ｐ297-303_臨床血液54-10_35教育講演_u.vitolo4c.mcd臨 床 血 液 54：10
The 75th Annual Meeting of the Japanese Society of Hematology Annalisa CHIAPPELLA, Giulia BENEVOLO and Umberto VITOLO Key words : MALT, Testicular, CNS lymphomas Immunophenotype of MALT tumor cells is CD20+, CD79a+, CD5,, CD10,, CD23,, and the marginal Primary extranodal lymphomas represented an hetero- zone cell-associated antigens CD21 and CD35; some cases geneous entity of non-Hodgkin lymphomas (NHL), cha- were CD5+. MALT cells are characterized by chromoso- racterized by the involvement of non-nodal sites. Extra- mal translocations, like t(11;18)(q21; q21), t(1;14)(p22; nodal lymphomas account for approximately 20─45％ of all q32), t(14;18)(q32; q21), t(3;14)(p14. 1; q32), that cause non-Hodgkin lymphomas and include different histologies the production of a chimeric protein (API2-MALT1) or a and different sites: splenic marginal zone lymphoma, transcriptional deregulation (Bcl10, MALT1, FOXP1), extranodal marginal zone lymphoma of mucosa associated with involvement of NFkB pathway.
lymphoid tissue (MALT), primary mediastinal (thymic) MALT subtypes have a strong correlation with an large B-cell lymphoma, primary effusion lymphoma and antigenic stimulation with consequent chronic inflamma- intravascular lymphoma, primary central nervous system tory disorder and proliferation of lymphoid cells: in gastric lymphoma, primary testicular lymphoma, lung lympho- MALT the antigenic stimulation is related to Helicobacter ma, primary breast lymphoma, primary bone lymphomas pylori infection, in ocular adnexal MALT lymphomas to and primary ocular adnexal lymphoma. Enteropathy type Chlamidia psittaci, in immunoproliferative small intestinal T-cell lymphoma, extranodal natural killer NK/T-cell lym- disease to Campylobacter jejuni and in cutaneous MALT phoma, hepatosplenic T-cell lymphoma, mycosis fun- to Borrelia burgdoferi 4∼7).
goides, primary cutaneous CD30+ T-cell lymphomas and Primary ocular adnexal lymphoma are localized in 75％ subcutaneous panniculitis-like are extranodal T-cell lym- of cases in the orbital fat, and in 25％ in the conjuntive.
phomas1∼3). In this report, we present the most frequent Ocular adnexal MALT lymphomas proliferation is thought extranodal lymphomas, gastric MALT lymphomas, and to be related to a chronic antigenic stimulation induced by two interesting extranodal entities as primary testicular Chlamidia psittaci. This stimulation induced genetic in- lymphoma and primary central nervous system lympho- stability with subsequent chromosomal abnormalities and mas because of their newtherapeutic findings.
clonal growth independent from antigenic stimulation; furthermore, tumor progression to a more aggressive histologic type of lymphoma (diffuse large B-cell lympho- Extranodal marginal zone lymphoma of mucosa- ma) can be induced by mutations of tumor suppressor associated lymphoid tissue represent 7─8％ of NHL and genes, p53 and p16.
50％ of gastric lymphomas. MALT lymphomas are more There is not a consensus on the treatment; according to frequent in elderly, with a median age of 60 years.
clinical presentation, the primary ocular adnexal lympho- ma may be treated, sometimes after a period of watch and wait, with surgery, local radiotherapy, systemic chemoim- Hematology, Città della Salute e della Scienza Hospital, Torino, munotherapy like chlorambucil with/without monoclonal − 臨 床 血 液 − antibody anti-DC20 Rituximab; in cases with Chlamidia demonstrated, in a series of 93 patients affected by low- psittaci positivity, a treatment with oral doxycycline for grade gastric MALT lymphoma, no statistically significant three weeks showed encouraging results. In an Italian difference in terms of overall survival and event free trial, 44 patients were assessed for Chlamydia infections survival between patients treated with chemotherapy by polymerase chain reaction. In 34 patients with mea- alone, surgery alone, surgery with additional chemother- surable disease, a treatment with doxycycline was given.
