There may be debate about whether to start Rituximab with another cytostatic drug or in monotherapy, but given the lack of survival benefit with early initiation of treatment, the NCCN guidelines recommend waiting and seeing, unless GELF criteria are met to initiate treatment: GELF criteria (Follicular Lymphoma Study Group): - Involvement of ≥3 nodal areas, each with a diameter ≥ 3 cm. - Any nodal or extranodal mass with a diameter ≥ 7 cm. - B symptoms. - Splenomegaly. - Pleural effusion or ascites. - Cytopenias (leukocytes < 1.0 x 109 / L and/or platelets < 100 x 109 / L). - Leukemia (> 5.0 x 109 /L of malignant cells).

There may be debate about whether to start Rituximab with another cytostatic drug or in monotherapy, but given the [HIDDEN], the NCCN guidelines recommend waiting and seeing, unless GELF criteria are met to initiate treatment: GELF criteria (Follicular Lymphoma Study Group): - Involvement of ≥3 nodal areas, each with a diameter ≥ 3 cm. - Any nodal or extranodal mass with a diameter ≥ 7 cm. - B symptoms. - Splenomegaly. - Pleural effusion or ascites. - Cytopenias (leukocytes < 1.0 x 109 / L and/or platelets < 100 x 109 / L). - Leukemia (> 5.0 x 109 /L of malignant cells).

A 78-year-old woman with a history of type 2 diabetes treated with oral antidiabetics, hypertension treated with beta-blockers and ACE inhibitors, and NYHA grade 1 congestive heart failure with LVEF of 48%, and currently asymptomatic. Functional status: ECOG 0. History of 2 years of evolution of small lumps in the neck. Biopsy of cervical adenopathy: follicular lymphoma grade 2. Extension study: Hb 12 g/dL, Leukocytes 6,900/microL (Neutrophils 60%, Lymphocytes 27%, Monocytes 6%, Eosinophils 4%, Basophils 4%), Platelets 220,000/microL. MO: infiltrate by follicular lymphoma. Creatinine 1.5 mg/dL, LDH 235 U/L, Beta2 microglobulin 2.1 microg/mL. CT: lymphadenopathies less than 3 cm in cervical, axillary, retroperitoneal, iliac and inguinal territories; liver and spleen are normal. Which of the following treatments is the most appropriate?

Rituximab-CHOP (Cyclophosphamide, Adriamycin, Vincristine, Prednisone).

Rituximab-CVP (Cyclophosphamide, Vincristine, Prednisone).

Do not treat and monitor (wait and see).

[Chronic lymphocytic leukemia].

Chronic lymphocytic leukemia (CLL) is a lymphoproliferative disorder that accounts for approximately 30 % of adult leukemias and 25 % of Non-Hodgkin lymphomas (NHL). It is the most common form of leukemia in the western world (incidence 3-5/100 000). Elderly people are mainly affected, median age at diagnosis is around 70 years and there is a slight predominance in men. The etiology of the disease is unknown. The initial symptoms are nonspecific. Cervical lymphadenopathy and splenomegaly followed by general fatigue are seen most commonly. Other possible symptoms include night sweats, fever, loss of weight (so-called B symptoms) and frequent infections. Several patients develop autoimmune complications as autoimmune hemolytic anemia (AIHA) or immune thrombocytopenia (ITP). To confirm the diagnosis more than 5000 B-lymphocytes/µl need to be present. The expression of the typical surface markers CD5, CD19, and CD23 has to be confirmed by flow cytometry. Imaging studies as X-ray of the chest, ultrasound of the abdomen, or CT scan are used to assess the degree of lymphadenopathy or organomegaly. A bone marrow biopsy is not mandatory for the diagnosis. According to the European Binet staging system, CLL is divided into 3 stages (A, B and C). Patients in Binet stage A have 0 to 2 areas of node or organ enlargement with normal levels of hemoglobin and platelets. Binet stage B patients have 3 to 5 areas of node or organ enlargement and normal or slightly decreased levels of hemoglobin and platelets. Binet stage C patients have anemia (hemoglobin < 10 g/dl) and/or thrombocytopenia (platelet counts < 100 000/µl), with or without lymphadenopathy or organomegaly. As there is no survival benefit associated with early intervention, asymptomatic patients with early stage CLL (Binet stage A and B) are usually not treated but are followed on a "watch and wait" principle. Treatment indications include stage Binet C or signs of an active disease as rapidly progressive lymphadenopathy or organomegaly together with physical limitation, B symptoms that cannot be tolerated, rapidly deteriorating blood values, or rapidly increasing leukocyte counts. The patient's physical condition has major impact on the treatment decision. Currently immunochemotherapy with fludarabine, cyclophosphamide and the CD20-antibody rituximab (FCR) is the standard of care in previously untreated and physically fit CLL-patients. An alternative regimen is the combination of bendamustine and rituximab (BR). Physically compromised patients can be treated with the oral drug chlorambucil or with bendamustine with or without rituximab. Due to high morbidity and mortality, allogeneic stem cell transplantation is limited to a small group of patients and should be discussed in a high-risk situation, such as 17p deletion, lack of response to standard therapy or early relapse.

