Minimale Resterkrankung bei follikulären Lymphomen und Mantellzell-Lymphomen

Zusammenfassung

Hintergrund und Fragestellung Quantitative Real-time-PCR Analysen ermöglichen es, bei Patienten mit follikulären Lymphomen (FL) und Mantelzell-Lymphomen (MCL) peripher zirkulierende Lymphomzellen mit hoher Empfindlichkeit und Reproduzierbarkeit zu bestimmen. Ein Ziel unserer Untersuchungen war es, die Frage zu beantworten, ob bei Patienten mit Mantelzell-Lymphom und follikulärem Lymphom anhaltende molekulare Remissionen erreicht werden können und ob diese einen prognostischen Stellenwert für das Überleben der Patienten haben.

Patienten und Methodik Zehn Patienten mit FL in langanhaltender kompletter Remission nach einer Strahlentherapie sowie 24 Patienten mit FL und bei 8 Patienten mit MCL, die in einer randomisierten Studie mit einer Chemotherapie mit oder ohne Rituximab (MCP, R-MCP) behandelt wurden, wurden mittels quantitativer Real-time-Polymerase-Kettenreaktion auf zirkulierende Lymphomzellen untersucht. Die molekularen Ergebnisse (Kinetik der minimalen Resterkrankung) wurden mit dem klinischen Therapieerfolg verglichen.

Ergebnisse Zirkulierende t(14;18) positive Zellen konnten bis zu 18 Jahre nach Diagnosestellung eines FL in langanhaltender kompletter Remission nachgewiesen werden. Im Stadium III/IV wurden molekulare Remissionen in einem hohem Patientenanteil nur durch die Kombination MCP+R erreicht, dies war mit einem deutlich besseren rezidivfreien Überleben assoziiert. Bei Patienten mit Mantelzell-Lymphomen waren nur geringe Raten molekularer Remissionen feststellbar, die zudem nur von kurzer Dauer waren.

Folgerung Basierend auf den Befunden des molekularen Monitorings können neue, individuelle Therapiestrategien für Patienten entwickelt werden, die auf die Standardtherapie nicht adäquat ansprechen. Der Stellenwert der molekularen Diagnostik muss jedoch in prospektiven klinischen Studien weiter bestätigt werden.

Summary

Background and objective: In patients with follicular lymphoma and mantle cell lymphoma circulating lymphoma cells can be detected by quantitative real-time PCR with a high sensitivity and reproducibility. With this study we wanted to ascertain wether a continuous molecular remission achieved in patients with mantle cell lymphoma and follicular lymphoma has an impact on survial of these patients.

Patient and methods We conducted these investigations in 32 patients (24 with follicular lymphoma and 8 with mantle cell lymphoma) who were treated in a randomized trial with chemotherapy plus/minus rituximab (MCP, R-MCP). A further ten patients had follicular lymphoma (stage I and II) in long-term complete remission after radiation therapy.

Results Up to 18 years after initial diagnoses of a stage I or II follicular lymphoma circulating t(14;18) positive cells could be detected in the peripheral blood. In advanced stage follicular lymphoma patients molecular remissions could only be achieved when they were treated with combined chemo-immunotherapy (MCP+R). A significantly higher relapse-free survival correlates with sustained molecular remission. In contrast, the frustrating clinical results obtained from the treatment of patients with mantle cell lymphoma corresponded to an achievement of only short molecular remissions in very few patients.

Conclusions The consequent application of quantitative real-time PCR will further improve current treatment strategies in lymphoma patients. Especially, individual treatment options can be developed for patients who do not respond to a standard chemotherapy or progression of disease is recognized, if results of molecular monitoring will be confirmed in large prospective studies.

