research paper
Nordic MCL2 trial update: six-year follow-up after intensive immunochemotherapy for untreated mantle cell lymphoma followed by BEAM or BEAC + autologous stem-cell support: still very long survival but late relapses do occur
Christian H. Geisler,1 Arne Kolstad,2 Anna Laurell,3 Mats Jerkeman,4 Riikka Ra¨ty,5 Niels S. Andersen,1 Lone B. Pedersen,1 Mikael Eriksson,4 Marie Nordstro¨m,6 Eva Kimby,6 Hans Bentzen,7 Outi Kuittinen,8 Grete F. Lauritzsen,2 Herman Nilsson-Ehle,9 Elisabeth Ralfkiær,1 Mats Ehinger,4 Christer Sundstro¨m,3 Jan Delabie,2 Marja-Liisa Karjalainen-Lindsberg,5 Peter Brown1 and Erkki Elonen5 for the Nordic Lymphoma Group 1
Rigshospitalet, Copenhagen, Denmark, 2The
Norwegian Radium Hospital, Oslo, Norway, 3
Uppsala University Hospital, Uppsala, Sweden,
4
Skane University Hospital, Lund, Sweden,
5
Helsinki University Central Hospital, Helsinki,
Finland, 6Karolinska Institute, Stockholm, Sweden, 7Aarhus University Hospital, Aarhus, Denmark, 8Oulu University Hospital, Oulu, Finland and 9Sahlgrenska Hospital, Gothenburg, Sweden Received 20 January 2012; accepted for publication 04 April 2012
Summary Mantle cell lymphoma (MCL) is a heterogenic non-Hodgkin lymphoma entity, with a median survival of about 5 years. In 2008 we reported the early – based on the median observation time of 4 years – results of the Nordic Lymphoma Group MCL2 study of frontline intensive induction immunochemotherapy and autologous stem cell transplantation (ASCT), with more than 60% event-free survival at 5 years, and no subsequent relapses reported. Here we present an update after a median observation time of 6·5 years. The overall results are still excellent, with median overall survival and response duration longer than 10 years, and a median eventfree survival of 7·4 years. However, six patients have now progressed later than 5 years after end of treatment. The international MCL Prognostic Index (MIPI) and Ki-67-expression were the only independent prognostic factors. Subdivided by the MIPI-Biological Index (MIPI + Ki-67, MIPI-B), more than 70% of patients with low-intermediate MIPI-B were alive at 10 years, but only 23% of the patients with high MIPI-B. These results, although highly encouraging regarding the majority of the patients, underline the need of a risk-adapted treatment strategy for MCL. The study was registered at www.isrctn.org as ISRCTN 87866680. Keywords: mantle cell lymphoma, autologous stem cell transplant, high-dose AraC, rituximab, pre-emptive therapy.
Correspondence: Dr Christian H. Geisler, Haematology 4042, Rigshospitalet, 9 Blegdamsvej, Copenhagen 2100, Denmark. E-mail:
[email protected] Registered at www.isrctn.org as ISRCTN 87866680 Presented in part at the 2011 ICML Lugano, Switzerland.
Mantle cell lymphoma (MCL) was previously considered a non-Hodgkin lymphoma subtype with a poor prognosis and a median survival of 3–5 years (Weisenburger & Armitage, 1996; Herrmann et al, 2009). Recent results of trials of intensive frontline immunochemotherapy with or without ª 2012 Blackwell Publishing Ltd British Journal of Haematology, 2012, 158, 355–362
high-dose therapy with autologous stem cell support (ASCT) (Romaguera et al, 2005; Geisler et al, 2008; Hermine et al, 2010) have been encouraging, and MCL can now be regarded a more heterogenic disease, with subgroups of patients achieving long-term disease control (Geisler et al, 2010; First published online 29 May 2012 doi:10.1111/j.1365-2141.2012.09174.x
C. H. Geisler et al and standard blood tests. For the present update, however, patients in remission beyond 5 years of follow-up also underwent a whole body CT scan.
Romaguera et al, 2010). Indeed, in our MCL2 trial (Geisler et al, 2008), a phase-II study of intensive immuno-chemotherapy followed by ASCT in 160 MCL patients, no relapses had been reported later than 5 years after end of treatment. However, that report was based on a median observation time of only 4 years in patients alive in remission (range 1·7 –7·4 years). Here we present an update of these results after a median observation time of 6·5 years of patients alive in remission, (range 4–10 years).