InternalMed_Harrison

Patients with follicular lymphoma have a high rate of histologic transformation to diffuse large B-cell lymphoma (5–7% per year). This is recognized ~40% of the time during the course of the illness by repeat biopsy and is present in almost all patients at autopsy. This transformation is usually heralded by rapid growth of lymph nodes—often localized—and the development of systemic symptoms such as fevers, sweats, and weight loss. Although these patients have a poor prognosis, aggressive combination chemotherapy regimens can sometimes cause a complete remission in the diffuse large B-cell lymphoma, at times leaving the patient with persisting follicular lymphoma. With more frequent use of R-CHOP to treat follicular lymphoma at diagnosis, it appears that the rate of histologic progression is decreasing. R-CHOP or bendamustine plus rituximab with intermittent rituximab maintenance for 2 years are the most commonly used treatment approaches.

Intravascular lymphomas

At diagnosis, IVBCL must be regarded as an aggressive and disseminated malignancy requiring systemic chemotherapy. In the absence of long- or short-term, controlled clinical trials on treating this lymphoma, individuals with IVBCL have been treated with the standard regimen used to treat diffuse large B-cell lymphomas viz., the CHOP chemotherapy regimen which consists of cyclophosphamide, hydroxydaunorubicin (also termed doxorubicin or adriamycin), oncovin (also termed vincristine), and a corticosteroid (i.e. either prednisone or prednisolone) plus the monoclonal antibody immunotherapy agent, Rituximab. This immunochemotherapeutic regimen has achieved an overall survival rate at 3 years of 81%; this overall survival rate using CHOP before Retuximab was added to the regimen was only 33%. However, highly toxic reactions to Rituximab such as pulmonary failure may occur and require delay or interrupting the use of this drug. High dose chemotherapy regimens followed by autologous stem-cell

InternalMed_Harrison

Five clinical risk factors: Age ≥60 years Serum lactate dehydrogenase levels elevated Performance status ≥2 (ECOG) or ≤70 (Karnofsky) Ann Arbor stage III or IV >1 site of extranodal involvement Patients are assigned a number for each risk factor they have Patients are grouped differently based on the type of lymphoma For diffuse large B-cell lymphoma: 0, 1 factor = low risk: 35% of cases; 5-year survival, 73% 2 factors = low-intermediate risk: 27% of cases; 5-year survival, 51% 3 factors = high-intermediate risk: 22% of cases; 5-year survival, 43% 4, 5 factors = high risk: 16% of cases; 5-year survival, 26% For diffuse large B-cell lymphoma treated with R-CHOP: 0 factor = very good: 10% of cases; 5-year survival, 94% 1, 2 factors = good: 45% of cases; 5-year survival, 79% 3, 4, 5 factors = poor: 45% of cases; 5-year survival, 55% Abbreviations: ECOG, Eastern Cooperative Oncology Group; R-CHOP, rituximab, cyclophosphamide, doxorubicin, vincristine, prednisone.

CHOP (chemotherapy)

In most other non-Hodgkin lymphomas (excluding some aggressive forms), standard-dose [R]-CHOP is generally used as first-line therapy. Uses and indications Normal cells are more able than cancer cells to repair damage from chemotherapy drugs. This regimen can also be combined with the monoclonal antibody rituximab if the lymphoma is of B cell origin; this combination is called R-CHOP. Typically, courses are administered at an interval of two or three weeks (CHOP-14 and CHOP-21 respectively). A staging CT scan is generally performed after three cycles to assess whether the disease is responding to treatment. In patients with a history of cardiovascular disease, doxorubicin (which is cardiotoxic) is often deemed to be too great a risk and is omitted from the regimen. The combination is then referred to as COP (cyclophosphamide, Oncovin, and prednisone or prednisolone) or CVP (cyclophosphamide, vincristine, and prednisone or prednisolone).

