Outi Kuittinen

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.

Up-Front Autologous Stem-Cell Transplantation in Peripheral T-Cell Lymphoma: NLG-T-01

PURPOSE Systemic peripheral T-cell lymphomas (PTCLs) respond poorly to conventional therapy. To evaluate the efficacy of a dose-dense approach consolidated by up-front high-dose chemotherapy (HDT) and autologous stem-cell transplantation (ASCT) in PTCL, the Nordic Lymphoma Group (NLG) conducted a large prospective phase II study in untreated systemic PTCL. This is the final report, with a 5-year median follow-up, of the NLG-T-01 study. PATIENTS AND METHODS Treatment-naive patients with PTCL age 18 to 67 years (median, 57 years) were included. Anaplastic lymphoma kinase (ALK) -positive anaplastic large-cell lymphoma (ALCL) was excluded. An induction regimen of six cycles of biweekly CHOEP (cyclophosphamide, doxorubicin, vincristine, etoposide, and prednisone) was administered (in patients age > 60 years, etoposide was omitted). If in complete or partial remission, patients proceeded to consolidation with HDT/ASCT. RESULTS Of 166 enrolled patients, 160 had histopathologically confirmed PTCL. The majority presented with advanced-stage disease, B symptoms, and elevated serum lactate dehydrogenase. A total of 115 underwent HDT/ASCT, with 90 in complete remission at 3 months post-transplantation. Early failures occurred in 26%. Treatment-related mortality was 4%. At 60.5 months of median follow-up, 83 patients were alive. Consolidated 5-year overall and progression-free survival (PFS) were 51% (95% CI, 43% to 59%) and 44% (95% CI, 36% to 52%), respectively. Best results were obtained in ALK-negative ALCL. CONCLUSION Dose-dense induction followed by HDT/ASCT was well tolerated and led to long-term PFS in 44% of treatment-naive patients with PTCL. This represents an encouraging outcome, particularly considering the high median age and adverse risk profile of the study population. Therefore, dose-dense induction and HDT/ASCT are a rational up-front strategy in transplantation-eligible patients with PTCL.

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.

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.

Neurolymphomatosis: an International Primary CNS Lymphoma Collaborative Group report.

Neurolymphomatosis (NL) is a rare clinical entity. The International Primary CNS Lymphoma Collaborative Group retrospectively analyzed 50 patients assembled from 12 centers in 5 countries over a 16-year period. NL was related to non-Hodgkin lymphoma in 90% and to acute leukemia in 10%. It occurred as the initial manifestation of malignancy in 26% of cases. The affected neural structures included peripheral nerves (60%), spinal nerve roots (48%), cranial nerves (46%), and plexus (40%) with multiple site involvement in 58%. Imaging studies often suggested the diagnosis with 77% positive magnetic resonance imaging, and 84% (16 of 19) positive computed tomography-positron emission tomography studies. Cerebrospinal fluid cytology was positive in 40%, and nerve biopsy confirmed the diagnosis in 23 of 26 (88%). Treatment in 47 patients included systemic chemotherapy (70%), intra-cerebrospinal fluid chemotherapy (49%), and radiotherapy (34%). Response to treatment was observed in 46%. The median overall survival was 10 months, with 12- and 36-month survival proportions of 46% and 24%, respectively. NL is a challenging diagnosis, but contemporary imaging techniques frequently detect the relevant neural invasion. An aggressive multimodality therapy can prevent neurologic deterioration and is associated with a prolonged survival in a subset of patients.

Primary treatment with autologous stem cell transplantation in mantle cell lymphoma: outcome related to remission pretransplant

Objectives: The aim of the first Nordic mantle cell lymphoma (MCL) protocol was to study the clinical significance of an augmented CHOP induction chemotherapy followed by high‐dose chemotherapy and autologous stem cell transplantation (ASCT) and to examine the prognostic significance of stem cell contamination rates in newly diagnosed patients with MCL.