Literatur

• 1 Andersen N S, Donovan J W, Zuckerman A, Pedersen L, Geisler C, Gribben J G. Real-time polymerase chain reaction estimation of bone marrow tumor burden using clonal immunoglobulin heavy chain gene and bcl-1/JH rearrangements in mantle cell lymphoma.  Exp Hematol. 2002;  30 703-710
• 2 Corradini P, Ladetto M, Zallio F, Astolfi M, Rizzo E, Sametti S, Cuttica A, Rosato R, Farina L, Boccadoro M, Benedetti F, Pileri A, Tarella C. Long-term follow-up of indolent lymphoma patients treated with high-dose sequential chemotherapy and autografting: evidence that durable molecular and clinical remission frequently can be attained only in follicular subtypes.  J Clin Oncol. 2004;  22 1460-1468
• 3 Czuczman M S, Grillo-Lopez A J, McLaughlin P, White C A, Saleh M, Gordon L, LoBuglio A F, Rosenberg J, Alkuzweny B, Maloney D. Clearing of cells bearing the bcl-2 [t(14;18)] translocation from blood and marrow of patients treated with rituximab alone or in combination with CHOP chemotherapy.  Ann Oncol. 2001;  12 109-114
• 4 Czuczman M S, Grillo-Lopez A J, White C A, Saleh M, Gordon L, LoBuglio A F, Jonas C, Klippenstein D, Dallaire B, Varns C. Treatment of patients with low-grade B-cell lymphoma with the combination of chimeric anti-CD20 monoclonal antibody and CHOP chemotherapy.  J Clin Oncol. 1999;  17 268-276
• 5 Czuczman M S, Weaver R, Alkuzweny B, Berlfein J, Grillo-Lopez A J. Prolonged clinical and molecular remission in patients with low-grade or follicular non-Hodgkin’s lymphoma treated with rituximab plus CHOP chemotherapy: 9-year follow-up.  J Clin Oncol. 2004;  22 4711-4716
• 6 Dölken G. Detection of minimal residual disease.  Adv Cancer Res. 2001;  82 133-185
• 7 Dölken G, Illerhaus G, Hirt C, Mertelsmann R. BCL-2/JH rearrangements in circulating B cells of healthy blood donors and patients with nonmalignant diseases.  J Clin Oncol. 1996;  14 1333-1344
• 8 Dölken L, Schüler F, Dölken G. Quantitative detection of t(14;18)-positive cells by real-time quantitative PCR using fluorogenic probes.  Biotechniques. 1998;  25 1058-1064
• 9 Donovan J W, Ladetto M, Zou G, Neuberg D, Poor C, Bowers D, Gribben J G. Immunoglobulin heavy-chain consensus probes for real-time PCR quantification of residual disease in acute lymphoblastic leukemia.  Blood. 2000;  95 2651-2658
• 10 Finke J, Slanina J, Lange W, Dölken G. Persistence of circulating t(14;18)-positive cells in long-term remission after radiation therapy for localized-stage follicular lymphoma.  J Clin Oncol. 1993;  11 1668-1673
• 11 Forstpointner R, Dreyling M, Repp R, Hermann S, Hanel A, Metzner B, Pott C, Hartmann F, Rothmann F, Rohrberg R, Bock H P, Wandt H, Unterhalt M, Hiddemann W. The addition of rituximab to a combination of fludarabine, cyclophosphamide, mitoxantrone (FCM) significantly increases the response rate and prolongs survival as compared with FCM alone in patients with relapsed and refractory follicular and mantle cell lymphomas: results of a prospective randomized study of the German Low-Grade Lymphoma Study Group.  Blood. 2004;  104 3064-3071
• 12 Herold M, Pasold R, Srock S, Neser S, Niederwieser D, Dölken G, Naumann R, Fietz T, Freund M. et al . Results of a Prospective Randomised Open Label Phase III Study Comparing Rituximab Plus Mitoxantrone, Chlorambucile, Prednisolone Chemotherapy (R-MCP) Versus MCP Alone in Untreated Advanced Indolent Non-Hodgkin’s Lymphoma (NHL) and Mantle-Cell-Lymphoma (MCL) [abstr 584].  Blood. 2004;  104 169a
• 13 Hirt C, Dölken G. Quantitative detection of t(14;18)-positive cells in patients with follicular lymphoma before and after autologous bone marrow transplantation.  Bone Marrow Transplant. 2000;  25 419-426
• 14 Hirt C, Schuler F, Dolken L, Schmidt C A, Dolken G. Low prevalence of circulating t(11;14)(q13;q32)-positive cells in the peripheral blood of healthy individuals as detected by real-time quantitative PCR.  Blood. 2004;  104 904-905
• 15 Hirt C, Schüler F, Schwenke C, Kiefer T, Herold M, Dölken G. High percentage of molecular remissions in advanced stage follicular lymphoma (FL) patients treated with chemoimmunotherapy in comparison to chemotherapy alone [abstr 1402].  Blood. 2002;  100 362
