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Contains fulltext : 225496.pdf (Publisher’s version ) (Open Access) 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/m(2) 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.

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.

Contains fulltext : 208562.pdf (Publisher’s version ) (Closed access)

PurposeCardiovascular 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 MaterialsPatients 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.ResultsBaseline 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 (PConclusionsScreening 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.

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.

Purpose In 2006, we published the results of the European Organisation for Research and Treatment of Cancer phase III trial EORTC 20981 on the role of rituximab in remission induction and maintenance treatment of relapsed/resistant follicular lymphoma (FL). At that time, the median follow-up for the maintenance phase was 33 months. Now, we report the long-term outcome of maintenance treatment, with a median follow-up of 6 years. Patients and Methods Overall, 465 patients were randomly assigned to induction with either six cycles of cyclophosphamide, doxorubicin, vincristine, prednisone (CHOP) or rituximab plus CHOP (R-CHOP). Those in complete remission or partial remission after induction (n = 334) were randomly assigned to maintenance treatment with rituximab (375 mg/m2 intravenously once every 3 months) or observation. Results Rituximab maintenance significantly improved progression-free survival (PFS) compared with observation (median, 3.7 years v 1.3 years; P < .001; hazard ratio [HR], 0.55), both after CHOP induction (P < .001; HR, 0.37) and R-CHOP (P = .003; HR, 0.69). The 5-year overall survival (OS) was 74% in the rituximab maintenance arm, and it was 64% in the observation arm (P = .07). After progression, a rituximab-containing salvage therapy was given to 59% of patients treated with CHOP followed by observation, compared with 26% after R-CHOP followed by rituximab maintenance. Rituximab maintenance was associated with a significant increase in grades 3 to 4 infections: 9.7% v 2.4% (P = .01). Conclusion With long-term follow-up, we confirm the superior PFS with rituximab maintenance in relapsed/resistant FL. The improvement of OS did not reach statistical significance, possibly because of the unbalanced use of rituximab in post-protocol salvage treatment.

Contains fulltext : 80496.pdf (Publisher’s version ) (Closed access) Mantle cell lymphoma (MCL) has a dismal outcome when treated with conventional chemotherapy. This single arm phase 2 study evaluated intensive consolidation treatment of patients with newly diagnosed MCL up to the age of 65 years, responsive to R-CHOP (rituximab, cyclophosphamide, oncovin, adriamycin, prednisolone). Endpoints for evaluation were toxicity, failure-free survival (FFS) and overall survival (OS). Eighty-seven patients were treated with three cycles of R-CHOP. Sixty-six patients responded to R-CHOP with at least a partial response, 62 continued protocol treatment with high-dose cytarabine (Ara-C; 2000 mg/m(2), bid. over 4 d) and 61 patients received rituximab and stem cell harvest, followed by BEAM (carmustine, etoposide, Ara-C, melphalan) and autologous stem cell rescue. Non-haematological toxicity, grades III and IV, was seen in 8% of the patients after R-CHOP, in 22% after high-dose Ara-C and in 55% after BEAM. The overall response rate was 70% (complete response rate 64%, partial response rate 6%), FFS and OS at 4 years were 36 +/- 7% and 66 +/- 6%, respectively. The FFS and OS at 4 years from the evaluation after BEAM in the 61 R-CHOP responsive patients was 46 +/- 9% and 79 +/- 7%, respectively. In conclusion, high-dose Ara-C and BEAM with stem cell rescue in newly diagnosed MCL patients responsive to R-CHOP is a manageable treatment with respect to toxicity. This regimen leads to long-term, but probably not durable, remissions.

Purpose: To evaluate the roles of radiation dose, chemotherapy, and other factors in the etiology of stomach cancer in long-term survivors of testicular cancer or Hodgkin lymphoma. Methods and Materials: We conducted a cohort study in 5,142 survivors of testicular cancer or Hodgkin lymphoma treated in the Netherlands between 1965 and 1995. In a nested case-control study, detailed information on treatment, smoking, gastrointestinal diseases, and family history was collected for 42 patients with stomach cancer and 126 matched controls. For each subject, the mean radiation dose to the stomach was estimated. Relative risks (RRs) of stomach cancer and the radiation-related excess relative risk (ERR) per gray were calculated by conditional logistic regression analysis. Results: The risk of stomach cancer was 3.4-fold increased compared with the general population. The risk increased with increasing mean stomach dose (p for trend, = 13,000 mg) vs.

We evaluated the role of rituximab during remission induction chemotherapy in relapsed aggressive CD20+ non-Hodgkin lymphoma. Of 239 patients, 225 were evaluable for analysis. Randomized to DHAP (cisplatin-cytarabine-dexamethasone)-VIM (etoposide-ifosfamide-methotrexate)-DHAP (cisplatin-cytarabine-dexamethasone) chemotherapy with rituximab (R; R-DHAP arm) were 119 patients (113 evaluable) and to chemotherapy without rituximab (DHAP arm) 120 patients (112 evaluable). Patients in complete remission (CR) and partial remission (PR) after 2 chemotherapy courses were eligible for autologous stem-cell transplantation. After the second chemotherapy cycle, 75% of the patients in the R-DHAP arm had responsive disease (CR or PR) versus 54% in the DHAP arm (P = .01). With a median follow-up of 24 months, there was a significant difference in failure-free survival (FFS24; 50% vs 24% vs, P < .001), and progression free survival (PFS24; 52% vs 31% P < .002) in favor of the R-DHAP arm. Cox-regression analysis demonstrated a significant effect of rituximab treatment on FFS24 (HR 0.41, 95% confidence interval [CI] 0.29-0.57 versus 0.51, 95% CI 0.37-0.70) and overall-survival (OS24: HR 0.60 [0.41-0.89] vs 0.76 [0.52-1.10]) when adjusted for time since upfront treatment, age, World Health Organization performance status, and secondary age-adjusted international prognostic index. These results demonstrate improved FFS and PFS for relapsed aggressive B-cell NHL if rituximab is added to the re-induction chemotherapy regimen.

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.

