Erkki Elonen

Prognostic Subgroups in B-Cell Chronic Lymphocytic Leukemia Defined by Specific Chromosomal Abnormalities

BACKGROUND AND METHODS Specific chromosomal abnormalities have been shown to affect the overall survival of patients with acute leukemia, but the possibility that specific chromosomal defects may influence the course of B-cell chronic lymphocytic leukemia (CLL) is controversial. We assessed this possibility as follows: blood mononuclear cells from 433 patients with B-cell CLL in five European centers were cultured with B-cell mitogens, and banded metaphases were studied. RESULTS Three hundred ninety-one patients could be evaluated cytogenetically, and 218 had clonal chromosomal changes. The most common abnormalities were trisomy 12 (n = 67) and structural abnormalities of chromosome 13 (n = 51; most involving the site of the retinoblastoma gene) and of chromosome 14 (n = 41). Patients with a normal karyotype had a median overall survival of more than 15 years, in contrast to 7.7 years for patients with clonal changes. Patients with single abnormalities (n = 113) did better than those with complex karyotypes (P less than 0.001). Patients with abnormalities involving chromosome 14q had poorer survival than those with aberrations of chromosome 13q (P less than 0.05). Among patients with single abnormalities, those with trisomy 12 alone had poorer survival than patients with single aberrations of chromosome 13q (P = 0.01); the latter had the same survival as those with a normal karyotype. A high percentage of cells in metaphase with chromosomal abnormalities, indicating highly proliferative leukemic cells, was associated with poor survival (P less than 0.001). Cox proportional-hazards analysis identified age, sex, the percentage of cells in metaphase with chromosomal abnormalities, and the clinical stage of the disease (Binet classification system) as independent prognostic variables. CONCLUSIONS Chromosomal analysis provides prognostic information about overall survival in addition to that supplied by clinical data in patients with B-cell CLL.

Long-term progression-free survival of mantle cell lymphoma after intensive front-line immunochemotherapy with in vivo–purged stem cell rescue: a nonrandomized phase 2 multicenter study by the Nordic Lymphoma Group

Mantle cell lymphoma (MCL) is considered incurable. Intensive immunochemotherapy with stem cell support has not been tested in large, prospective series. In the 2nd Nordic MCL trial, we treated 160 consecutive, untreated patients younger than 66 years in a phase 2 protocol with dose-intensified induction immunochemotherapy with rituximab (R) + cyclophosphamide, vincristine, doxorubicin, prednisone (maxi-CHOP), alternating with R + high-dose cytarabine. Responders received high-dose chemotherapy with BEAM or BEAC (carmustine, etoposide, cytarabine, and melphalan/cyclophosphamide) with R-in vivo purged autologous stem cell support. Overall and complete response was achieved in 96% and 54%, respectively. The 6-year overall, event-free, and progression-free survival were 70%, 56%, and 66%, respectively, with no relapses occurring after 5 years. Multivariate analysis showed Ki-67 to be the sole independent predictor of event-free survival. The nonrelapse mortality was 5%. The majority of stem cell products and patients assessed with polymerase chain reaction (PCR) after transplantation were negative. Compared with our historical control, the Nordic MCL-1 trial, the event-free, overall, and progression-free survival, the duration of molecular remission, and the proportion of PCR-negative stem cell products were significantly increased (P < .001). Intensive immunochemotherapy with in vivo purged stem cell support can lead to long-term progression-free survival of MCL and perhaps cure. Registered at www.isrctn.org as #ISRCTN 87866680.

Dasatinib crosses the blood-brain barrier and is an efficient therapy for central nervous system Philadelphia chromosome–positive leukemia