Follicular lymphoma

latter regimens, the regimens have shown similar results when analyzed based on poor treatment responses (~10-20% poor responses). Bendamustine with rituximab may be preferable to R-CHOP or R-CVP for treating low-grade (i.e. Grades 1, 2, and possibly 3A) FL; R-CHOP may be preferred in FL that has high-risk characteristics (e.g. high levels of Beta-2 macroglobulin or bone marrow involvement). The combination of lenalidomide with rituximab has shown good potential in treating indolent cases of FL.

First_Aid_Step2

■Treatment is based on histopathologic classification rather than on stage. Symptomatic patients are treated with radiation and chemotherapy T AB LE 2.7 -8. Presentation of Non-Hodgkin’s Lymphoma Painless peripheral adenopathy. Cytopenia from bone marrow involvement. Fatigue and weakness. Peripheral adenopathy, splenomegaly, hepatomegaly. Adenopathy. Extranodal disease (GI, GU, skin, thyroid, CNS). B symptoms (temperature > 38.5°C, night sweats, weight loss). Mass formation (e.g., abdominal mass with bowel obstruction in Burkitt’s lymphoma; mediastinal mass and SVC syndrome in lymphoblastic lymphoma). Bulky adenopathy, splenomegaly, hepatomegaly. Masses (abdominal, testicular, mediastinal). Skin f ndings. Low Intermediate to high (CHOP: cyclophosphamide [Cytoxan], Adriamycin, Oncovin [vincristine], and prednisone).

Marginal zone B-cell lymphoma

Current treatment recommendations for patients with symptomatic or rapidly progressive SMZL rely on drugs. Rituximab, a commercial preparation of a monoclonal antibody directed at the CD20 protein on B-cells, is significantly active in SMZL, with short-term treatments (e.g. ~4 weeks) achieving overall response rates of 90-100%, complete remission rates of >50%, and a 7-year progression-free survival rate of 69%. Long-term maintenance therapy with rituximab appears to improve these results and patients who relapse after rituximab therapy commonly respond to a second course of the drug. Prior to rituximab availability, single drug chemotherapy (e.g. chlorambucil, cyclophosphamide, fludarabine, pentostatin, 2CDA, or bendamustine) and multiple drug regimens (i.e. the CVP regimen of cyclophosphamide, vincristine, and prednisone, or the CHOP regimen of CVP plus doxorubicin) were used to treat the disease. However, current studies indicate that these chemotherapeutic agents are not superior

[Evolution of patients with rheumatoid arthritis treated with immunosuppressive agents between 1965 and 1973].

The authors report the results of a study of 139 of their patients with severe rheumatoid arthritis, treated with chlorambucil of cyclophosphamide between 1965 and December 1973, with an observation period of 4 to 12 years. 8 patients were lost to follow-up, 38 died and 93 were reexamined. In this series 7 deaths were attributed to hemolymphoreticulopathy of various cytological types; 6 deaths were due to visceral cancer and 2 others to cancer of the tonsils. They confirm that such treatments increase the risk of hemopathy but apparently not the risk of visceral cancer. The risk was not a function of the total dose of the drug administered since no neoplasia was observed in the 25 subjects who received the highest doses. The addition of chlorambucil to cyclophosphamide seems to increase the risk of hemopathy. It was noticed that the 7 cases of hemolymphoreticulopathy occured after 60 years.

First-line R-CVP versus R-CHOP induction immunochemotherapy for indolent lymphoma with rituximab maintenance. A multicentre, phase III randomized study by the Polish Lymphoma Research Group PLRG4.