We evaluated the role of rituximab (R) both in remission induction and maintenance treatment of relapsed/resistant follicular lymphoma (FL). A total of 465 patients were randomized to induction with 6 cycles of cyclophosphamide, doxorubicin, vincristine, and prednisone (CHOP) (every 3 weeks) or R-CHOP (R: 375 mg/m2 intravenously, day 1). Those in complete remission (CR) or partial remission (PR) were randomized to maintenance with R (375 mg/m2 intravenously once every 3 months for a maximum of 2 years) or observation. R-CHOP induction yielded an increased overall response rate (CHOP, 72.3%; R-CHOP, 85.1%; P < .001) and CR rate (CHOP, 15.6%; R-CHOP, 29.5%; P < .001). Median progression-free survival (PFS) from first randomization was 20.2 months after CHOP versus 33.1 months after R-CHOP (hazard ratio [HR], 0.65; P < .001). Rituximab maintenance yielded a median PFS from second randomization of 51.5 months versus 14.9 months with observation (HR, 0.40; P < .001). Improved PFS was found both after induction with CHOP (HR, 0.30; P < .001) and R-CHOP (HR, 0.54; P = .004). R maintenance also improved overall survival from second randomization: 85% at 3 years versus 77% with observation (HR, 0.52; P = .011). This is the first trial showing that in relapsed/resistant FL rituximab maintenance considerably improves PFS not only after CHOP but also after R-CHOP induction.

Many women develop breast cancer after treatment for Hodgkin lymphoma (HL) at a young age. We estimated this future risk, taking into account age and calendar year of HL diagnosis, HL treatment information, population breast cancer incidence rates, and competing causes of death.Relative risks of breast cancer for categories defined by radiation dose to the chest (0, 20-40 Gy, oror = 40 Gy) and use of alkylating agents (yes or no) were estimated from a case-control study conducted within an international population-based cohort of 3817 female 1-year survivors of HL diagnosed at age 30 years or younger from January 1, 1965, through December 31, 1994. To compute cumulative absolute risks of breast cancer, we used modified standardized incidence ratios to relate cohort breast cancer risks to those in the general population, enabling application of population-based breast cancer rates, and we allowed for competing risks by using population-based mortality rates in female HL survivors.Cumulative absolute risks of breast cancer increased with age at end of follow-up, time since HL diagnosis, and radiation dose. For an HL survivor who was treated at age 25 years with a chest radiation dose of at least 40 Gy without alkylating agents, estimated cumulative absolute risks of breast cancer by age 35, 45, and 55 years were 1.4% (95% confidence interval [CI] = 0.9% to 2.1%), 11.1% (95% CI = 7.4% to 16.3%), and 29.0% (95% CI = 20.2% to 40.1%), respectively. Cumulative absolute risks were lower in women treated with alkylating agents.Breast cancer projections varied considerably by type of HL therapy, time since HL diagnosis, and age at end of follow-up. These estimates are applicable to HL survivors treated with regimens of the past and can be used to counsel such patients and plan management and preventive strategies. Projections should be used with caution, however, in patients treated with more recent approaches, including limited-field radiotherapy and/or ovary-sparing chemotherapy.

Alloantibody tests demonstrate immunological causes of insufficient increments in random platelet transfusions. The value of a positive or negative test result in predicting the outcome of human leucocyte antigen (HLA)-matched transfusions in patients refractory to leucodepleted random platelet transfusions has not been assessed. We retrospectively evaluated the outcome of the first HLA-matched platelet transfusion in 72 patients with haematological diseases in two ways: first, the strategy according to which the patient was selected for HLA-matched platelet transfusions was analysed. The strategies were: (i) results of alloantibody tests were not available, (ii) a positive alloantibody test, (iii) a negative alloantibody test. Secondly, the outcome of the first HLA-matched transfusion was investigated relative to the results of alloantibody tests, irrespective of the decision strategy. No significant association was found between the decision strategy and the outcome of the first HLA-matched platelet transfusion. Positive alloantibody tests, however, predicted a better outcome of the first HLA-matched platelet transfusion (P = 0.04 and P = 0.03 after 1 and 16 h respectively). In patients refractory to random platelet transfusions, positive alloantibody tests predicted a better outcome of HLA-matched platelet transfusions. Patients with negative alloantibody tests, however, may benefit from HLA-matched platelet transfusions.

ContextSecond cancer is the leading cause of death in long-term survivors of Hodgkin disease (HD), with exceptionally high risks of breast cancer among women treated at a young age. Quantitative associations between radiotherapy dose delivered to the breast and administered chemotherapy have not been reported to date in large series, nor has the influence of ovarian exposures on subsequent risk.ObjectiveTo quantify the long-term risk of breast cancer associated with use of radiotherapy and chemotherapy to treat young women with HD.Design, Setting, and SubjectsMatched case-control study of breast cancer within a cohort of 3817 female 1-year survivors of HD diagnosed at age 30 years or younger, between January 1, 1965, and December 31, 1994, and within 6 population-based cancer registries. The study was conducted March 1, 1996, through September 30, 1998.Main Outcome MeasuresRelative risk (RR) of breast cancer associated with radiation dose delivered to site of breast cancer or to ovaries and with cumulative dose of alkylating agents.ResultsBreast cancer occurred in 105 patients with HD who were matched to 266 patients with HD but without breast cancer. A radiation dose of 4 Gy or more delivered to the breast was associated with a 3.2-fold (95% confidence interval [CI], 1.4-8.2) increased risk, compared with the risk in patients who received lower doses and no alkylating agents. Risk increased to 8-fold (95% CI, 2.6-26.4) with a dose of more than 40 Gy (P