Although imatinib, a BCR-ABL tyrosine kinase inhibitor, is used to treat acute Philadelphia chromosome-positive (Ph(+)) leukemia, it does not prevent central nervous system (CNS) relapses resulting from poor drug penetration through the blood-brain barrier. Imatinib and dasa-tinib (a dual-specific SRC/BCR-ABL kinase inhibitor) were compared in a preclinical mouse model of intracranial Ph(+) leukemia. Clinical dasatinib treatment in patients with CNS Ph(+) leukemia was assessed. In preclinical studies, dasatinib increased survival, whereas imatinib failed to inhibit intracranial tumor growth. Stabilization and regression of CNS disease were achieved with continued dasa-tinib administration. The drug also demonstrated substantial activity in 11 adult and pediatric patients with CNS Ph(+) leukemia. Eleven evaluable patients had clinically significant, long-lasting responses, which were complete in 7 patients. In 3 additional patients, isolated CNS relapse occurred during dasatinib therapy; and in 2 of them, it was caused by expansion of a BCR-ABL-mutated dasatinib-resistant clone, implying selection pressure exerted by the compound in the CNS. Dasatinib has promising therapeutic potential in managing intracranial leukemic disease and substantial clinical activity in patients who experience CNS relapse while on imatinib therapy. This study is registered at ClinicalTrials.gov as CA180006 (#NCT00108719) and CA180015 (#NCT00110097).

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

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 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.

Gain of 3q and deletion of 11q22 are frequent aberrations in mantle cell lymphoma

We used comparative genomic hybridization (CGH) to screen for DNA copy number changes in 34 specimens from 27 cases of mantle cell lymphoma (MCL). The most common gains were detected at 3q (52%), 8q (30%), and 15q (26%), whereas the most frequent losses involved 13q (41%), 1p (33%), 6q (30%), 9p (30%), and 11q (30%). The gain of 3q, with a minimal common region at 3q26.1‐27, appeared in more than half of the lymphomas, suggesting the location of an important oncogene here. A common deleted region at 11q22 was found in one‐third of the patients, which suggests that this region may harbor a tumor suppressor gene important in the tumorigenesis of MCL. The mean number of changes was higher in more aggressive blastoid variants of MCL than in lymphomas with typical morphology. Our results show that the chromosomal regions affected in MCL are highly consistent and are different from those seen in other types of non‐Hodgkins lymphoma. Genes Chromosomes Cancer 21:298–307, 1998.

The Mantle Cell Lymphoma International Prognostic Index (MIPI) is superior to the International Prognostic Index (IPI) in predicting survival following intensive first-line immunochemotherapy and autologous stem cell transplantation (ASCT)

Mantle cell lymphoma (MCL) has a heterogeneous clinical course. The recently proposed Mantle Cell Lymphoma International Prognostic Index (MIPI) predicted the survival of MCL better than the International Prognostic Index in MCL patients treated with conventional chemotherapy, but its validity in MCL treated with more intensive immunochemotherapy has been questioned. Applied here to 158 patients of the Nordic MCL2 trial of first-line intensive immunochemotherapy followed by high-dose chemotherapy and autologous stem cell transplantation, the MIPI and the simplified MIPI (s-MIPI) predicted survival significantly better (P < .001) than the International Prognostic Index (P > .004). Both the MIPI and the s-MIPI mainly identified 2 risk groups, low and intermediate versus high risk, with the more easily applied s-MIPI being just as powerful as the MIPI. The MIPI(B) (biological), incorporating Ki-67 expression, identified almost half of the patients as high risk. We suggest that also a simplified MIPI(B) is feasible.

Ki-67 expression level, histological subtype, and the International Prognostic Index as outcome predictors in mantle cell lymphoma

Abstract: Objectives : Mantle cell lymphoma (MCL) is characterised by translocation t(11;14) (q13;q32) leading to rearrangement of bcl1/CCND1 and overexpression of the cell‐cycle regulatory protein cyclin D1. We assessed the significance of the cell proliferation rate as an outcome predictor with the five components of the International Prognostic Index (IPI) and the histological subtypes of MCL. Patients and methods : The hospital case records and histopathological material of 127 patients diagnosed with MCL in a single centre were reviewed. The cell proliferation rate was assessed by Ki‐67 immunostaining and mitosis counting. Coxs multivariate regression model was used in multivariate survival analyses. The median follow‐up time was 87 months. Results : The mantle zone/nodular subtype of the common variant (19%) was associated with median survival of 70 months, the diffuse subtype of the common variant (64%) of 35 months, and the blastoid subtype (17%) of 11 months ( P  < 0.001). Patients with Ki‐67 expression in ≥ 26% (the upper tertile) of the lymphoma cells had median survival of only 13 months as compared with 45 months in the rest of the patients ( P  < 0.001). In a multivariate analysis high Ki‐67 expression, Ann Arbor stage III–IV, and age over 60 yr had independent influence on survival, whereas serum lactate dehydrogenase level, the number of extranodal disease sites, and performance status did not. Conclusions : The IPI may not be an optimal tool for outcome prediction in MCL, and a better prognostic index may be obtained by including Ki‐67 expression and possibly the histological subtype in the index.