R-CVP (cyclophosphamide, vincristine, prednisone) and R-CHOP (cyclophosphamide, doxorubicin, vincristine, prednisone + rituximab) are immunochemotherapy regimens frequently used for remission induction of indolent non-Hodgkin lymphomas (iNHLs). Rituximab maintenance (RM) significantly improves progression-free survival (PFS) in patients with complete/partial remission (CR/PR). Here we report the final results of a randomized study comparing R-CVP to R-CHOP both followed by RM. Untreated patients in need of systemic therapy with symptomatic and progressive iNHLs including follicular (FL) and marginal zone lymphoma (MZL), mucosa-associated lymphoid tissue (MALT), small lymphocytic (SLL), and lymphoplasmacytic (LPL) lymphoma were eligible. Patients were randomized to receive R-CVP or R-CHOP for eight cycles or until complete response (CR). All patients with CR/PR (partial response) received RM 375 mg/m<sup2</sup q 2 months for 12 cycles. Primary endpoint was event-free survival (EFS). Two-hundred and fifty patients [FL 42%, MZL/MALT 38%, LPL/ Waldenström Macroglobulinaemia (WM) 11%, SLL 9%] were enrolled and randomized (R-CHOP: 127, R-CVP: 123). Median age was 56 years (21-85), 44% were male, 90% were in stage III-IV, 43% of FL patients had a Follicular Lymphoma International Prognostic Index (FLIPI) score ≥3, and 33·4% of all patients had an IPI score ≥3. At the end of induction treatment, the CR/PR rate was 43·6/50·9% and 36·3/60·8% in the R-CHOP and R-CVP groups (P = 0·218) respectively. After a median follow-up of 67, 66, and 70 months, five-year EFS was 61% vs. 56% (not significant), progression-free survival (PFS) was 71% vs. 69% (not significant) and overall survival (OS) was 84% vs. 89% in the R-CHOP vs. the R-CVP arm respectively. Grade III/IV adverse events (65 vs. 22) occurred in 40 (33·1%) and 18 (15·3%) patients, P = 0·001; neutropenia in 16 (11·6%) and 4 (3·4%) patients, P = 0·017; infection in 14 (10·7%) and 3 (2·5%) patients,; P = 0·011; and a second neoplasm in three versus seven patients., in the R-CHOP and the R-CVP groups respectively. This multicentre randomized study with >five-year follow-up shows similar outcome in patients with indolent lymphoma in need of systemic therapy treated with R-CVP or R-CHOP immunochemotherapy and rituximab maintenance in both arms. The minor toxicity of the R-CVP regimen makes it a reasonable choice for induction treatment, leaving other active agents like doxorubicin or bendamustin for second-line therapy.

Pediatric-type follicular lymphoma

Virtually all cases of PTFL, even if treated with minimal interventions such as surgical removal or a watch-and-wait approach, have had a relatively benign and sometimes remitting and relapsing course. Thus, past recommendations that these patients need to be evaluated by bone marrow biopsy, lumbar puncture, or other invasive and/or expensive procedures requires revaluation. The evaluation of therapeutic regimens used to treat PTFL is complicated by their purely retrospective nature and inclusion of cases which in retrospect were likely cases of large B-cell lymphoma with IRF4 rearrangement. In any event, many of these cases were treated with chemotherapeutic regimens, principally, CHOP (i.e. cyclophosphamide, hydroxydaunorubicin, vincristine, prednisone) or R-CHOP (i.e. CHOP plus rituximab) while others, which likely excluded large B-cell lymphoma with IRF4 rearrangement, were treated with surgical removal, localized radiation therapy, and/or watch-and-wait strategies. All of these

[International prognostic index in diffuse B large cell lymphosarcoma].

To evaluate efficacy of the International Prognostic Index (IPI) in relation to diffuse B-large cell lymphosarcoma (BLCLS), to identify significant prognostic factors. The trial enrolled 121 patients (67 males and 54 females, mean age 54 years) suffering from BLCLS with involvement of the lymph nodes, spleen, tonsils. The diagnosis was made according to WHO criteria. 83 patients (29 with local lesion of lymph nodes, 10 with primary lesion of the tonsils, 9 with primary lesion of the spleen and 35 with generalized lesion) received polychemotherapy (PCT): CHOP-21, R-CHOP-21. Patients with primary splenic lesion have undergone splenectomy followed by CHOP-21 PCT, radiotherapy on the splenic region and that of regional lymph nodes. Radiation therapy was also given to patients with stage I-II, 38 patients received NHL-BFM-90 PCT. In distribution of patients into prognosis groups according to IPI 5-year event-free survival on CHOP-21 and R-CHOP-21 therapy was 83% in the group of low risk, 79% in the group of low/intermediate risk, 52% in the group of high/intermediate risk, 34% in the group of a high risk. However, there were poor outcomes in the group of low risk (recurrence, resistance) and long-term persistent remissions in high risk groups. Frequency and duration of complete remissions depended on location of the primary lesion. Five-year event-free survival in patients with solitary lesion of the peripheral lymph nodes on CHOP-21, R-CHOP-21 in spite of their size (bulky) and high concentration of lactate dehydrogenase) was 97% while in tonsillar lesion (according to IPI all the patients entered groups of low and low/intermediate risk) - 50%. All the patients with primary splenic lesion according to IPI had high risk but after splenectomy and PCT (CHOP-21, R-CHOP-21) followed by radiotherapy they demonstrated 100% 5-year event-free survival (follow-up since 1998). Determination of prognosis groups in BLCLS is not valid as such distribution gives no grounds for choice of adequate therapy. A decisive prognostic factor is now site of the lesion.