71 Background: Survivors of Hodgkin lymphoma (HL) are at risk for late adverse effects of treatment. The Dutch BETER consortium, consisting of healthcare providers, researchers and patient representatives, has set up survivorship care clinics where HL survivors are screened for late effects. Methods: In order to assess patient characteristics and clinical attendance rates, descriptive statistics were calculated for data on HL survivors who were invited to attend the BETER clinics in the University Medical Center Utrecht (UMCU) and Erasmus University Medical Center (EMC). Results: Overall 291 survivors were invited to attend one of the two BETER clinics. Median age at invitation was 46 years (interquartile range IQR: 40-55 years), median age at HL diagnosis 29 years (IQR: 22-37 years) and median time since diagnosis 16 years (IQR: 11-22 years). Survivors were referred to the BETER clinic by the general EMC/UMCU outpatient clinics where they were still under surveillance (42%) or invited by phone (37%) or letter (20%). While 79% of survivors responded to the invitation, only 53% of all patients actually visited the BETER clinic. Most common reasons to not attend were: undergoing surveillance or treatment for late effects elsewhere (91%) and unwillingness to attend (8%; e.g. due to financial or emotional burden). Ninety-eight% of survivors who were still under surveillance in EMC/UMCU hospitals attended the BETER clinic, as opposed to only 19% of survivors who were no longer under surveillance. Survivors initially invited by letter were more likely to attend (38%) than those who were first contacted by phone (11%). Age at invitation and age at HL diagnosis were similar in those who did and did not attend. Similar data for another 3 clinics are being collected and will be presented at the ASCO Survivorship Symposium. Conclusions: These preliminary data show that only half of HL survivors who were invited, attended a BETER clinic. Unfortunately, survivors who were no longer under medical surveillance were less likely to attend, especially when first contacted by phone. Future, more detailed, evaluation of (non-)attendance in more BETER clinics may reveal the need for additional implementation measures to improve the BETER survivorship care program.

This study involved 12 patients with multiple myeloma (MM), in whom malignant plasma cells did not contain immunoglobulin heavy chain (IgH) protein chains. Southern blot analysis revealed monoallelic Jh gene rearrangements in 10 patients, biallelic rearrangement in 1 patient, and biallelic deletion of the Jh and Cμ regions in 1 patient. Heteroduplex polymerase chain reaction analysis enabled the identification and sequencing of 9 clonal Jhgene rearrangements. Only 4 of the joinings were complete Vh-(D)-Jhrearrangements, including 3 in-frame rearrangements with evidence of somatic hypermutation. Five rearrangements concerned incomplete Dh-Jh joinings, mainly associated with deletion of the other allele. Curiously, in at least 1 of these 5 cases the second allele seemed to be in germline configuration, whereas the in-frame Vκ-Jκgene rearrangements contained somatic mutations. The configuration of the IGH genes was further investigated by use of Ch probes. In 5 patients the rearrangements in the Jh and Ch regions were not concordant, probably caused by illegitimate IGH class switch recombination (chromosomal translocations to 14q32.3). These data indicate that in many IgH− MM patients illegitimateIGH class switch rearrangement or illegitimate deletion of the functional Vh-(Dh)-Jhallele are responsible for IgH negativity. For example, the exclusive presence ofDh-Jhrearrangements in combination with mutated IGK genes can only be explained in terms of normal B-cell development, if the second (functional) IGH allele is deleted, which was probably the case in most patients. Therefore, defects at the DNA level are responsible for the lack of IgH protein production in most IgH− MM patients.

Summary points About 8000 people in the United Kingdom are diagnosed with leukaemia each year, and in 2010, 4504 people died in the UK from this disease.1 Leukaemia encompasses a clinically and pathologically diverse set of conditions whose incidence and prevalence are rising. In the past, leukaemia was classified on the basis of the morphological characteristics of abnormally proliferating leucocytes in the blood and bone marrow. Emerging genetic data, however, have shown genomic heterogeneity in what were thought to be homogeneous disorders, prompting the World Health Organization to revise the classification.2 Despite these advances, the profound immunological and haematological disturbances inherent in most leukaemias and the systemic side effects of chemotherapy remain complex challenges. This is a two part review with the first part focusing on the current diagnosis and management of leukaemia. The second part will consider the types of support patients need in the community. #### Sources and selection criteria We searched PubMed for clinical trials and the Cochrane Library for meta-analyses. We also sought expert opinion from experienced consultant haematologists. Keywords used were leuk(a)emia, chemotherapy, supportive care, and community care. We also reviewed guidelines from the British Committee for Standards in Haematology and the National Institute for Health and Clinical Excellence. Leukaemia is a cancer of circulating white blood cells. Leukaemias are divided into acute and chronic types. When immature white blood cells or …

Hemolysis due to donor-derived B lymphocytes has been reported in patients who have undergone ABO-nonidentical orthotopic liver transplantation (OLT). Yet, until now, little was known about the management of this transplantation-induced hemolysis. In this report we describe our experience with hemolysis in a patient after OLT. In addition, based on theoretical assumption, we hypothesize that corticosteroids can be helpful in the management of ABO-nonidentical OLT-induced hemolysis.

The purpose of a classification is not only to group diseases with the same biological characteristics, but also to get insight into the pathogenesis and to define subgroups with different prognoses and different therapeutic approaches. In acute leukaemias the classification now most widely used is the French-American-British (FAB) classification as proposed in 1976, which was based on morphology and cytochemistry [l]. The FAB group felt that discrimination of myeloblasts from lymphoblasts on morphological characteristics only was insufficient. For this reason they proposed to define the difference between acute myeloid leukaemia @ML) and acute lymphoblastic leukaemia (ALL) by the positivity or negativity respectively of the blasts for the myeloperoxidase (MPO) or Sudan B Black reaction. Within acute myeloid leukaemia 6 categories were discriminated (Ml-M61 by morphology and the use of o-naphthyl acetate esterase (ANAE) to discriminate monoblasts from myeloblasts [ 1,2]. Later, immunological markers were used to define

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.

Summary 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.

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.

Malignant mesothelioma is a relatively uncommon malignancy. Although the pathogenesis is primarily related to asbestos, the disease may be associated with radiation exposure. Recently, increased risks for second primary mesothelioma after radiation for lymphoma have been reported. Because these findings are based on small numbers of patients, they need to be confirmed. We examined mesothelioma risk in 2567 5-year survivors of Hodgkin lymphoma. The risk was almost 30-fold increased in Hodgkin lymphoma patients treated with irradiation compared with the general population. Although histology and survival of the mesothelioma cases were comparable with cases from the general population, asbestos exposure and the proportion of males were lower than expected. The evidence for radiotherapy as cause for mesothelioma independent of exposure to asbestos is expanding, and the diagnosis of mesothelioma should be kept in mind whenever related symptoms arise in patients who had previous irradiation.