Pre-Emptive Treatment With Rituximab of Molecular Relapse After Autologous Stem Cell Transplantation in Mantle Cell Lymphoma

PURPOSE Minimal residual disease (MRD) is predictive of clinical progression in mantle-cell lymphoma (MCL). According to the Nordic MCL-2 protocol we prospectively analyzed the efficacy of pre-emptive treatment using rituximab to MCL patients in molecular relapse after autologous stem cell transplantation (ASCT). PATIENTS AND MATERIALS MCL patients enrolled onto the study, who had polymerase chain reaction (PCR) detectable molecular markers and underwent ASCT, were followed with serial PCR assessments of MRD in consecutive bone marrow and peripheral blood samples after ASCT. In case of molecular relapse with increasing MRD levels, patients were offered pre-emptive treatment with rituximab 375 mg/m(2) weekly for 4 weeks. RESULTS Of 160 MCL patients enrolled, 145 underwent ASCT, of whom 78 had a molecular marker. Of these, 74 were in complete remission (CR) and four had progressive disease after ASCT. Of the CR patients, 36 underwent a molecular relapse up to 6 years (mean, 18.5 months) after ASCT. Ten patients did not receive pre-emptive treatment mainly due to a simultaneous molecular and clinical relapse, while 26 patients underwent pre-emptive treatment leading to reinduction of molecular remission in 92%. Median molecular and clinical relapse-free survival after pre-emptive treatment were 1.5 and 3.7 years, respectively. Of the 38 patients who remain in molecular remission for now for a median of 3.3 years (range, 0.4 to 6.6 years), 33 are still in clinical CR. CONCLUSION Molecular relapse may occur many years after ASCT in MCL, and PCR based pre-emptive treatment using rituximab is feasible, reinduce molecular remission, and may prevent clinical relapse.

Trisomy 12 in B cells of patients with B-cell chronic lymphocytic leukemia.

Trisomy 12 is the most frequently reported chromosome abnormality in patients with B-cell chronic lymphocytic leukemia, but only normal karyotypes are found in one third of patients with that disorder. Moreover, samples from patients with trisomy 12 also have many normal metaphases. To identify immunologically the cells in which both the trisomy 12 and the normal karyotypes occur, we studied two patients with B-cell chronic lymphocytic leukemia--one whose neoplastic cells demonstrated lambda light-chain clonality and one whose cells had kappa light-chain clonality. We used a recently developed cytogenetic method that allows simultaneous analysis of cell morphology, immunologic phenotype, and karyotype in the same mitotic cell. In cultures of blood cells stimulated with pokeweed mitogen and tetradecanoylphorbol acetate, all the mitotic cells with either the lambda or the kappa immunoglobulin had trisomy 12, whereas all the cells that lacked these light chains or that had T-cell markers (OKT8 or OKT4) had normal karyotypes. These results show that trisomy 12 in B-cell chronic lymphocytic leukemia occurs in the neoplastic B cells, but not in the T cells, and they thus provide an explanation for the common finding of mitoses with normal karyotypes in patients with B-cell chronic lymphocytic leukemia.

Cytogenetic findings and survival in b-cell chronic lymphocytic leukemia. Second IWCCLL compilation of data on 662 patients

Chromosome analysis on CLL-cells from 649 patients revealed clonal changes in 311 cases (48%). The most common abnormalities were trisomy 12 (n = 112), and structural changes on the long arm of chromosome 13 (n = 62), most of them interstitial deletions or translocations involving 13q14, the site of the retinoblastoma gene. Complex karyotypes were associated with poor prognosis, although karyotypic changes rarely develop during the course of the disease. Among patients with single chromosomal abnormalities those with trisomy 12 had a poor survival, whereas those with structural changes on chromosome 13 had as good a prognosis as patients with a normal karyotype.