apy or radiotherapy, or antibiotics against Helicobacter Chlamidia psittaci DNA was detected in 89％ of the pylori infection, with 5-year overall survival 82％ (95％ biopsies. After doxycycline treatment, 48％ of the patients confidence interval [CI], 67％─91％). H. pylori infection is achieved a regression of Chlamidia DNA and clinical ultimately eradicated with dual or triple therapy in more overall response rate was 65％8).
than 90％ of the patients. Anti-helicobacter therapy with The gastric MALT lymphoma tumor-genesis is predom- proton-pump inhibitor plus clarithromycin-based triple inantly related to Helicobacter pylori infection, that cause therapy with either amoxicillin or metronidazole is usually the presence of T-cells activated and an antigenic effective. Histologic regression of the MALT lymphoma stimulation (Fig. 1).
was documented in 65─75％ of the patients after the Gastric MALT lymphoma patients usually have no sys- antibiotic treatment to eradicate HP infection. The time temic symptoms; dyspepsia and epigastric pain are needed to achieve a remission is variable with a range common symptoms. Staging includes gastroduodenal end- from very fewmonths to >12 months. It is advisable to oscopy with biopsies and ultrasound endoscopy to wait for at least 12 months before starting another investigate gastric-wall infiltration, if feasible. The most treatment in patients who achieve a clinical and endo- common staging system was the revised version of the scopic remission together with eradication of H. pylori, Blackledge staging system that was recommended for although patients may have persistent lymphoma at the general use by the international workshop of Lugano micorscopic level. In a recent systematic reviewof the literature analysing data from 32 studies including 1,408 Nowadays, more modern staging systems were out- patients, the gastric MALT lymphoma remission rate after lined, such as the"Paris staging system"that takes into HP eradication was 77.5％11).
account more accurate features such as the depth of In this review, several factors have been identified that gastric wall involvement, a characteristic that may predict predicted lymphoma remission with HP eradication the lymphoma response to H. pylori eradication 10).
treatment. Response rate was significantly higher in pa- The treatment of choice for localized disease is tients with stage I than stage II lymphoma (78.4％ vs 55.6 eradication of Helicobacter pylori with antibiotics. The In- ％) and in Asian than in Western groups (84.1％ vs 73.8 ternational Extranodal Lymphoma Study Group (IELSG) ％; p=.0001). Neoplasia confined to the submucosa Gastric MALT lymphoma and H.pylori 臨 床 血 液 54：10
regressed more frequently than that with deeper invasion disease should be considered for systemic treatment.
(82. 2％ vs 54. 5％; p=.0001); patients with lymphoma Rituximab plus chemotherapy is an appropriate treatment localized to the distal stomach experienced regression choice as other indolent B-cell lymphomas if treatment is more frequently than those with lymphoma of the required. Also in case of failure to antibiotic treatment, proximal stomach (91.8％ vs 75.7％; p=.0037). The chemoimmunotherapy is a good treatment option and may remission rate was higher among patients without the be indicated in case of contraindications to radiotherapy. It API2-MALT1 translocation than in those with this is hard to decide what is the best treatment between sys- translocation (78％ vs 22.2％; P=.0001)11).
temic chemoimmunotherapy and radiotherapy in localised The complete remission after HP eradication is main- gastric MALT lymphoma and may depend on the local tained for years in most cases, and offers a chance of cure.
expertise of the attending physicians15). It is noteworthy Nakamura et al conducted a multicenter cohort study of that patients with t(11;18) are likely to be be unresponsive a large number of patients with gastric MALT lymphoma to alkylating agents as a sole treatment16).
to evaluate the long-term outcome of the disease after In a recent multicenter international trial, IELSG-19 Helicobacter pylori eradication12). Four hundred and study, patients affected by MALT extranodal lymphoma twenty patients with gastric low-grade MALT lymphoma not responding or not suitable for local therapy, were who were given successful H pylori eradication and randomized to receive chlorambucil alone versus chloram- followed up for at least 3 years, were registered from 21 bucil plus rituximab versus rituximab alone. Chlorambucil participating institutes. Responders to treatment were was given daily 6 mg/sqm orally for six weeks. Re- defined as patients whose post-treatment biopsies showed sponding patients continued daily chlorambucil for 14 complete histological response (ChR) or probable mini- consecutive days every 28 days for four cycles. In the mal residual disease (pMRD). The reported response rate Rituximab plus chlorambucil arm, rituximab at standard was 77％ (323 patients) to H pylori eradication.