Diffuse large B-cell lymphoma

First-line therapy for patients with the GBC variant of DLBCL, NOS is R-CHOP. R-CHOP consists of rituximab, three chemotherapy drugs (cyclophosphamide, doxorubicin, and vincristine) and a glucocorticoid (either prednisone or prednisolone). The regimen achieves cure, relapse following remission, and unresponsive rates of 60–70%, 30–40% and <10%, respectively, in GBC variant cases. Relapses generally occur within the first 3 years of diagnosis with few cases doing so after 5 years. Patients who are refractory to, relapse within 1 year of diagnosis before starting, relapse within 6 months after completing, or progress within 2 years of starting R-CHOP have poorer prognoses. R-CHOP is less effective and not recommended for patients who have MYC, BL2, and/or BL6 rearrangements regardless of their GBC, ABC, or non-GBC type. One recommendation for treating these DH/THL cases is the DA-R-EPOCH regimen (dose-adjusted rituximab, etoposide, prednisolone, oncovin, cyclophosphamide, and

[Changes in the prognosis and treatment of Waldenström macroglobulinemia. Literature overview and own experience].

Waldenström macroglobulinemia is defined by the presence of monoclonal immunoglobulin IgM type (M-IgM) and evidence of lymphoplasmacytic bone marrow infiltration. The disease has an indolent course, the treatment is only initiated when the disease has begun to damage its carrier. The following symptoms are regarded as proven indications for initiating therapy: B symptoms, symptomatic lymphadenopathy, splenomegaly, anemia with hemoglobin below 100 g / l or thrombocytopenia < 100 × 10(9)/l, caused by lymphoplasmacytic bone marrow infiltration. Frequent indications for initiating treatment include clinical evidence of hyperviscosity or cryoglobulinemia. M-IgM tends to have a character of autoantibody reaching up to 50 %, which may harm the organism, and therefore any proven damage to the organism by an autoimmune activity of M-IgM is also an indication for treatment. The text includes an overview of rare and very rare types of damage to the organism by M-IgM autoimmune activity. A combination of rituximab, cyclophosphamide and dexamethasone (RCD) is recommended for the initial treatment, possibly extended to R-CHOP regimen (rituximab, cyclophosphamide, vincristine, doxorubicin and prednisone). In our cohort of 43 patients the therapy involving a combination of R-CHOP achieved 3 (8.1 %) complete remissions and 31 (83.8 %) partial remissions. The remission in 75 % of the patients lasted more than 3 years. In case of recurrence after > 2 years, the same therapy can be used, in case of a relapse within a shorter period of time different treatment schedules are recommended. High-dose chemotherapy with an autologous transplant of stem cells obtained from peripheral blood is only recommended after the first recurrence for people under 65 years of age without contraindications. The text analyses the benefits of the new drugs for the treatment of Waldenström macroglobulinemia (bendamustine, thalidomide, lenalidomide, ibrutinib and high-dose chemotherapy).

Epstein–Barr virus-associated lymphoproliferative diseases

No controlled studies on the treatment of the disease have been reported. Stage I and II localized FTCL has been treated with surgery, X-ray therapy, PUVA therapy, topical steroids, chlormethine, and/or carmustine. More extensive stage III and IV disease has been treated with single chemotherapy drugs (e.g. methotrexate); multiple chemotherapy drug regimens (e.g. CHOP, R-CVP (i.e. rituximab, cytoxin, vincristine, prednisone); with Rituximab, bortezomib, thalidomide, interferon-alpha, interferon-gamma, bexarotene, gemcitabine; and with hematopoietic stem cell transplantation. Responses to these treatments were variable and often disappointing. Most recently, however, bendamustine combined with rituximab or rituximab combined with cyclophosphamide, doxorubicin, vincristine, and prednisone have achieved partial response rates of >90% even in patients with advanced stage disease. While complete remission rates are substantially lower than 90% and treated patients have inevitably relapsed,

[Complete remission of relapsed mixed cellularity Hodgkin's disease treated with rituximab].