6 Background: Survivors of Hodgkin lymphoma (HL) are at increased risk of various late adverse effects of treatment, leading to substantial excess morbidity and mortality. Long-term follow-up care programs have been established for childhood cancer survivors, but not yet for HL survivors. The Dutch BETER consortium (Better care after Hodgkin lymphoma: Evaluation of long-term Treatment Effects and screening Recommendations) has developed a nationwide infrastructure for Survivorship Care Clinics for HL survivors. The consortium aims to: 1) establish follow-up guidelines for survivors; 2) identify survivors eligible for follow-up care; 3) educate survivors about late adverse treatment effects; and 4) provide risk-based care. Methods: Evidence-based follow-up guidelines were developed according to international standards. The guideline development group consisted of clinicians, methodological experts and patient representatives. To be eligible for follow-up care patients must have survived ≥ 5 yrs and have been treated at ages 15-70 years after 1969. Survivors were identified through the Netherlands Cancer Registry and hospital-based registries. Tracing of current addresses was done through the nationwide database of Municipal Offices. Results: We developed guidelines forsecond malignancies, cardiovascular disease, thyroid disease, osteoporosis and functional asplenia infection prophylaxis. Recommendations are given for fertility care and therapy for neck muscle weakness. We have identified and traced a cohort of 12,000 HL survivors in 23 centers, covering about 80% of HL patients in the Netherlands, of whom 8,500 appear to be eligible for follow-up care. For all survivors, treatment data were collected from the medical records to provide risk-based screening recommendations. A website and a survivorship care plan were developed to educate survivors about late effects. A nationwide database, including screening and adverse events data, is in development to evaluate the follow-up guidelines for diagnostic value and efficacy. Conclusions: We expect that the BETER project will improve healthy life expectancy of HL survivors. Evaluation of follow-up care will lead to a more evidence-based follow-up program.

Increased CD38 expression by leukemic cells has been suggested as an adverse prognostic factor in B-CLL. Several approaches have been proposed to quantify its level of expression by flow cytometry.We compared the use of (i) the percentage of CD38 positive cells, (ii) CD38 antibodies bound per cell (ABC), and (iii) a semi-quantitative method based on the shape of the CD38 histogram, within a cohort of 78 B-CLL patients.A decreased overall survival was seen with30% CD38 positivity among B-CLL cells, with CD38 ABC100, and with bimodal or unimodal, strongly positive CD38 histograms. However, patients with unimodal weakly positive CD38 histograms also showed a significantly reduced survival as did patients with intermediate proportions (i.e. 5-30%) of CD38+ cells. Furthermore, within the group with5% CD38 positivity among their B-CLL cells, 84% of patients showed prognostically favourable mutated IGVH gene segments and 100% had low ZAP70 gene expression. For 5-30% CD38 positivity, these proportions were 50 and 83%, while for30% CD38 positivity, these proportion were only 28 and 56%, respectively.We found a simple method of quantitation of CD38 expression (i.e.,5% CD38 positivity among B-CLL cells) to be sufficient to identify patients with an unfavourable prognosis. The level of CD38 expression as defined with this method correlated well with the IGVH mutation status and ZAP70 gene expression.

Current knowledge of Epstein–Barr virus (EBV)–specific T-cell responses in the cerebrospinal fluid (CSF) of patients with EBV-related lymphoproliferative disease (EBV-LPD) in the central nervous system (CNS) is very limited. Here, we present two recipients of hematopoietic stem cell transplants with EBV-LPD in the CNS. EBV-specific CD8+ T lymphocytes were detected in CSF and peripheral blood using major histocompatibility complex (MHC) class I multimers loaded with EBV-derived peptides. The appearance of EBV-specific CD8+ T cells in CSF and blood correlated with neurological improvement and disappearance of EBV-LPD. These observations suggest a role for EBV-specific CD8+ T cells in the control of EBV-LPD in the CNS. Ann Neurol 2005;58:788–792

Background: Female survivors of Hodgkin’s disease (HD) have a strongly elevated risk of breast cancer, but factors responsible for the increased risk are not well known. Methods: We investigated the effects of radiation dose, chemotherapy (CT), and reproductive factors on breast cancer risk in a nested case–control study in The Netherlands in a cohort of 770 female patients who had been diagnosed with HD before age 41. Detailed treatment information and data on reproductive factors were collected for 48 case patients who developed breast cancer 5 or more years after diagnosi so f HD and 175 matched control subjects. The radiation dose was estimated to the area of the breast where the case patient’s tumor had developed and to a comparable location in matched control subjects. Relative risks (RRs) of breast cancer were calculated by conditional logistic regression. Statistical tests were two-sided. Results: The risk of breast cancer increased statistically significantly with radiation dose (Ptrend = .01); patients who received 38.5 Gy or more had an RR of 4.5 (95% confidence interval [CI] = 1.3 to 16) times that of patients who received less than 4 Gy. Patients who received both CT and radiotherapy (RT) had a statistically significantly lower risk than those treated with RT alone (RR = 0.45, 95% CI = 0.22 to 0.91). Breast cancer risk increased with increasing radiation dose among patients who received RT only (RR = 12.7, 95% CI = 1.8 to 86, for patients receiving 38.5 Gy) but not among patients treated with CT and RT. Sixty-nine percent of control subjects treated with RT and more than six cycles of CT, but only 9% of those who received RT alone, reached menopause before age 41. Reaching menopause before age 36 was associated with a strongly reduced risk of breast cancer (RR = 0.06, 95% CI = 0.01 to 0.45). Conclusion: Breast cancer risk increases with increasing radiation dose up to at least 40 Gy. The substantial risk reduction associated with CT may reflect its effect on menopausal age, suggesting that ovarian hormones promote tumorigenesi sa fter radiation has produced an initiating event. [J Natl Cancer Inst 2003;95:971–80]