dose 375 mg/sqm was added on days 1, 8, 15, 22, 56, 84, The absence of H pylori, submucosal invasion deter- 112, and 140. The results between chlorambucil versus mined by endoscopic ultrasonography and t(11;18)/API2- rituximab plus chlorambucil showed and advantage in MALT1 were independent predictors of resistance to H rituximab plus chlorambucil arm in term of event-free pylori eradication in a logistic regression analysis.
survival (5-year EFS 68％ versus 50％; p . 002); overall Moreover, Cox multivariate analysis revealed endoscopic survival was similar. Toxicities prophyle was superimpos- non-superficial type to be an independent prognostic able in the two arms17).
factor for adverse freedom from treatment failure, overall The pathogenetic relevance in MALT of a constitutive survival and event-free survival12).
activation of NF-kB pathway was the rationale for testing In H. pylori-negative gastric MALT lymphoma, antibiot- bortezomib in extranodal marginal zone B-cell lymphoma ic treatment has been described in a limited number of pa- of MALT-type in relapse; this trial was performed by tients. In these cases a regression of the lymphoma after IELSG. Thirty-one patients with relapsed/refractory antibiotic treatment is unlikely, but the administration of MALT lymphoma were enrolled and treated with bortezo- an anti-helicobacter regimen was tested based on mib 1.3 mg/sqm i.v., on days 1, 4, 8, and 11, for up to six occasional lymphoma responses that were described cycles every 21 days. In this relapsed setting, the overall (possibly due to a false-negative test or to infection by response rate was 48％ and after a median follow-up of 24 other Helicobacter species). In a series of six published months, the median duration of response was not studies, including 108 HP negative patients that were treated solely with antibiotic regimen as initial treatment, Primary testicular lymphoma
23 patients (21％) were shown to respond to thistreatment alone13).
Primary testicular lymphoma (PTL), represent 1─2％ of In patients who fail antibiotic therapy, treatment options all NHL, roughly 5％ of all testicular malignancies. The include radiotherapy and systemic treatment and the most frequent histology is diffuse large B-cell lymphomas choice is based on the stage of disease. Radiotherapy may (90％), and more than 80％ of PTL are diagnosed in the give good disease control in localized disease as reported by several authors14). Patients with advanced symptomatic Somatic hypermutation of immunoglobulin heavy-chain − 臨 床 血 液 − gene, indicating a possible antigen-driven stimulation, was efficacy of a combined treatment strategy (R-CHOP21 described in PTL. The loss of HLA-DR and -DQ ex- plus both CNS and testicular prophylaxis). Fifty-three pa- pression associated with homozygous deletions of the tients were enrolled and treated with standard dose of R- corresponding genes was common in DLBCL-PTL; they CHOP21; stage I patients received six courses of R- manifested also a higher frequencies of HLA-DRB1＊15 CHOP21, stage II patients received a total of six or eight and HLA-DRB1＊12. These features may suggest an courses of R-CHOP21. CNS prophylaxis with intrathecal antigen-driven mechanism in the pathogenesis of PTL.
methotrexate, weekly for four times, during the first two Diagnosis should be performed by histology with R-CHOP21 courses, was planned. At the end of chemoim- orchiectomy. Bilateral involvement is relatively frequent in munotherapy, prophylactic irradiation to the contralateral PTL even in PTL patients without clinical evidence of dis- testis at 25 to 30 Gy was given; in stage II disease, beyond ease; structures within the scrotum and regional retroperi- prophylactic testicular radiotherapy, patients received in- toneal lymph-nodes may be involved at diagnosis: 70─80％ volved field radiotherapy. Results showed, with a median of patients are at diagnosis in localized stages I and II with follow-up of 65 months, 5-year progression-free survival regional lymphnode involvement.
and overall survival rates of 74％ and 85％. With this Classical clinical presentation includes unilateral pain- approach, the 5-year cumulative incidence of CNS relapse less scrotal swelling, sometimes with scrotal pain; hy- was reduced to 6％ and no contralateral testis relapses drocele is observed in 43％ of cases. Systemic symptoms were recorded 22).
are present only in advanced stage.