Cure rates of Hodgkin's disease (HD) with chemotherapy and/or radiotherapy are high. However, a few patients are refractory to treatment or relapse. We describe a patient with mixed cellularity (MC)-type HD with frequent relapses. As all Hodgkin's or Hogan-Reed-Sternberg (HRS) cells expressed CD20, treatment with the anti-CD20 monoclonal antibody rituximab was given. A 55-year-old man presented with cervical lymphadenopathy. Biopsy revealed HD of MC type in stage IVA (Ann Arbor classification). Complete remission (CR) was achieved after six cycles of doxorubicin-bleomycin-vinblastin-dacarbazine (ABVD) and cyclophosphamid-vincristine-procarbazine-prednison (COPP) regimens. The first relapse occurred 12 months later and was treated with DEXA-BEAM and autologous peripheral blood stem cell transplantation. 7 years later, the patient relapsed again. Histology confirmed the initial diagnosis. Staging revealed a stage IVA. A partial remission was induced with two further DEXA-BEAM cycles (dexamethasone, BCNU [1,3-bis(2-chloroethyl)-1-nitrosourea], ectoposide, ara-C, melphalan). 4 months later, the disease progressed. Despite treatment with gemcitabine there was no response. As all Hogan-Reed-Sternberg (HRS) cells were CD20 positive, rituximab (monoclonal antibodies) was given at a dose of 375 mg/m2 once a week for 4 weeks in an outpatient setting. Treatment was well tolerated. A complete remission was achieved 2 months later. No infectious episodes occurred. After 30 months, the patient relapsed again. A second treatment with rituximab yielded another complete remission which was maintained for 20 months. HRS cells are derived from germinal center B-cells in more than 90% of cases, B-cell markers being present in 80% of classical HD. CD20 expressions vary from 21-80%. A few patients with HD treated with rituximab have been reported. Most of these cases had lymphocyte-predominant HD. In our patient the safety and efficacy of rituximab in relapsed CD20-positive classical HD of an MC type was demonstrated to achieve long-lasting remission.

Lenalidomide maintenance after autologous haematopoietic stem-cell transplantation in mantle cell lymphoma: results of a Fondazione Italiana Linfomi (FIL) multicentre, randomised, phase 3 trial.

