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
MCL
2 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 event‐free 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.
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BFBNIB, FZAB, GIS, IJS, KILJ, NLZOH, NUK, OILJ, SBCE, SBMB, UL, UM, UPUK
Autologous stem cell transplantation (ASCT) leads to induction of molecular remission in mantle cell lymphoma (MCL). A large proportion of the patients, however, relapse after ASCT. Increasing levels ...of minimal residual disease (MRD) in consecutive BM samples after ASCT have been observed prior to relapse by us and others, whereas patients in continuous clinical remission have remaining low levels of MRD. In the present 2nd Nordic MCL Phase 2 trial we aimed to direct preemptive treatment to patients in clinical remission but with increasing levels of MRD at high risk of relapse after ASCT. We used a combined standard nested and quantitative real-time PCR analysis to estimate MRD levels (Andersen et al, 2002, Exp. Hematol). According to the protocol consecutive BM and PB samples were procured and shipped for central PCR analysis every 3–4 months post-transplant. Preemptive therapy consisted of four weekly doses 375 mg/m2 of Rituximab. Of the 161 MCL cases included in the trial 81 cases underwent ASCT and had PCR markers available. CR-rate after ASCT was 92%. In total 852 post-transplant BM/PB samples were monitored for MRD. 47 of 81 (58%) cases remained standard nested PCR negative after ASCT for a median follow-up time of 2.7 years (range: 0.14–5.7 years). In 4 (8%) of these a clinical relapse was observed without any PCR detectable MRD present in BM or PB after ASCT, including at time of clinical relapse. In 34 (42%) of 81 cases standard nested PCR was positive at least once after ASCT. The majority of the PCR positive cases (26/34 cases, 76%) converted from standard nested PCR negative to positive during post-transplant follow-up, thus, these cases relapsed molecularly. 8 (24%) of 34 cases remained standard nested PCR positive after ASCT. In these, a rising level of MRD was detected by real-time PCR analysis in 4 cases. The remaining 4 cases either had stable low or declining levels of MRD. Of the 30 cases which relapsed molecularly 8 cases simultaneously underwent a clinical relapse leaving no therapeutical window for preemptive treatment. One case refused preemptive treatment. All molecular relapse occurred within 3 years after ASCT, except in 1 case. In total 21 cases have received preemptive treatment. 19/21 (90%) cases became standard nested PCR negative (18 cases) or reduced to low MRD level (1 case). 2/21 cases remained PCR positive and relapsed after 3 and 6 months, respectively. 16/21 cases remain in clinical CR for a median follow-up time of 1.4 years after preemptive treatment (range: 0.25 to 3.8 years) and 5/21 cases have relapsed. Of the latter cases the 3 of the 5 became PCR negative for 6–9 months before relapse. Of note, two cases have received preemptive treatment twice after a second molecular relapse after which they again became PCR negative. Preemptive treatment has not been reported in lymphoma before. Our results in MCL suggest that the large number of cases who remain in molecular remission after intensified ASCT may be followed by MRD monitoring and treated at molecular relapse instead of receiving maintenance therapy. However, 4 of these cases relapsed. Here, more than PCR methods are needed for early stage disease detection. Our results indicate that preemptive treatment using Rituximab can successfully reinduce molecular remission and prolong time to relapse. Finally, more patients may have PCR markers available by applying frozen diagnostic lymph node material.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
We have recently identified and cloned a novel disease specific gene CLLU1, with a strong prognostic significance in a small test cohort of CLL patients (ASH 2004, #770). To validate this finding in ...a larger series, 176 newly diagnosed, previously untreated CLL patients referred to Rigshospitalet, Copenhagen in 1991–1999, were investigated. Clinical characteristics of the population were: 116 stage A patients (66 %), median age 69.9 years, 98 males (56%), median follow up 59 months. The end points for the statistical analysis were overall survival and time to initiation of treatment. At time of analysis 91 (52%) patients had died and 104 (59%) had commenced treatment. Frozen patient samples, taken at time of diagnosis, were investigated for CLLU1 expression, as well as for mutational status, CD38 expression, ZAP-70 expression and cytogenetic