Invasive fungal infections in autologous stem cell transplant recipients: a nation-wide study of 1188 transplanted patients

Abstract:  Based on small single‐centre series, the risk of invasive fungal infections (IFI) has been considered small in autologous stem cell transplant (ASCT) recipients. Purpose: To analyse epidemiological and clinical features of (IFI) among ASCT recipients in Finland 1990–2001. Patients: During the study period, 1188 adult patients received high‐dose therapy supported by ASCT in six centres. Altogether, 1112 patients (94%) received blood progenitor cells. The graft was CD34+ selected in 261 patients (22%). The major diagnostic groups were non‐Hodgkins lymphoma (n = 417), multiple myeloma (n = 395), breast cancer (n = 132) and Hodgkins lymphoma (n = 53). Results: Eighteen patients (1.5%) with IFI were identified. The incidence of proven or probable invasive aspergillosis was 0.8%, followed by candidaemia with an incidence of 0.3%. The median time to the diagnosis of IFI was 35 d (6–162) from the progenitor cell infusion. In fourteen patients (78%) IFI was diagnosed during lifetime and they were treated with antifungal therapy for a median of 50 d. Nine patients (64%) were cured. Conclusions: IFI appears to be a rare event after ASCT and Aspergillus infections seem to be predominant. These epidemiological features have an impact in planning prophylactic and empirical antifungal strategies in ASCT recipients.

Early treatment-related mortality in adult autologous stem cell transplant recipients: a nation-wide survey of 1482 transplanted patients.

Abstract:  Objectives: To evaluate early (<100 d) treatment‐related mortality (TRM) in autologous stem cell transplant (ASCT) recipients. Patients: Altogether 1482 adult patients received ASCT in six Finnish centres 1990–2003. The most common diagnoses were non‐Hodgkins lymphoma (NHL) (n = 542), multiple myeloma (MM) (n = 528), breast cancer (BC) (n = 132), Hodgkins lymphoma (n = 86) and chronic lymphocytic leukaemia (CLL) (n = 63). Results: Forty‐two patients (2.8%) died from treatment‐related reasons <100 d from ASCT. The median time to death was 38 d from ASCT (0–99). The risk of TRM varied according to the diagnoses. The highest risk was observed in patients with AL amyloidosis (24%) followed by NHL (4.4%) and MM (1.9%). No early TRM was observed in patients transplanted for BC or CLL. Infections were the cause of death in 16 patients (fungal 7, bacterial 6, viral 3). Organ toxicity was responsible for early death in 26 patients (heart 9, lungs 7, other 10). Conclusions: This nation‐wide survey indicated a low early TRM in ASCT recipients in general, but higher risks in patients with AL amyloidosis or NHL. In addition to patient selection, also optimization of transplant procedure may be needed in these patient groups to reduce early TRM.

15-year follow-up of the Second Nordic Mantle Cell Lymphoma trial (MCL2) : Prolonged remissions without survival plateau

In recent decades, the prognosis of Mantle Cell Lymphoma (MCL) has been significantly improved by intensified first‐line regimens containing cytarabine, rituximab and consolidation with high‐dose‐therapy and autologous stem cell transplantation. One such strategy is the Nordic MCL2 regimen, developed by the Nordic Lymphoma Group. We here present the 15‐year updated results of the Nordic MCL2 study after a median follow‐up of 11·4 years: For all patients on an intent‐to‐treat basis, the median overall and progression‐free survival was 12·7 and 8·5 years, respectively. The MCL International Prognostic Index (MIPI), biological MIPI, including Ki67 expression (MIPI‐B) and the MIPI‐B including mIR‐18b expression (MIPI‐B‐miR), in particular, significantly divided patients into distinct risk groups. Despite very long response durations of the low and intermediate risk groups, we observed a continuous pattern of relapse and the survival curves never reached a plateau. In conclusion, despite half of the patients being still alive and 40% in first remission after more than 12 years, we still see an excess disease‐related mortality, even among patients experiencing long remissions. Even though we consider the Nordic regimen as a very good choice of regimen, we recommend inclusion in prospective studies to explore the benefit of novel agents in the frontline treatment of MCL.

Late non‐relapse mortality among adult autologous stem cell transplant recipients: a nation‐wide analysis of 1482 patients transplanted in 1990–2003

Introduction:  Data on the incidence and causes of late (>100 d) non‐relapse mortality (NRM) in autologous stem cell transplant (ASCT) recipients is limited.