Pathology revision All biopsies were reviewed by one of the central pathology board members. Only cyclinD1-positive MCL cases were included. Ki67 expression was assessed semiquantitatively by ‘eyeballing’ by the central pathology reviewer. The recorded expression was used for the MIPI-B calculation. Acknowledging the margin of uncertainty of Ki-67 eyeballing, however (Klapper et al, 2009), Ki-67 was entered as 33 vs. >33% Ki-67 expression for the multivariate outcome analysis.
Material and methods This trial was approved by the national medicines agencies and science ethics committees in Denmark, Finland, Norway and Sweden and informed consent was obtained from all patients. One hundred and sixty untreated patients less than 66 years of age, with cyclinD1+ MCL according to World Health Organization (WHO) criteria (Swerdlow et al, 2001) on central pathology review, received six cycles of intensive induction chemotherapy with an augmented CHOP (cyclophosphamide, doxorubicin, vincristine, prednisolone) regimen (maxi-CHOP) alternating with high-dose cytarabine (AraC) (Fig 1). Rituximab (R) was given day 1 from cycle 4 in the first 116 patients, then from cycle 4. In cycle 6 (highdose AraC used for stem-cell mobilization) rituximab was given also on day 9 for in vivo purging. Following a sufficient stem cell harvest, the patients underwent high-dose chemotherapy with BEAM (carmustine, etoposide, AraC, melphalan) or BEAC (carmustine, etoposide, AraC, cylcophosphamide) and ASCT. A complete work-up including history, physical examination, blood and bone-marrow examination and computerized tomography (CT) scans was done at study entry, after cycle 5, two months after the ASCT, and subsequently every 6 months for 5 years or until relapse. After 5 years the patients continued follow-up with annual clinical assessment
Minimal residual disease Primers were sought established for molecular follow-up with polymerase chain reaction (PCR), either for the t(11;14) or clonal immunoglobulin heavy chain gene rearrangement (Andersen et al, 2009). Responding patients with available primers were studied for molecular relapse in the blood and the bone marrow every 6 months until relapse or up to for 5 years after the ASCT. Patients with solely molecular relapse (PCR conversion from negative to positive or increasing minimal residual disease (MRD) by quantitative PCR, but otherwise without any clinical or radiological evidence of disease), were offered pre-emptive therapy with rituximab 375 mg/m2 weekly, four doses.
Statistics Survival curves were created according to the Kaplan–Meier method, curve comparisons by log rank tests. Multivariate analysis was performed by Cox proportional hazard analysis, given as hazard ratios with 95% confidence intervals. A signif-
RESTAGE
INDUCTION
Maxi
C H O P Week: 1
A r a C 4
Maxi
C H O P 7
RESTEM-CELL: STAGE HARVEST REINFUSION
R
R
RR
A r a C
Maxi
A r a C
10
13
Maxi-CHOP: Cyclophosphamide 1200 mg/m2 D1 Doxorubicin 75 mg/m2 D1 Vincristine 2 mg total D1 Prednisone 100 mg D1-5 AraC: Four 3-h- infusions/cycle: < 60 years 3 g/m2 , > 60 years 2 g/m2 R: Rituximab 375 mg/m2
C H O P
16
RR RR
B E A M/C 19
for mol. relapse
20
BEAM/C: BCNU 300 mg/m2 D1 AraC 400 mg/m2 D2-5 Etoposide 200 mg/m2 D2-5 Melphalan 140 mg/m2 D6 or Cyclophosphamide 1500 mg/m2 D2-5 R: Rituximab 375 mg/m2
Fig 1. Treatment outline of the MCL2 Trial.
356
ª 2012 Blackwell Publishing Ltd British Journal of Haematology, 2012, 158, 355–362
Nordic MCL2 Trial Update icance level of 0·05%, two-sided, was used. For this update, the database was closed on 31 December 2010. For the trial, the response criteria of the National Cancer Institute (NCI) guidelines (Cheson et al, 1999) were used, but for this update we used the end-points described in the revised NCI guidelines 2007 (Cheson et al, 2007): Event-free survival (EFS), based on intention-to-treat, was calculated from entry onto study to failure of treatment due to any event including lymphoma or toxicity, or death from any cause. Survival (OS), based on intention-to-treat, was measured from entry onto study to death from any cause. Response duration was defined as the time from documented complete or partial response to the time of progression or relapse. Solely molecular relapse as defined above was not recorded as a relapse. The Mantle Cell Lymphoma International Prognostic Index (MIPI), based on WHO performance status, white blood cell count (WBC), lactate dehydrogenase (LDH) Level, and age, and the MIPIbiological (MIPI-B), which also incorporated Ki-67 expression, were assessed according to Hoster et al (2008).