aberrations. CLLU1 expression was assayed by QRT-PCR using the cDNA1 splice variant, and expressed as fold upregulation above the CLLU1 level in normal B-cells. CD38 and ZAP-70 analysis was performed by flow cytometry, using a 20 % cut-off level. Cytogenetic analysis was performed by FISH. The previously reported (ASH 2004, #770) median upregulation of CLLU1 in CLL cells was accurately reproduced and confirmed (25.5-fold (N = 176) vs. 27.7-fold (N = 59) in test population). Also in accordance with the pilot study, segregation of the patients based on the median CLLU1 expression level divided the population in two groups with significantly different times to initiation of treatment and borderline significant difference in overall survival. However, further analysis found an optimal cut-off level at 40-fold upregulation of CLLU1 expression; use of this cut-off demonstrated a highly significant difference in overall survival for patients with upregulated expression of CLLU1 (p = 0.0023). The median overall survival was 60.2 months for patients with CLLU1 expression above 40-fold compared to 100.8 months for the group with lower expression level. Likewise the time to initiation of first treatment was significantly shorter in the high-level expression group (p = 0.0018, median time to first treatment 9.3 months vs. 54.9 months). Furthermore, CLLU1 expression was upregulated in all poor prognostic subgroups investigated: Binet stage B or C, IgVH unmutated, unfavorable cytogenetics, high CD38 expression and high ZAP-70 expression. Our new study confirms that CLLU1 is a strong prognostic factor in CLL, comparable to other established prognostic markers. The exclusive upregulation of CLLU1 expression in CLL suggests a putative role for CLLU1 in the pathogenesis of CLL, and makes this gene a strong candidate for future gene-targeted treatment strategies.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
One of the best predictors of poor outcome in CLL is the absence of somatic hypermutations in the Ig-genes of the leukemic cells. This prognostic dichotomy, between cases of mutated and unmutated ...CLL, enabled us to screen for a gene associated with poor outcome CLL using differential display RT-PCR. We identified a novel transcript from chromosome 12q22, which by RT-PCR and Northern blotting seemed to be selectively over-expressed in CLL patients with poor prognosis. No matching genes or ESTs were annotated in the region, but screening of a cDNA library from unmutated CLL patients resulted in cloning of 7 cDNAs, which probably derived from alternative splicing of a common transcript. The majority of the transcripts had no significant reading frames, but one splice variant may encode a protein of 121 amino acids. Despite very low primary sequence similarity, structure modelling revealed that the peptide potentially can fold into a structure remarkably similar to human IL-4. By RT-PCR the various transcripts were undetectable in a panel of normal tissues and cell lines. Using quantitative RT-PCR (QRT-PCR), we could however detect minute amounts of the mRNAs in normal B-cells; the level was similar or slightly higher in good prognosis patients and much higher in poor prognosis patients. The expression level of the two major mRNAs was 24–50 fold higher in patients with unmutated Ig-genes compared to patients with somatic hypermutation (p<0.0001), and 20–30 fold higher in ZAP-70 positive patients compared to ZAP-70 negative patients (p<0.0001). The median time to treatment for patients with overexpression of the mRNAs (n=26) was 11 months compared to 104 months for patients with normal expression (n=31) (p=0.0005). The median overall survival for patients with overexpression was 97 months while patients with low expression had not reached a median overall survival at their last follow up (p=0.03). This prognostic power was comparable to that provided by mutational status, and stronger than that provided by ZAP-70 or CD38 expression. Finally, in 56 patients the gene dosage as defined in QRT-PCR was inversely proportional with time to treatment (p= 0.006). This novel gene therefore has several features that make it a candidate to be the first disease specific gene identified in CLL.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
Mantle cell lymphoma (MCL) is considered incurable, with a median survival of 4 years. Intensive immunochemotherapy and autologous stem-cell (ASC) support has appeared promising in small patient ...cohorts, but has not been tested in large, consecutive series. Here we report the final results of the 2nd Nordic MCL (MCL2) trial after a median of 3 years follow-up from study entry.