Contains fulltext : 143691.pdf (Publisher’s version ) (Open Access) BACKGROUND: The use of involved-field radiotherapy after chemotherapy for advanced Hodgkin's lymphoma is controversial. METHODS: We randomly assigned patients with previously untreated stage III or IV Hodgkin's lymphoma who were in complete remission after hybrid chemotherapy with mechlorethamine, vincristine, procarbazine, prednisone, doxorubicin, bleomycin, and vinblastine (MOPP-ABV) to receive either no further treatment or involved-field radiotherapy. Radiotherapy consisted of 24 Gy to all initially involved nodal areas and 16 to 24 Gy to all initially involved extranodal sites. Patients in partial remission were treated with 30 Gy to nodal areas and 18 to 24 Gy to extranodal sites. RESULTS: Of 739 patients, 421 had a complete remission; 161 of these patients were assigned to no further treatment, and 172 to involved-field radiotherapy. The median follow-up was 79 months. The five-year event-free survival rate was 84 percent in the group that did not receive radiotherapy and 79 percent in the group that received involved-field radiotherapy (P=0.35). The five-year overall survival rates were 91 and 85 percent, respectively (P=0.07). Among the 250 patients in partial remission after chemotherapy, the five-year event-free and overall survival rates were 79 and 87 percent, respectively. CONCLUSIONS: Involved-field radiotherapy did not improve the outcome in patients with advanced-stage Hodgkin's lymphoma who had a complete remission after MOPP-ABV chemotherapy. Radiotherapy may benefit patients with a partial response after chemotherapy.

Introduction High-dose cytarabine containing immuno-chemotherapy followed by autologous stem cell transplantation (ASCT) has been established as standard first-line treatment in younger mantle cell lymphoma (MCL) patients (ESMO guideline, Ann Oncol 2013). However, the role of total body irradiation (TBI) as conditioning regimen for ASCT has not been clarified so far. A retrospective EBMT survey of 418 MCL patients suggested a benefit of TBI with respect to the rate of relapse in patients who achieved a partial remission before ASCT (Rubio et al., ASH 2010). We combined the individual patient data of the Nordic MCL2 trial (Geisler et al., Blood 2008), the HOVON 45 trial (van’t Veer et al., BJH 2008, both without TBI), and the high-dose cytarabine containing study arm of the European MCL Younger trial (Hermine et al., ASH 2012, with TBI) to evaluate potential differences in long term outcome. Methods All trials included patients with advanced stage MCL up to 66 years and a central review of histology. Induction treatment of Nordic MCL2 consisted of 6 alternating courses of Maxi-CHOP or high-dose cytarabine (12g/m2 per cycle, 8g/m2 in patients > 60 years, total cumulative dose 24-36g/m2) combined with 4-6 cycles rituximab, in HOVON 45 three courses R-CHOP were followed by one cycle of high-dose cytarabine (16g/m2), and in MCL Younger patients received 6 alternating courses of R-CHOP or R-DHAP (4g/m2 cytarabine per cycle, total cumulative dose 12g/m2). Conditioning before ASCT consisted of BEAM or BEAC in Nordic MCL2, and BEAM in HOVON 45, whereas a TBI-containing regimen (TAM: 10 Gray TBI, 6g/m2 cytarabine, 140mg/m2 melphalan) was applied in MCL Younger. We compared baseline characteristics, progression free survival (PFS) overall survival (OS) after ASCT from the three patient cohorts with adjustment for MIPI (Hoster et al., Blood 2008) and quality of remission before ASCT. Results In Nordic MCL2, HOVON 45, and MCL Younger 145, 61, and 171 patients were transplanted in complete (CR) or partial (PR) remission (median age 57, 55, and 56 years, p=0.24). According to MIPI, 46%, 56%, and 67% were low risk, whereas 22%, 13%, and 11% were high risk patients (p=0.006). Five-year PFS after ASCT was 61%, 50%, and 78%, respectively (p Conclusion The longer PFS after ASCT of MCL Younger compared to HOVON 45 patients may be due to the different time schedule of cytarabine during induction or to a higher efficacy of TBI vs. BEAM, as the total chemotherapy doses were comparable and we adjusted for MIPI. We could not see an improved PFS after ASCT of MCL Younger compared to Nordic MCL2 patients transplanted in CR or unconfirmed CR and, after adjustment for the different risk profiles, this was also not clearly seen for patients transplanted in PR. Taking into account the substantially higher cytarabine dose in Nordic MCL2 during induction one might speculate that this fact at least partially compensated for a higher efficacy of TBI. Multivariable analyses incorporating additional prognostic factors (Ki-67 and MRD) will help to clarify the impact of the individual parts of the current multimodal approach in younger MCL patients. On behalf of the European Mantle Cell Lymphoma Network Disclosures: No relevant conflicts of interest to declare.

8568 Background: Cardiovascular diseases are the most common non-malignant cause of death in Hodgkin Lymphoma (HL) survivors, especially those who had mediastinal irradiation as part of their treatment. We investigated the role of CT coronary angiography (CTA) as a screening tool for coronary artery disease (CAD) in asymptomatic HL survivors, related findings to stress testing and subsequent interventions. We also evaluated acceptance of screening. Methods: Patients were eligible if at least 10 years disease-free and treated with mediastinal radiotherapy. All patients were screened with ECG, stress testing and CTA. Primary endpoint was significant CAD (stenosis >50%) on CTA. A sample size of 50 patients would achieve ≥80% power to detect a difference of 13% (≥20% vs a population proportion of 7%) using a two-sided binominal test. Allowing for non-evaluable and false-positive scans, we considered CTA screening to be indicated for testing in a larger population if in ≥six patients revascularization would be necessary. Results: Fifty-two patients were included, 48 patients underwent CTA. Median age was 47 years, time since HL diagnosis 21 years. Most patients had no risk factors for CAD. There were 45 evaluable scans. Prevalence of significant CAD on CTA was found in 20% (N=9), and significantly increased compared to the 7% expected abnormalities (p=0.01, 95% CI 8.3-31.7%). In 5 of the 8 patients who underwent conventional angiography, significant CAD was confirmed, and revascularization performed. Two patients were started on medication. Stress testing was inaccurate for determining CAD: all participants were asymptomatic and 1 patient with significant CAD had signs of ischemia. Ninety percent of the participants were content with the screening offered in this study, regardless whether the CTA showed abnormalities or not. Conclusions: Prevalence of significant CAD among HL survivors is high. In our participants even the most severe and life-threatening CAD was not preceded by typical symptoms. In symptomatic cardiac patients revascularization improves survival. This might justify both screening by CTA and intervention in this asymptomatic population, but needs to be further evaluated in a larger cohort. Clinical trial information: NCT01271127.