Results One hundred and sixty patients were included between 2000 and 2006. Based on intention-to treat, the projected 10-year OS and EFS of all 160 patients was 58 and 43%, respectively, while the 10-year response duration of the 145 responders who underwent ASCT was 55% (Fig 2). Thus, the median OS and response duration has not been reached at 10 years, while the median EFS of all patients based on intention-totreat was 7·4 years. Compared to our 2008 report (Geisler et al, 2008), however, some late relapses have now occurred: Of a total of 79 events recorded, 60 (75%) were due to lymphoma relapse, and six occurred later than five years after the transplant, the latest almost 9 years later.
and MIPI-B (Fig 3B) separated the risk groups significantly, regarding all endpoints, but particularly the MIPI-B divided patients into two almost equally large groups: a low/intermediate-risk group of 59% in which the median OS, EFS or response duration have not yet been reached, and a MIPI-B high-risk group of 41% with median OS, EFS and response duration of 4·5, 2·7 and 2·8 years, respectively. Of note, in the MIPI-B low-risk group no relapse has yet been reported later than 4 years after end of treatment. In multivariate analyses (Table II), mainly Ki67 and WHO performance status were significant. Replacing the MIPI components age, WBC, LDH and performance by MIPI, MIPI and Ki-67 became the sole independently significant variables (Table III). When these were replaced by MIPI-B, this became the only independent outcome predictor (Table IV).
Pre-emptive treatment As previously reported (Andersen et al, 2009) 74 patients with a molecular marker proceeded to follow-up after ASCT. At closure of the database a solely molecular relapse had occurred in 36 patients, 8 within the first year, 28 up to 4 years later, while 33 remained in clinical and molecular remission. Of the 36 patients who were candidates for preemptive rituximab therapy, 32 received it and 26 (81%) responded by reverting to a PCR-negative state for at least one successive sample of blood and bone marrow after the treatment. Ten (38%) of the PCR responders have subsequently relapsed clinically. Figure 4 shows the clinical response duration on intention-to-treat of the 36 patients. Patients with short (11 x 109/l, increased LDH, and Ki-67 expression reached significance, whereas age, sex, stage and cytological variant did not (Table I). Both MIPI (Fig 3A)
Toxicity A total of 12 non-relapse deaths (7·5%) have now occurred: four during ASCT (one due to graft failure, three to infections), and three later from heart failure (8, 20, and 28 months after ASCT), for a total of 7 (4·4%) deaths deemed treatment-related, while five deaths in years 5-6 were not deemed related: One pulmonary embolus, one sudden death, and three cases of new malignancy. In total, six new malignancies were reported (one myelodysplasia, cancers of breast, colon, bile ducts, kidney, prostate), of which only the myelodysplasia was deemed treatment-related.
Discussion
Fig 2. Overall and event-free survival (EFS), and response duration in all patients. ª 2012 Blackwell Publishing Ltd British Journal of Haematology, 2012, 158, 355–362
We present here the encouraging results of an update of a cohort of younger MCL patients followed for a long time after treatment with intensive immunochemotherapy, in which the median survival has not been reached after 357
C. H. Geisler et al Table I. Clinicopathological findings of the 160 patients
10-year EFS
10-year OS
10-year duration
response
Variable
No. (%)
%
P
%
P
%
P
Male Female Age 60 years >60 years Stage II–III IV WHO Performance status 0–1 2 Splenomegaly Yes No UK WBC 11 9 109/l >11 9 109/l LDH /ULN 1 >1 Cytological variant Common Blastoid/pleomorphic Ki-67 expression 0–33% >33% MIPI Low Intermediate High MIPI-B Low Intermediate High
113 (71) 47 (29)
36 46
0·584
64 56
0·469
60 53
0·043
118 (74) 42 (26)
49 26
0·192
60 49
0·198
61 38
0·074
24 (15) 136 (85)
57 39
0·365
59 57
0·178
69 51
0·3
148 (93) 12 (7)
44 16
