Bortezomib maintenance after R-CHOP, cytarabine and autologous stem cell transplantation in newly diagnosed patients with mantle cell lymphoma, results of a randomised phase II HOVON trial.

Rituximab-containing induction followed by autologous stem cell transplantation (ASCT) is the standard first-line treatment for young mantle cell lymphoma patients. However, most patients relapse after ASCT. We investigated in a randomised phase II study the outcome of a chemo-immuno regimen and ASCT with or without maintenance therapy with bortezomib. Induction consisted of three cycles R-CHOP (rituximab, cyclophosphamide, doxorubicin, vincristine, prednisone), two cycles high-dose cytarabine, BEAM (carmustine, etoposide, cytarabine, melphalan) and ASCT. Patients responding were randomised between bortezomib maintenance (1·3 mg/m2 intravenously once every 2 weeks, for 2 years) and observation. Of 135 eligible patients, 115 (85%) proceeded to ASCT, 60 (44%) were randomised. With a median follow-up of 77·5 months for patients still alive, 5-year event-free survival (EFS) was 51% (95% CI 42-59%); 5-year overall survival (OS) was 73% (95% CI 65-80%). The median follow-up of randomised patients still alive was 71·5 months. Patients with bortezomib maintenance had a 5-year EFS of 63% (95% CI 44-78%) and 5-year OS of 90% (95% CI 72-97%). The patients randomised to observation had 5-year PFS of 60% (95% CI, 40-75%) and OS of 90% (95% CI 72-97%). In conclusion, in this phase II study we found no indication of a positive effect of bortezomib maintenance after ASCT.

Soluble CD52 is an indicator of disease activity in chronic lymphocytic leukemia.

CD52 is a glycoprotein expressed on normal as well as leukemic immune cells and shed as soluble CD52 (sCD52). We studied sCD52 levels in three CLL cohorts: the 'early', the 'high-risk', and the 'ibrutinib-treated'. The 'high-risk' patients had significantly higher sCD52 levels than the 'early' patients. For the 'early' patients, high sCD52 levels were associated with a significantly shorter time to first treatment. Regarding prognostic factors, no clear correlations with stage, IGHV, or beta-2-microglobulin were found; in a cox multivariate analysis of the 'early' patients, sCD52 and IGHV both had independent prognostic value. Following chemo-immunotherapy, sCD52 decreased in parallel with leukocytes while during ibrutinib treatment and ibrutinib-induced ymphocytosis, sCD52 decreased along with lymph node reductions. In vitro IgM stimulation of CLL cells led to increased sCD52 levels in the medium. Our findings indicate that sCD52 reflects disease activity and potentially treatment efficacy in CLL.

The HOVON68 CLL trial revisited: performance status and comorbidity affect survival in elderly patients with chronic lymphocytic leukemia.

In the HOVON68 CLL trial, patients 65 to 75 years of age had no survival benefit from the addition of low-dose alemtuzumab to fludarabine and cyclophosphamide (FC) in contrast to younger patients. The reasons are explored in this 5-year trial update using both survival analysis and competing risk analysis on non-CLL-related mortality. Elderly FCA patients died more frequently from causes not related to CLL, and more often related to comorbidity (mostly cardiovascular) than to infection. In a Cox multivariate analysis, del(17p), performance status >0, and comorbidity were associated with a higher non-CLL-related mortality in the elderly independent of the treatment modality. Thus, while the 'fit' elderly with no comorbidity or performance status of 0 might potentially benefit from chemo-immunotherapy with FC, caution is warranted, when considering alemtuzumab treatment in elderly patients with cardiovascular comorbidity.

[The BETER survivorship care initiative for Hodgkin lymphoma; tailored survivorship care for late effects of treatment]. / BETER na hodgkinlymfoom; nazorg op maat voor langetermijneffecten van de behandeling.

The Dutch BETER consortium has established a national care infrastructure for Hodgkin lymphoma survivors. 'BETER' [the Dutch word for 'better'] stands for Better care after Hodgkin lymphoma (HL): Evaluation of long-term Treatment Effects and screening Recommendations. The survivorship care focuses on long-term effects of HL treatment. Over 10,000 HL survivors who were treated in the period spanning 1965-2008 have been identified. As part of the survivorship care initiative, specific BETER out-patient clinics have been set up. A dedicated website, www.beternahodgkin.nl, provides HL survivors with relevant information. The stakeholders of the BETER survivorship care programme aim to achieve an improved healthy life expectancy for patients treated for HL.

Impact of cardiovascular counseling and screening in Hodgkin lymphoma survivors.