• 16 Jacquy C, Lambert F, Soree A, Van D S, Heusterspreute M, Bosly A, Ferrant A, Parma J, Bron D, Martiat P. Peripheral blood stem cell contamination in mantle cell non-Hodgkin lymphoma: the case for purging?.  Bone Marrow Transplant. 1999;  23 681-686
• 17 Jaeger U, Kainz B. Monitoring minimal residual disease in AML: the right time for real time.  Ann Hematol. 2003;  82 139-147
• 18 Lenz G, Dreyling M, Hoster E, Wormann B, Duhrsen U, Metzner B, Eimermacher H, Neubauer A, Wandt H, Steinhauer H, Martin S, Heidemann E, Aldaoud A, Parwaresch R, Hasford J, Unterhalt M, Hiddemann W. Immunochemotherapy with rituximab and cyclophosphamide, doxorubicin, vincristine, and prednisone significantly improves response and time to treatment failure, but not long-term outcome in patients with previously untreated mantle cell lymphoma: results of a prospective randomized trial of the German Low Grade Lymphoma Study Group (GLSG).  J Clin Oncol. 2005;  23 1984-1992
• 19 Lopez-Guillermo A, Cabanillas F, McLaughlin P, Smith T, Hagemeister F, Rodriguez M A, Romaguera J E, Younes A, Sarris A H, Preti H A, Pugh W, Lee M S. The clinical significance of molecular response in indolent follicular lymphomas.  Blood. 1998;  91 2955-2960
• 20 Mac Manus M P, Hoppe R T. Is radiotherapy curative for stage I and II low-grade follicular lymphoma? Results of a long-term follow-up study of patients treated at Stanford University.  J Clin Oncol. 1996;  14 1282-1290
• 21 Mandigers C M, Meijerink J P, Mensink E J, Tonnissen E L, Hebeda K M, Bogman M J, Raemaekers J M. Lack of correlation between numbers of circulating t(14;18)-positive cells and response to first-line treatment in follicular lymphoma.  Blood. 2001;  98 940-944
• 22 Montoto S, Lopez-Guillermo A, Colomer D, Esteve J, Bosch F, Ferrer A, Villamor N, Moreno C, Campo E, Montserrat E. Incidence and clinical significance of bcl-2/IgH rearrangements in follicular lymphoma.  Leuk Lymphoma. 2003;  44 71-76
• 23 Rambaldi A, Lazzari M, Manzoni C, Carlotti E, Arcaini L, Baccarani M, Barbui T, Bernasconi C, Dastoli G, Fuga G, Gamba E, Gargantini L, Gattei V, Lauria F, Lazzarino M, Mandelli F, Morra E, Pulsoni A, Ribersani M, Rossi-Ferrini P L, Rupolo M, Tura S, Zagonel V, Zaja F, Zinzani P, Reato G, Foa R. Monitoring of minimal residual disease after CHOP and rituximab in previously untreated patients with follicular lymphoma.  Blood. 2002;  99 856-862
• 24 Schüler F, Dölken S, Hirt C, Dölken M, Mentel R, Gürtler L, Dölken G. No Evidence for Simian Virus 40 DNA Sequences in Malignant Non-Hodgkin Lymphomas.  Int J Cancer. 2005;  (in press)
• 25 The Non-Hodgkin’s Lymphoma Classification Project . A Clinical Evaluation of the International Lymphoma Study Group Classification of Non-Hodgkin’s Lymphoma.  Blood. 1997;  89 3909-3918
• 26 Tsimberidou A M, McLaughlin P, Younes A, Rodriguez M A, Hagemeister F B, Sarris A, Romaguera J, Hess M, Smith T L, Yang Y, Ayala A, Preti A, Lee M S, Cabanillas F. Fludarabine, mitoxantrone, dexamethasone (FND) compared with an alternating triple therapy (ATT) regimen in patients with stage IV indolent lymphoma.  Blood. 2002;  100 4351-4357
• 27 van der Velden V, Hochhaus A, Cazzaniga G, Szczepanski T, Gabert J, van Dongen J J. Detection of minimal residual disease in hematologic malignancies by real-time quantitative PCR: principles, approaches, and laboratory aspects.  Leukemia. 2003;  17 1013-1034
• 28 Vandenberghe E, De Wolf-Peeters C, Vaughan H G, Vaughan H B, Pittaluga S, Anderson L, Linch D C. The clinical outcome of 65 cases of mantle cell lymphoma initially treated with non-intensive therapy by the British National Lymphoma Investigation Group.  Br J Haematol. 1997;  99 842-847
• 29 Vaughan H B, Vaughan H G, MacLennan K A, Anderson L, Linch D C. Clinical stage 1 non-Hodgkin’s lymphoma: long-term follow-up of patients treated by the British National Lymphoma Investigation with radiotherapy alone as initial therapy.  Br J Cancer. 1994;  69 1088-1093
• 30 Weisenburger D D, Vose J M, Greiner T C, Lynch J C, Chan W C, Bierman P J, Dave B J, Sanger W G, Armitage J O. Mantle cell lymphoma. A clinicopathologic study of 68 cases from the Nebraska Lymphoma Study Group.  Am J Hematol. 2000;  64 190-196
• 31 Zucca E, Roggero E, Pinotti G, Pedrinis E, Cappella C, Venco A, Cavalli F. Patterns of survival in mantle cell lymphoma.  Ann Oncol. 1995;  6 257-262