Summary points Although curative chemotherapy is typically delivered in the inpatient setting, patients are at home for substantial periods of time while they progress through treatment. Patients with chronic leukaemia are usually treated entirely as outpatients. Almost all of these patients will develop complications from their disease or its treatment, and after completing chemotherapy, some patients will experience late complications. A balance between hospital and community based care is vital to optimise treatment efficacy and avoid unnecessary hospital admissions. This article reviews some of the adverse effects of leukaemia chemotherapy that non-specialists should be aware of and considers the longer term problems seen in survivors. #### Sources and selection criteria We searched PubMed for clinical trials and the Cochrane Library for meta-analyses. We also sought expert opinion from experienced consultant haematologists. Keywords used were leuk(a)emia, chemotherapy, supportive care, and community care. We also reviewed guidelines from the British Committee for Standards in Haematology and the National Institute for Health and Clinical Excellence. ### Treatment and prevention of infection including neutropenic sepsis Neutropenic sepsis is a medical emergency, and prompt treatment with intravenous antibiotics is usually life saving.1 Although incidence depends on regimen intensity, all patients on chemotherapy are at risk. Patients may present with non-specific symptoms, rigors, or symptoms associated with the infection site. Patients are advised to contact the acute oncology service available at their local treatment centre, and to monitor …

Background: Microscopic peripheral blood and bone marrow cell evaluation remains a milestone in the diagnostic of hematology. Many factors contribute to the lack of standardization of this diagnostic test, such as differences in the procedure, staining, degree of skill in interpretation and glossary. However the new WHO classification highlights the importance of morphological aspects, quantitative as well qualitative, for a better stratification of patients in the diagnosis of haematological malignancies, particularly myeloid malignancies and above all myelodysplasia (MDS). In this high technology era, we have the opportunity to exchange, via the internet, images and information without geographic limitation, sparing time and resources. This represents a great opportunity to try to get a consensus for blood cell morphology. The European LeukemiaNet (ELN) Network of excellence is an EU project funded by the 6th FP, involving 174 centres from 28 countries. Its major goal is the construction of a cooperative network for improving leukemia diagnosis, care and research. Within the activities of the Diagnostic Platform (WP10), focused on Flow Cytometric and Morphological panels, a European Morphology Consensus Faculty (EMCF), composed of 21 expert morphologists from 13 European countries, has been organized with the following goals: to harmonize the identification of hematological cells for a common European morphological diagnostic pathway, in terms of cell lineage, maturation level, normality/abnormality and glossary, to take into account specific national skills, competences and methods, to provide the patients with the same morphological diagnosis all over Europe. The first step was to create a consensus-based cell library of meaningful blood cell images identified and named by top level European morphologists and agreed by EMCF, as a valuable tool of traininig. We are presenting the final results of the first study of the EMCF. Methods: From May to July 2007 we collected from all the EMCF members 164 images containing 438 labelled blood cells with the following distribution: Granulocytic series n=126 (28.5%), Erythroid series n=77 (17.5%), Monocytic series n=35 (8%), Lymphoid series n=107 (24.,5%), Megakaryocytic series n=23 (5.,5%), Blasts (not otherwise specified) n=29 (6.5%) Other n= 41 (9.5%). All the images were uploaded to a restricted web page together with an Excel file containing the author’s proposal for each cell. Faculty Members were asked to fill the Excel file with their agreed or personal alternative definition for each labelled cell. On January 2008 cells lacking a full agreement were submitted to a Delphi scoring procedure: a minimum of 3 agreements was needed for a cell to be scored in the Delphi questionnaire. By July 2008 we have received the Delphi files for the final evaluation of the study results. Evaluation rules: Full consensus: cells with an agreement of at least 17 out of 21 (>80%) EMFC members. Delphi questionnaire for all the cells with an agreement Results: We reached a full agreement (consensus ≥17/21) on > 59% of all submitted cells. The main discrepancies in the morphological consensus concern the groups of blast and monocytic series, while for the other groups of cells the distribution is similar. After the Delphi scoring we reached an agreement on all the 216 submitted cells. The EMCF created a new category “Cell to delete” for 8 cells due to a not perfect quality of images. This image library is composed of 430 cells now identified through a consensus method by a European Morphology Consensus Faculty and the cells will be uploaded onto the ELN web site, with a clear identification of those cells identified with a Delphi scoring procedure. Moreover cell names are harmonized and this represents the first morphological European glossary. Future developments: The second extended Faculty including morphologists from 16 European countries has been formed with the aim to apply the consensus glossary to identify a new set of cells submitted by the authors without any suggestions. A meeting is planned to discuss the results.

Background. The predictive value of assessment of minimal residual disease after induction treatment in follicular lymphoma (FL) is still controversial. Last year we published the results of a prospective randomized phase III intergroup trial evaluating the role of rituximab (R) both in remission induction and maintenance treatment of 465 relapsed /resistant FL patients. Major conclusions were that addition of R to CHOP induction yielded an increased ORR and CR rate, and that R maintenance strongly improved median progression free survival (PFS; both after induction with CHOP and R-CHOP) and overall survival when compared to observation (van Oers et al Blood2006;108:3295). We now report on the Bcl-2/IgH PCR analysis in this study. Study design. Peripheral blood (PB) and bone marrow (BM) samples where obtained before the start of the induction therapy, at the end of the induction therapy and at the end of the 2 years maintenance/ observation period. The percentage of Bcl-2/IgH MBR+ cells was quantified by genomic qPCR with a sensitivity of at least one Bcl-2/IgH MBR+ cell among 10,000 normal cells (primer and probe sequences are available on request. The main question of our analysis was whether the primary endpoints of the study (response rate /quality for the induction phase and PFS for the maintenance phase) were correlated with results of the Bcl-2/IgH PCR in PB or BM. Results. Molecular biology data were available from 250 patients, evenly distributed amongst the therapeutic arms, both for induction and maintenance. Before treatment 48.5% and 42.0% of assessable patients had a positive Bcl-2/IgH PCR in BM and PB respectively. At the end of induction this had decreased to 28.6% and 17.3% respectively, and at the end of maintenance/observation to 10.5% and 10.6%. Conversion of positive to negative values were more frequent with R-CHOP induction (BM: P=0.026 and PB: P=0.003), and with R maintenance (BM: P=0.005). Percentages and levels of Bcl-2/IgH positivity in PB and BM correlated well at the three sampling time points. Bcl-2/IgH PCR results at diagnosis did not predict for overall response or complete remission rates after induction treatment, but BM results predicted PFS (P=0.04). Rather surprisingly, Bcl-2/IgH PCR results of BM and PB at the end of induction treatment were not predictive for PFS: 3 years PFS was 46% and 38% in the BM− and BM+ group respectively (p=0.4), and 51% and 42% in the PB-and PB+ group respectively (p=0.4).The highly significant improvement of PFS by R maintenance versus observation was observed in both Bcl-2/IgH PCR PB/BM positive and negative groups. Finally, patients who still had a positive Bcl-2/IgH PCR in PB or BM at the end of the 2 years of R maintenance/observation had a significantly shorter PFS (from end of maintenance/observation) than those who were Bcl-2/IgH PCR negative. Conclusion: Bcl-2/IgH PCR results in BM or PB at the end of CHOP or R-CHOP induction treatment are not useful for decisions on subsequent therapy in patients with relapsed/resistant follicular lymphoma.