The pattern of CNS recurrence in PTL is a mixture of The key points on which is based PTL treatment are a meningeal and brain relapses20). For this reason, the high risk of extranodal relapses, a high risk of contrala- optimal strategy for preventing CNS relapse is no well teral testicular failure and a high risk of CNS recurrence.
defined and under investigation. To properly assess the The outcome of PTL was poor, with 5-year survival ranged best strategy for CNS prophylaxis in patients with PTL, a from 16％ to 50％ and median survival of 12─24 months newprospective study (IELSG-30) is ongoing to test the according to the different series of patients. With use of drugs with a higher CNS bioavailability, such as locoregional treatment alone, including orchiectomy alone intrathecal liposomal cytarabine and/or the addition of or radiation therapy on lomboaortic or iliac lymph nodes systemic intermediate-dose methotrexate after full stand- after orchiectomy the overall relapse rate was upper to ard six courses of R-CHOP21 and contralateral testis radiotherapy, with the aim to prevent CNS relapses (Fig.
On this basis, a systemic treatment is mandatory. The introduction of anthracycline-containing regimens was Primary central nervous system lymphoma
associated with a 5-yr survival of 30─60％, but a con-tinuous relapse pattern was registered. In two retrospec- tive survey of 373 PTL (IELSG)20) and 769 PTL patients (PCNSL) represent less than 1％ of all NHL and roughly (SEER)21), the median overall survival was of 4 to 5 years, 2─3％ of all brain tumor. Median age at diagnosis was 62 with a continuous risk of relapse and deaths due to lym- years. The most frequent histological subtype is diffuse phoma, even 10 years after diagnosis. Long term relapses large B-cell lymphoma. In 60％ of the cases there is a at extranodal sites were frequent, especially in the CNS supratentorially localization; 5％ of patients showa and the contralateral testis, even in patients treated with leptomeningeal involvement and 20％ a intraocular lesion.
anthracycline-cointaining regimens. Radiotherapy to the Clinical symptoms are neurological deficits and/or contralateral testis almost abrogates the risk of local neuropsychiatric symptoms; symptoms due to increased failure20); CNS relapses remained a dismal issue, with 5- intracranial pressure are often present, with headache, and 10-year risks of 20％ and 35％. The addition of blurred vision and neurophaties.
rituximab to cyclophosphamide, doxorubicin, vincristine, Bcl6 translocation was described in 30─40％ of PCNSL, and prednisone every 21 days (R-CHOP21) significantly with decreased or absent expression of HLA class I and II improves OS and progression-free survival (PFS) com- pared with CHOP alone. A prospective trial was conducted Staging includes: contrast-enhanced cranial magnetic by IELSG, IELSG10, with the aim to test the safety and resonance imaging, full-body CT-scan and bone marrow 臨 床 血 液 54：10
either methotrexate 3.5 g/sqm on day 1 or methotrexate3.5 g/sqm on day 1 plus cytarabine 2 g/sqm twice a day ondays 2─3; regimens were administered every 3 weeks andwere followed by whole-brain irradiation. After chemother- apy, the complete remission rate was of 18％ versus 46％,respectively in high-dose methotrexate alone versus high- dose citarabine plus methotrexate, (p=0.006). Grade 3─4haematological and non-hematological toxicities were more frequent in the high-dose cytarabine plus methotrex- ate group than in the methotrexate group; no statistical differences in terms of treatment-related deaths were reported. The study demonstrated that in patients aged 75 years and younger affected by PCNSL, the addition of high-dose cytarabine to high-dose methotrexate should improve the outcome with acceptable toxicity compared with high-dose methotrexate alone. Progression free survival was statistically significantly improved for pa- tients treated with high-dose methotrexate plus cytarabine(HR 0.54; 95％ CI 0.31 to 0.92; p .01), but this observation Protocol IELSG30 - Treatment scheme did not translate to a statistical significant OS benefit 27).