Methods: This unrandomized phase-II trial included 159 untreated patients younger than 66 years, 84% stage IV, 128 with classical, 31 with blastoid/pleomorphic cytology. Following 6 cycles of intensive induction immunochemotherapy with alternating cycles of rituximab (R) + maxi-CHOP and R+ high-dose AraC, responders received BEAM/BEAC with in-vivo purged (R) ASC support.
Results: 153 patients (96%) responded to induction therapy with CR in 55% and PR in 41%. The 5-year event-free (EFS) and overall survival (OAS) are 63% and 74% respectively on intention-to-treat, and the 144 (91%) responders who completed treatment had 72% 5-year response duration, with plateaus emerging in all three curves at these levels.
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There were 6 treatment-related deaths (3,8%). Of 77 patients with available primers, 90% had become PCR-negative two months posttransplant; those who remained PCR-negative more than 1 year posttransplant had a significantly longer clinical response duration than patients who did not (P<0.0001). Of 42 stem-cell products assessed 88% were PCR-negative as compared to only 12% in the MCL1 study (P<0.001). In a multivariate analysis including age, sex, international prognostic index (IPI), cytological variants and Ki-67 proliferation index, only IPI and Ki-67 were independent predictors of EFS and response duration respectively, and only IPI and cytological variant of OAS. Compared to the 41 patients of 1st Nordic MCL study who received 4 cycles of maxi-CHOP without rituximab before BEAM or BEAC + ASCT (1), the OAS, EFS and response duration were highly significantly increased.
Conclusion: The demonstration of long-term event-free survival in a large, consecutive prospective series now for the first time indicates that intensive immunochemotherapy including AraC and Rituximab with in-vivo purged stem-cell support may cure mantle cell lymphoma.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
The 2nd. Nordic Lymphoma Group mantle cell lymphoma (MCL2) protocol has demonstrated the importance of Ara-C and Rituximab in the induction chemotherapy and stem-cell mobilisation before high-dose ...therapy and autologous stem-cell transplant (1). By July 2005, 128 patients (83% stage IV) had completed protocol treatment consisting of 3 series of R-CHOP and 3 series of R-Ara-C, stem-cell harvest and high-dose therapy with BEAM/BEAC with ASCT. The 5-year failure-free and overall survival is 50% and 83% respectively, significantly higher than the historic control group of the Nordic MCL1 protocol with the same treatment without HD-Ara-C and Rituximab (P<0.0001). Patients with a molecular marker (t(11;14) or clonal IgH rearrangement) identified at the time of diagnosis in bone marrow and blood, undergo regular molecular follow-up posttransplant,. Patients who turn PCR-positive or increase their qPCR signal, without clinical disease, are offered preemptive treatment with Rituximab 375 mg/m2 Wx4.
Of 75 patients with molecular markers who had completed treatment, 55 remain PCR-negative and 20 have become/remained PCR-pos. posttransplant. Clinical relapse ocurred significantly more often in the latter group (11 of 20) than in the PCR-neg. patients (4 of 55) (P<0.0001) (Fig.1).
Ten of the 20 PCR-positive patient did not receive preemptive rituximab: five due to immediate clinical relapse, 2 due to stable qPCR signals, one due to protocol error and two await treatment. Of 10 patients who did receive preemptive rituximab 8 again became PCR-negative and 2 remain PCR-positive. Six of the 10 Rituximab treated patients remain in clinical and molecular remission 200–600 days after the Rituximab treatment (Fig. 2).
