HIV-infected patients.
- Published
- 2011
- Full Text
- View/download PDF
50. Low-dose decitabine versus best supportive care in elderly patients with intermediate- or high-risk myelodysplastic syndrome (MDS) ineligible for intensive chemotherapy: final results of the randomized phase III study of the European Organisation for Research and Treatment of Cancer Leukemia Group and the German MDS Study Group.
- Author
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Lübbert M, Suciu S, Baila L, Rüter BH, Platzbecker U, Giagounidis A, Selleslag D, Labar B, Germing U, Salih HR, Beeldens F, Muus P, Pflüger KH, Coens C, Hagemeijer A, Eckart Schaefer H, Ganser A, Aul C, de Witte T, and Wijermans PW
- Subjects
- Aged, Aged, 80 and over, Antimetabolites, Antineoplastic therapeutic use, Azacitidine adverse effects, Azacitidine therapeutic use, Decitabine, Disease-Free Survival, Female, Humans, Male, Middle Aged, Myelodysplastic Syndromes complications, Myelodysplastic Syndromes drug therapy, Myelodysplastic Syndromes mortality, Quality of Life, Treatment Outcome, Azacitidine analogs & derivatives, Myelodysplastic Syndromes therapy, Palliative Care
- Abstract
Purpose: To compare low-dose decitabine to best supportive care (BSC) in higher-risk patients with myelodysplastic syndrome (MDS) age 60 years or older and ineligible for intensive chemotherapy., Patients and Methods: Two-hundred thirty-three patients (median age, 70 years; range, 60 to 90 years) were enrolled; 53% had poor-risk cytogenetics, and the median MDS duration at random assignment was 3 months. Primary end point was overall survival (OS). Decitabine (15 mg/m(2)) was given intravenously over 4 hours three times a day for 3 days in 6-week cycles., Results: OS prolongation with decitabine versus BSC was not statistically significant (median OS, 10.1 v 8.5 months, respectively; hazard ratio [HR], 0.88; 95% CI, 0.66 to 1.17; two-sided, log-rank P = .38). Progression-free survival (PFS), but not acute myeloid leukemia (AML) -free survival (AMLFS), was significantly prolonged with decitabine versus BSC (median PFS, 6.6 v 3.0 months, respectively; HR, 0.68; 95% CI, 0.52 to 0.88; P = .004; median AMLFS, 8.8 v 6.1 months, respectively; HR, 0.85; 95% CI, 0.64 to 1.12; P = .24). AML transformation was significantly (P = .036) reduced at 1 year (from 33% with BSC to 22% with decitabine). Multivariate analyses indicated that patients with short MDS duration had worse outcomes. Best responses with decitabine versus BSC, respectively, were as follows: complete response (13% v 0%), partial response (6% v 0%), hematologic improvement (15% v 2%), stable disease (14% v 22%), progressive disease (29% v 68%), hypoplasia (14% v 0%), and inevaluable (8% v 8%). Grade 3 to 4 febrile neutropenia occurred in 25% of patients on decitabine versus 7% of patients on BSC; grade 3 to 4 infections occurred in 57% and 52% of patients on decitabine and BSC, respectively. Decitabine treatment was associated with improvements in patient-reported quality-of-life (QOL) parameters., Conclusion: Decitabine administered in 6-week cycles is active in older patients with higher-risk MDS, resulting in improvements of OS and AMLFS (nonsignificant), of PFS and AML transformation (significant), and of QOL. Short MDS duration was an independent adverse prognosticator.
- Published
- 2011
- Full Text
- View/download PDF
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