In the Cochrane metanalysis, experts concluded that biopsy. For diagnosis, stereotaxic biopsy is necessary; a the only one randomized small trail showed a benefit in diagnostic lumbar puncture completes the staging proce- terms of progression free survival and overall response rate, but these figures did not determine a statistically Treatment options for PCNSL include corticosteroids, significant difference in overall survival. In conclusion, chemotherapy and radiation. The use of corticosteroids is further randomized clinical trials to investigate the helpful to reduce neurological symptoms; an initial addition of different chemotherapy agents to high-dose radiological response to steroids represented a favorable methotrexate with a larger number of patients and longer prognostic marker, with survival of 117 months in re- follow-up are needed to determine whether the progres- sponders versus 5. 5 months in non-responders. Whole- sion free survival benefit will translate into an overall brain radiation therapy was an option used for several survival advantage.
years, but with poor results: median survival from 12 to 18 Moreover two further issues are no yet defined in the months and 5-year survival from 18％ to 35％. This option treatment of PCNSL: the role of Rituximab and the role of should be considered in unfit elderly people with con- high dose chemotherapy and autologous stem cell traindications to perform chemotherapy 25).
transplantation (HDC+ASCT). The efficacy of adding In a recent Cochrane metanalysis, 699 potentially Rituximab to systemic chemotherapy in PCNSL is unclear relevant references were analized26), but of these, only one because of its uncertain bioavailability in the CNS randomized controlled trial involving 79 patients was fluid 28∼31). HDC+ASCT has been applied as consolidation treatment in PCNSL with conflicting results 26, 32∼35). To In the IESLG phase II randomized trial, 79 patients with address these issue, a randomized trial on behalf of IELSG PCNSL at diagnosed were enrolled. Based on the is ongoing to investigate different induction treatments.
observation that chemotherapy with high-dose methotrex- PCNSL patients will be randomized to receive: a standard ate was the conventional approach to treat PCNSL, aim of treatment with high-dose methotrexate and high-dose the study was to demonstrate a superiority of polychemo- cytarabine versus the same combination chemotherapy therapy regimen (high-dose citarabine plus high-dose regimen with rituximab or with rituximab and thiotepa.
methotrexate) compared with high-dose methotrexate Patients who will achieve at least a stable disease after the alone. Patients were randomized to receive four courses of induction, will be randomly allocated to receive as − 臨 床 血 液 − Classification of Tumours of Haematopoietic and Lymphoid Tissues. Fourth Edition, Lyon, IARC Press; 2008.
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Mi KORU ME Support Group HAMILTON February 2014 Issue 30 "And now we welcome the New Year, Full of things that have never been." Rainer Maria Rilke New Year's greetings everyone, 2014 is well underway now with a start up of the year's activities. For some, a new year is no more than a change of a calendar. For others, the New Year symbolizes the beginning of a better tomorrow, and a new chapter in their lives. For many people a new year will inspire them to make resolutions, but despite good intentions, they are frequently broken! Often resolutions are centred on achieving better results or accomplishing more. Many people with ME/CFS and FM tend to be perfectionists and their self-esteem is tied in with their sense of achievement. Their typical goals for New Year are often unrealistic. Richard Eyre, in his book, ‘Don't Just Do Something, Sit There', argues that the traditional thinking about self improvement is out-dated or inaccurate. He feels we need new paradigms to ‘reflect our world as it really is, and our lifestyles as they really ought to be.' This is especially true for people with chronic illness. He thinks perhaps we need to rethink these annual goals and look to the New Year with a spirit of ‘anti-resolutions'. This means ‘releasing ourselves from the obligation of things we are not able to do and consider alternatives more supportive of healing and well-being'. He calls it ‘The art of letting go'. For example the goal ‘I will manage my time better so I can do more' can become ‘I will pace myself to allow for rest and recovery'. There is a healing value in ‘letting go'. Definitely food for thought!