PURPOSE: Cardiovascular disease (CVD) is the most common nonmalignant cause of death in Hodgkin lymphoma (HL) survivors, especially after mediastinal irradiation. The role of screening for CVD in HL survivors is unclear, but confrontation with risks of CVD may have a negative influence on health-related quality of life (HRQL). As part of a phase 2 screening study using computed tomography angiography (CTA) among HL survivors, an HRQL analysis was done to evaluate the emotional and practical burden and perceived benefits of screening and the effect of CVD-specific counseling on patient satisfaction. METHODS AND MATERIALS: Patients who participated in the screening study also took part in the HRQL study. The impact of undergoing screening was evaluated with a 9-item questionnaire, and impact on HRQL with the European Organization for Research and Treatment of Cancer (EORTC) Quality of Life Core Questionnaire C30, version 3.0. The effect of counseling of CVD on perceived provision of information was evaluated with EORTC INFO-25. All questionnaires were completed at baseline and after screening. RESULTS: Baseline questionnaires were received from 48 participants, and 43 completed questionnaires after screening. Mean age was 47 years, and mean time since diagnosis was 21 years. Of the total, 93% of subjects were content with participating, and 80% did not find the emphasis placed on late effects burdensome, although screening did have a small impact on social functioning and global quality of life. Perceived information on disease, medical tests, and treatment increased significantly after screening (P<.01). Differences were clinically relevant. There were no differences in perceived information between patients with and without screen-detected CVD. CONCLUSIONS: Screening was evaluated favorably, whether CTA showed abnormalities or not. Extensive counseling resulted in substantially increased provision of information and improved information satisfaction. Screening by means of CTA and subsequent cardiac intervention was highly valued, and the benefits were felt to outweigh the emotional and practical burden.

Frontline low-dose alemtuzumab with fludarabine and cyclophosphamide prolongs progression-free survival in high-risk CLL.

The randomized Haemato Oncology Foundation for Adults in The Netherlands 68 phase 3 trial compared front-line chemotherapy with chemotherapy plus the CD52 monoclonal antibody alemtuzumab for high-risk chronic lymphocytic leukemia, defined as at least 1 of the following: unmutated immunoglobulin heavy chain genes, deletion 17p or 11q, or trisomy 12. Fit patients were randomized to receive either 6 28-day cycles of oral FC chemotherapy (days 1 through 3: fludarabine 40 mg/m(2) per day and cyclophosphamide 250 mg/m(2) per day: n = 139) or FC plus subcutaneous alemtuzumab 30 mg day 1 (FCA, n = 133). FCA prolonged the primary end point, progression-free survival (3-year progression-free survival 53 vs 37%, P = .01), but not the secondary end point, overall survival (OS). However, a post hoc analysis showed that FCA increased OS in patients younger than 65 years (3-year OS 85% vs 76%, P = .035). FCA also increased the overall response rate (88 vs 78%, P = .036), and the bone marrow minimal residual disease-negative complete remission rate (64% vs 43%, P = .016). Opportunistic infections were more frequent following FCA, but without an increase in treatment related mortality (FCA: 3.8%, FC: 4.3%). FCA improves progression-free survival in high-risk chronic lymphocytic leukemia. As anticipated, FCA is more immunosuppressive than FC, but with due vigilance, does not lead to a higher treatment-related mortality. This study was registered at www.trialregister.nl as trial no. NTR529.

Pitfalls in the diagnosis of anaplastic large cell lymphoma with a small cell pattern.

Anaplastic large cell lymphoma with a small cell pattern is a rare T-cell lymphoma. This condition is more frequently seen in younger patients and should be considered when patients present with leucocytosis and constitutional symptoms. In this report, we describe our diagnostic work-up for one such case using blood, lymph node, and bone marrow aspirate samples, highlighting the variability of antigen expression seen in different sample types and methodologies. This case shows the importance of having a high index of suspicion and assessing CD30 and anaplastic lymphoma kinase expression in all suspected T-cell neoplasms even though this rare condition is not necessarily expected.

Plasma alemtuzumab levels in patients with chronic lymphocytic leukemia treated with alemtuzumab combined with chemotherapy reflect the efficacy of the treatment: a hypothesis.

In the HOVON68 trial comparing subcutaneous low-dose alemtuzumab (LD-A) used together with fludarabine (F) and cyclophosphamide (C) with FC alone in high-risk chronic lymphocytic leukemia (CLL), LD-AFC resulted in significantly more clinical and molecular responses than FC, but also in more opportunistic infections. In a subgroup analysis of alemtuzumab trough levels during treatment by a sensitive enzyme-linked immunosorbent assay (ELISA) method, detectable levels were found in 4/6 complete and 0/3 partial responders. A relationship between alemtuzumab plasma levels, response and duration of lymphocytopenia was evident. We hypothesize that following combination therapy, the response may not be a function of the alemtuzumab levels, but the opposite, that plasma alemtuzumab levels are a function of the efficacy of the entire treatment, and the fewer leukemic target cells that are remaining, the higher are the levels of plasma alemtuzumab. This concept may well provide a guide for alemtuzumab dosage in future trials.

High resolution melting analysis for detection of BRAF exon 15 mutations in hairy cell leukaemia and other lymphoid malignancies.