The Dutch Hemato-Oncology Study Group (HOVON) evaluated in a phase II trial the efficacy of the addition of rituximab, high dose Ara-C and autologous stem cell transplantation after BEAM conditioning to conventional CHOP in 88 previously untreated patients with mantle cell lymphoma, with respect to remission rate, failure free survival (FFS) and overall survival (OS). From 2002 to 2005, 86 eligible patients were included and evaluated. The male : female ratio was: 4 and the median age 55 years (32–66). Median follow-up of all patients still alive was 25.5 months. Patients were treated with R-CHOP21 x 3 (rituximab 375 mg/m2, cyclophosphamide 750 mg/m2, doxorubicin 50 mg/m2, vincristine 1.4 mg/m2 day 1 and prednisone 100 mg days 1 – 5). Stem cells were harvested after high dose Ara-C x 1 (2g/m2 BID days 1 – 4), followed by rituximab on day 11 for in vivo purging and G- CSF. After haematological recovery BEAM conditioning (carmustine 300mg/m2 day 1, Ara-C 200mg/m2 and etoposide 200 mg/m2 days 2 – 5 and melphalan 2 x 100 mg/m2 day 6) was given with autologous stem cell support day 8). After 3 x R-CHOP 17 patients did not reach PR and went off study, according to the protocol, and 5 patients were excluded for other reasons. Sixty four patients received HD Ara-C and 63 patients proceeded to BEAM. Haematological toxicity was as follows: the median time of recovery of leukocytes (> 1,0 x 109/l) from start of high dose Ara-C was 17 days (range: 0 – 59 days), from start of BEAM 26 days (range: 17 – 55). For platelets the median time to recovery (> 50 x 109/l) from start of high dose Ara-C was 23 days (range: 0 – 44 days) and from start of BEAM 25 days (range: 16 – 364). Non-hematological toxicity grade 3–4 was seen during CHOP in 13%, after HD Ara-C in 20%, mainly gastro-intestinal, and after BEAM in 51%, mainly gastro-intestinal and liver, of the patients. Grade 3–4 infections were seen during CHOP in 17%, after HD Ara-C in 30% and after BEAM in 59% of the patients. Responses to treatment are summarised in Table 1. At two years FFS was 67%, OS was 81%. An analysis restricted to the 63 patients who completed the protocol treatment showed FFS 90% and OS 98% at two years. We conclude that intensification of first line treatment with rituximab, HD Ara-C and BEAM is beneficial with respect to FFS and OS in younger MCL patients and that this regimen is well tolerated. Table 1. Response to treatment N CR PR NR/PD Not yet known after 3x CHOP 83 13 (16%) 51 (61%) 17 (20%) 2 after HD Ara-C 64 22 (34%) 28 (44%) 14 after BEAM 63 43 (68%) 13 (21%) 7 died early 1

Protein kinase C beta (PKCβ), a pivotal enzyme in B-cell signaling and survival, has been identified as a therapeutic target in B-cell malignancies. Recent studies show that PKCβ is overexpressed in a majority of patients (pts) with mantle cell lymphoma (MCL). Other studies implicate overactivation of the PI3K/AKT pathway in the pathogenesis of MCL. Enzastaurin, an oral serine/threonine kinase inhibitor, suppresses signaling through PKCβ and the PI3K/AKT pathway to induce tumor cell apoptosis, reduce proliferation, and suppress tumor-induced angiogenesis. The primary objective of this phase II, single-arm, multicenter trial was to determine the rate of freedom from progression (FFP) for ≥3 cycles (1 cycle = 28 days). Secondary endpoints included objective response rate (complete + partial) and toxicity. Pts with previously relapsed/refractory MCL, with no more than 4 prior regimens of therapy, received 500 mg enzastaurin orally, once daily, until disease progression or unacceptable toxicity. A total of 60 pts (18 female; 42 male), median age of 66 years (range: 45–85), median international prognostic index of 2 (range: 0–5), and an Eastern Cooperative Oncology Group performance status of 0–2 were enrolled. All pts had CD20 + MCL and failed multiple prior therapies (median = 2, range: 1–5). Most pts had received CHOP-based chemotherapy and/or rituximab. All enrolled pts received at least 1 dose of enzastaurin and were included in the safety and efficacy analysis. Three pts discontinued due to adverse events possibly related to study drug (diarrhea, renal impairment, and syncope). There were no drug-related deaths or grade (Gr) 4 toxicities. No drug-related bone-marrow toxicities, except Gr 3 anemia (1 pt), were reported. There was 1 case each of drug-related Gr 3 diarrhea, dyspnea, vomiting, hypotension, and syncope. Fatigue (Gr ≤2) was the most common toxicity (n = 5). No objective tumor responses were recorded. 22 of 60 enrolled pts (36.7%, 95% CI: 24.5%–48.9%) were FFP for ≥3 cycles. Six of these pts, who had failed prior chemotherapy and/or immunotherapy, achieved stable disease for ≥ 6 months. One pt was FFP for 22 months, and 2 pts are still on treatment for 8+ and 12+ months, respectively. Although no objective tumor responses occurred, 6 pts were FFP for 6 to 22 months. Oral enzastaurin was well tolerated for extended durations, suggesting it may be used as continuous or maintenance therapy after induction therapy and warrants further investigation in MCL.