Conclusions:
In MCL, molecular relapse is a harbinger of imminent clinical relapse, whereas continuous molecular remission is associated with prolonged disease-free survival (89% at 4 years)
Rituximab preemptive treatment can reinduce molecular remission and may delay clinical relapse. Following molecular relapse, only Rituximab treated patients (6 of 8 evaluable) remain disease-free.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
Methods: In the Nordic Lymphoma Group MCL Project newly diagnosed stage II-IV MCL patients < 66 years receive induction treatment and peripheral-blood stem-cell (PBSC) harvest, followed by BEAM/BEAC ...with PBSC support. In the MCL1 Protocol, the induction was maxi-CHOP x 3 (CTX 1200 mg/m2, doxorubicin 75 mg/m2, VCR 2mg D1, prednisolone 100 mg D1-5). Stem-cells were mobilised by maxi-CHOP + G-CSF. Because of the high failure rate in MCL1 (Figure 1) the MCL2 protocol was activated adding 2 series of high-dose Ara-C (3g/m2 BID D1-2) and 2 standard doses of rituximab (R) (375 mg/m2) to the induction program. Stem cells were mobilised by Ara-C + G-CSF + rituximab D1 + D9 for in-vivo purging. In both protocols patient-specific molecular markers were sought established before treatment start, and stem-cells and follow-up blood and bone-marrow samples assessed for MCL by PCR or flow cytometry.
Results: Table 1
Compared Results of the Nordic Lymphoma Group MCL1 and MCL2 Protocols
NORDIC MCL PROTOCOL #MCL1 (1997–2000)MCL2 (2000-)P valueNo. of Pts included/eval. for response42/42120/88Response pretransplant31/4286/880.002CR/resp pretransplant11/3151/860.04No. transplanted2786Eval. for response posttransplant2782CR/Response posttransplant25/2776/82NSMolecular response posttransplant5/1338/420.0003PCR-neg. stem-cell products (of tested)2/1622/250.000053-year failure-free survival (104 pts eval.)24%68%0.00013-year relapse-free survival (RFS)45%76%0.043-year molecular RFS survivalND67%3-year overall survival60%85%0.02Supported by the Nordic Cancer Union
Posttransplant maintenance treatment: In MCL2, patients in clinical stable response but molecular relapse are offered R 4 std. doses. So far, isolated molecular relapse occurred in 11 pts. of whom 10 received R: Four became PCR neg., one did not respond and later relapsed, five are not yet evaluable. Conclusion: By comparing MCL1 results with preliminary results of the still ongoing MCL2 study we conclude that the addition of HD Ara-C and R to the induction treatment significantly increases the
• clinical response rate pretransplant
• molecular response rate
• No. of tumor-cell free grafts
• failure-free, relapse-free and overall survival
Rituximab maintenance treatment can induce 2nd molecular remission, the clinical significance hereof still unknown.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
The uncoupling protein 1 (UCP1) is a hallmark of brown adipocytes and pivotal for cold- and diet-induced thermogenesis.
Here we report that cyclooxygenase (COX) activity and prostaglandin E(2) ...(PGE(2)) are crucially involved in induction of UCP1 expression in inguinal white adipocytes, but not in classic interscapular brown adipocytes. Cold-induced expression of UCP1 in inguinal white adipocytes was repressed in COX2 knockout (KO) mice and by administration of the COX inhibitor indomethacin in wild-type mice. Indomethacin repressed beta-adrenergic induction of UCP1 expression in primary inguinal adipocytes. The use of PGE(2) receptor antagonists implicated EP(4) as a main PGE(2) receptor, and injection of the stable PGE(2) analog (EP(3/4) agonist) 16,16 dm PGE(2) induced UCP1 expression in inguinal white adipose tissue. Inhibition of COX activity attenuated diet-induced UCP1 expression and increased energy efficiency and adipose tissue mass in obesity-resistant mice kept at thermoneutrality.
Our findings provide evidence that induction of UCP1 expression in white adipose tissue, but not in classic interscapular brown adipose tissue is dependent on cyclooxygenase activity. Our results indicate that cyclooxygenase-dependent induction of UCP1 expression in white adipose tissues is important for diet-induced thermogenesis providing support for a surprising role of COX activity in the control of energy balance and obesity development.
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DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Even though supplemental oxygen is used for the treatment of patients with hypoxemic respiratory failure, the most effective oxygenation targets are not known. In this randomized trial, a lower ...oxygenation target did not result in lower mortality than a higher target.
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