The BRAF V600E mutation has recently been described in all cases of hairy cell leukaemia (HCL). We have developed and validated a rapid and sensitive high-resolution melting analysis (HRMA) assay that detects BRAF exon 15 mutations when hairy cells are as low as 5-10% in a sample. All 48 HCL patients were positive for the BRAF V600E mutation, while 114 non-HCL cases were all V600E negative. Interestingly, we detected a novel BRAF D594N mutation in one patient with multiple myeloma. The HRMA assay offers a useful tool to aid the laboratory diagnosis of HCL.

Mixed-phenotype acute leukemia: clinical and laboratory features and outcome in 100 patients defined according to the WHO 2008 classification.

The features of 100 mixed-phenotype acute leukemias (MPALs), fulfilling WHO 2008 criteria, are documented. Myeloid and T-lineage features were demonstrated by cytoplasmic myeloperoxidase and CD3; B-lineage features were demonstrated by at least 2 B-lymphoid markers. There were 62 men and 38 women; 68% were adults. Morphology was consistent with acute lymphoblastic leukemia (ALL; 43%), acute myeloid leukemia (AML; 42%), or inconclusive (15%). Immunophenotyping disclosed B + myeloid (59%), T + myeloid (35%), B + T (4%), or trilineage (2%) combinations. Cytogenetics evidenced t(9;22)/(Ph(+)) (20%), 11q23/MLL rearrangements (8%), complex (32%), aberrant (27%), or normal (13%) karyotypes. There was no correlation between age, morphology, immunophenotype, or cytogenetics. Response to treatment and outcome were available for 67 and 70 patients, respectively; 27 received ALL, 34 AML, 5 a combination of ALL + AML therapy, and 1 imatinib. ALL treatment induced a response in 85%, AML therapy in 41%; 3 of 5 patients responded to the combination therapy. Forty (58%) patients died, 33 of resistant disease. Overall median survival was 18 months and 37% of patients are alive at 5 years. Age, Ph(+), and AML therapy were predictors for poor outcome (P < .001; P = .002; P = .003). MPAL is confirmed to be a poor-risk disease. Adults and Ph(+) patients should be considered for transplantation in first remission.

[Long-term complications following treatment of testicular cancer and Hodgkin lymphoma]. / Langetermijncomplicaties na behandeling voor zaadbalkanker en hodgkinlymfoom.

Patients who were treated in the past with radiotherapy or chemotherapy for testicular cancer or Hodgkin lymphoma are at risk of new malignancies and cardiovascular disease on the long run. Two patient groups who were diagnosed in various hospitals in the Netherlands as having testicular cancer and Hodgkin lymphoma in the period 1965-1995 have survived for a mean period of almost 20 years by now. Both patient groups have higher risks of a new malignancy or cardiovascular disease following radiotherapy and/or chemotherapy than the general population or patients treated without or with less intensive radiotherapy or chemotherapy. As recovery of Hodgkin lymphoma is only achieved by a more intensive treatment approach than the treatment approach for testicular cancer, the risks of a new malignancy or cardiovascular disease are considerably higher among survivors of Hodgkin lymphoma than among survivors of testicular cancer. In both patient groups the long-term risks of new malignancies and cardiovascular disease are still raised in both patient groups up to 25 years after treatment. Because of the relatively high risks of late treatment complications, recommendations for follow-up for survivors of testicular cancer and Hodgkin lymphoma are necessary.

Childhood near-tetraploid acute lymphoblastic leukemia: an EGIL study on 36 cases.

OBJECTIVES: Patients with near-tetraploid (karyotype: 81 - 103 chromosomes) acute lymphoblastic leukemia (NT-ALL) constitute about 1% of childhood ALL and data reported on them are limited and controversial. The aim of the study was to enlarge the knowledge on these rarely occurring ALL. METHODS: The members of the European Group for Immunophenotyping of Leukemias (EGIL) searched retrospectively their databases for NT-ALL patients. RESULTS: We collected data of 36 European children from seven European countries with NT-ALL diagnosed since 1992. All patients reached complete remission (CR) after induction chemotherapy. Their blasts were negative for peroxidase and BCR-ABL1. Ten children were diagnosed as T-cell ALL (T-ALL) EGIL categories (T-I n=2, T-II n=2, T-III n=3, T-IV n=3) and four displayed various structural chromosomal abnormalities. Eight of 10 T-ALL remained in 1st CR; one died in CR from sepsis and one is alive in 2nd CR. Median survival was 88 (7-213) months. B-cell precursor (BCP) ALL was diagnosed in 26 children. Thirteen were positive for ETV6-RUNX1 and are alive in 1st CR for 32-147 months. Ten children were ETV6-RUNX1 negative and remained in 1st CR for 16-163 months. One girl with hypodiploid and NT metaphases and ETV6-RUNX1-negative BCP-ALL and one of two boys with NT-BCP-ALL not examined for ETV6-RUNX1 died of infection after stem cell transplantation in 2nd/3rd CR. Secondary myelodysplastic syndrome developed in two patients with NT-BCP-ALL. CONCLUSIONS: Our data demonstrate immunophenotypic, cytogenetic, and molecular heterogeneity of NT-ALL and favorable prognosis of most NT-ALL across different immunophenotypic and/or genetic ALL subtypes.