Background: Chronic Lymphocytic Leukemia (CLL) has a variable clinical course, of which IgVH mutational status of the malignant B cells is a strong independent predictor for outcome. Objective: We studied the expression of 5 different genes for their value to predict IgVH mutational status and overall survival (OS). Methods: mRNA levels were quantified by real time PCR in lymphoprep separated but unsorted blood samples from 110 morphologically and fenotypically characterised CLL patients for the following genes: ZAP70, lipoprotein lipase (LPL), ADAM29, KIAA0610 and nRIP1. Expression levels were compared wih respect to IgVH mutational status (mutation = % germline < 98%), using logistic regression and with respect to OS (= time from day of laboratory tests to death due to any cause), using Cox regression analysis. Results: The predictive value of the expression of these 5 genes for IgVH mutational status is shown in table 1. Each of these genes showed to be an independent marker for the prediction of IgVH mutational status. LPL as a single marker was the best predictor for mutation. These factors taken together had a high predictive value towards mutational IgVH status (area under ROC curve = 0.93). table 1 N Odds ratio P value ZAP70 no 85 1 (>5.2) yes 25 0.098 0.002 LPL no 73 1 (>0.04) yes 37 0.029 30) yes 37 6.61 0.012 KIAA0610 no 81 1 (>0.25) yes 29 0.19 0.045 NRIP1 no 88 1 (>10) yes 22 48.73 0.008 The predictive value of IgVH mutation and the expression of these 5 genes for OS is shown in table 2. From the six parameters tested, IgVH mutational status and LPL were predictors for OS at a significant level of 5%, while ZAP70 was of borderline significance. table 2 Conclusion: measured in unsorted CLL samples, all genes, and especially LPL, had predictive value towards the presence of IgVH mutation. Expression of LPL and absence of mutation were adverse prognostic factors for survival. Thus, the replacement of the assessment of both IgVH mutational status and ZAP70 by assessment of LPL levels for the prediction of prognosis in CLL patients may be considered. N survival at 24months P value mutation no 36 70% yes 44 93% 0.041 ZAP70 no 66 87% yes 18 70% 0.078 LPL no 55 94% yes 29 66% 0.001 ADAM29 no 57 84% yes 27 84% 0.486 KIAA0610 no 63 88% yes 21 71% 0.133 NRIP no 71 81% yes 13 100% 0.167

In 230 cases of chronic lymphocytic leukemia (CLL), marker analysis was performed with rosette techniques and a panel of xeno-antisera. A monoclonal B-cell proliferation was found in the majority of cases (94%). In most cases, the B-cells carried IgM, with or without IgD. Cytoplasmic immunoglobulin-inclusion bodies were seen in 7% of the cases of B-CLL. The number of patients with non-B/non-T-CLL was small (2%) in this series. In eight patients (4%), a proliferation of T-cells was established. These patients had a different clinical presentation and marker analysis of the lymphocytes, together with functional studies, showed that this group represented a mixture of different disease processes. Functional analysis of the B-CLL cells in 19 cases showed a poor or absent mitogen response and in nine cases the absence of the capacity to differentiate in vitro into plasma cells and/or to produce immunoglobulins.

The blasts of 37 adult and 126 childhood cases of acute lymphoblastic leukaemia (ALL) were characterized with a panel of xeno-antisera and rosette tests. The Orthoclone® monoclonal antibodies (OKT series) were applied as well. Like other investigators, we were able to distinguish 4 major classes of ALL: T-ALL, common-ALL with the subclass pre-B-ALL, null-ALL, and B-ALL. We did not encounter a common-ALL antigen-positive T-ALL subclass. In both adult and childhood ALL, all classes were present, and in about the same frequency as reported by others. In children, common-ALL was the most frequent (66%); in adults, null-ALL (38%). T-ALL was seen both in adults and in children with about the same frequency (27 and 23%, respectively). We found pre-B-ALL only in children. Patients with B-ALL comprised the smallest group in both adults and children (8 and 1.5%, respectively). The application of the OKT antibodies led to recognition of 3 major subclasses of T-ALL: an immature, a common thymocyte and a mature thymocyte subclass. These antibodies were helpful in defining a better classification of null-ALL. With regard to remission induction and prognosis in adult ALL, complete remissions were always obtained in T-ALL, followed by 70% of complete remissions in common-ALL. The worst prognosis was encountered in null-ALL and B-ALL, with 50 and 0% remission, respectively, and a shorter survival in null-ALL of those patients who achieved complete remission. Thus, the high number of cases of null-ALL in adults partly explains the generally much worse prognosis for adult ALL.

In this review results are presented from several population-based epidemiological and immunological studies of children with leukaemia in The Netherlands, who were diagnosed between 1973 and 1982 through a nationwide co-operative group of paediatricians. From 1973 till 1980 annual incidence rates appeared to be 3.1 per 105 person-yr. No significant trend was observed in this period. However a preliminary analysis of patients in the 1980–1982 period showed an increase. Mortality rates are decreasing since 1973, as expected. Incidence rates and proportions of different morphological and immunological subtypes reflect the pattern of occurrence in populations with a high standard of living. A relatively high incidence rate of acute lymphocytic leukaemia (ALL) is observed with a peak at the age of 3–5. The proportion of patients with T-cell phenotype among ALL-patients, immunologically typed between 1979 and 1982, appeared to increase with age, while the proportion of common ALL decreased. Statistical analysis of the data of patients with ALL in the Western part of the country including areas with nuclear plants, gave no indication for the presence of clustering. Subclassification of childhood leukaemia (CL), notably ALL, may be necessary for obtaining more specific etiologic clues. In view of the incidence of CL and ALL large scale, immunological and epidemiological investigations of CL, and the related non-Hodgkin's lymphomas, preferably population-based, are necessary.

A fast and easy method for the production of monolayer plaque-assay slides, making use of double adhesive tape, is described.