Fit patients with mantle cell lymphoma aged 18-65 years are usually given cytarabine and rituximab-based induction regimens followed by autologous haematopoetic stem-cell transplantation (HSCT). We investigated whether post-autologous HSCT maintenance with lenalidomide improves progression-free survival in this population. This open-label, randomised, multicentre, phase 3 trial was done at 49 haematology and oncology units in Italy and Portugal. Eligible patients had Ann Arbor stage III or IV treatment-naive mantle cell lymphoma (or stage II plus bulky disease [≥5 cm] or B symptoms), and had evidence of cyclin D1 overexpression or the translocation t(11;14)(q13;q32). Patients were aged 18-59 years with Eastern Cooperative Oncology Group (ECOG) performance status 0-3, or aged 60-65 years with ECOG 0-2. After an optional prephase with vincristine and steroids (intravenous vincristine 1·4 mg/m<sup2</sup on day 1, oral prednisone 100 mg [total dose] on days 1-5), patients were given three courses of R-CHOP (21-day cycle, intravenous rituximab 375 mg/m<sup2</sup on day 1; intravenous doxorubicin 50 mg/m<sup2</sup, vincristine 1·4 mg/m<sup2</sup, and cyclophosphamide 750 mg/m<sup2</sup on day 2; oral prednisone 100 mg/m<sup2</sup on day 2-6). Patients then received one cycle of high-dose CTX (intravenous cyclophosphamide 4 g/m<sup2</sup on day 1, intravenous rituximab 375 mg/m<sup2</sup on day 4). After restaging, patients received two cycles of R-HD-cytarabine (high-dose intravenous cytarabine 2 g/m<sup2</sup every 12 h on days 1-3, intravenous rituximab 375 mg/m<sup2</sup on days 4 and 10). Patients with complete remission or partial remission proceeded to autologous HSCT and responding patients (complete remission or partial remission) with haematological recovery were randomly assigned (1:1) to receive 24 courses of oral lenalidomide maintenance (15 mg per day for patients with platelets >100 × 10<sup9</sup cells per L or 10 mg per day for platelets 60-100 × 10<sup9</sup cells per L, days 1-21 every 28 days) for 24 months, or observation. The primary endpoint was progression-free survival, measured in the randomised population. This study is registered with EudraCT (2009-012807-25) and ClinicalTrials.gov (NCT02354313). Between May 4, 2010, and Aug 24, 2015, 303 patients were screened for inclusion and 300 patients were enrolled (median age 57 years, IQR 51-62; 235 [78%] male). 95 patients were excluded before randomisation, mostly due to disease progression, adverse events, and inadequate recovery. 104 patients were randomly assigned to the lenalidomide maintenance group and 101 patients to the observation group. 11 (11%) of 104 patients assigned to lenalidomide did not start treatment (3 withdrew, 6 adverse events or protocol breach, 2 lost to follow-up). At a median follow-up of 38 months after randomisation (IQR 24-50), 3-year progression-free survival was 80% (95% CI 70-87) in the lenalidomide group versus 64% (53-73) in the observation group (log-rank test p=0·012; hazard ratio 0·51, 95% CI 0·30-0·87). 41 (39%) of 104 patients discontinued lenalidomide for reasons including death or progression. Treatment-related deaths were recorded in two (2%) of 93 patients in the lenalidomide group (1 pneumonia, 1 thrombotic thrombocytopenic purpura), and one (1%) of 101 in the observation group (pneumonia). 59 (63%) of 93 patients in the lenalidomide group had grade 3-4 haematological adverse events versus 12 (12%) of 101 patients in the observation group (p<0·0001). 29 (31%) of 93 patients in the lenalidomide group and eight (8%) of 101 patients in the observation group had grade 3-4 non-haematological adverse events (p<0·0001), of which infections were the most common.Serious adverse events were reported in 22 (24%) of 93 patients in the lenalidomide group and five (5%) of 101 patients in the observation group. Pneumonia and other infections were the most common serious adverse events. Despite non-negligibile toxicity, lenalidomide after autologous HSCT improved progression-free survival in patients with mantle cell lymphoma, highlighting the role of maintenance in mantle cell lymphoma. Fondazione Italiana Linfomi and Celgene.

[Non-Hodgkin's lymphoma of the Waldeyer's ring: the treatment results of the past 22 years and the significance of CHOP].

From 1966 through 1988, 124 patients with non-Hodgkin's lymphoma of the Waldeyer's ring were treated. Seventy patients were male, and 54 were female. Age ranged from 5 to 81 years with a median value of 53 years. Pathological slides were reviewed and reclassified according to the Working Formulation. Diffuse large cell type was most common (53%). Since 1981, CHOP has been incorporated into the treatment including stage I and II patients. During these 22 years, new imaging modalities have developed, and an upstage rate by using those modalities has increased from 5% to 9%. In order to make the comparison meaningful, we used clinical stage determined at the day of the first visit. Fifty-one patients were clinical stage I, 64 were stage II, seven were stage III, and two were stage IV. B symptom was seen in 8 patients. Relapse developed in 45 patients (41%) out of 111 who achieved complete remission, and distant relapse was most frequent (89%). Salvage therapy was successful in only three patients of the 45 relapsed patients. Overall 5-year freedom from relapse (FFR) were 38% for the patients treated until 1980, and 69% for the patients treated thereafter (p less than 0.01). Addition of CHOP to radiotherapy has increased 5-year FFR of the stage II patients from 31% to 81% (p less than 0.01). In stage I, 5-year FFR was 71% in the patients treated with CHOP and radiotherapy, and it was 27% treated without CHOP. But the difference has no statistical significance, and we can not rule out the presence of selection bias.(ABSTRACT TRUNCATED AT 250 WORDS)

Follicular lymphoma

Patients who relapse after initial therapy for FL may be followed closely without therapy if asymptomatic. When treatment is required, patients may be treated with the initial treatment regimen when such treatment led to a remission that lasted for at least one year; otherwise an alternative regimen is used. The regimens commonly used in relapsed lymphoma include R-CHOP, R-CVP, RFM (i.e. rituximab, fludarabine, and mitoxantrone), and RB (Bendamustine plus rituximab). Patients who suffer early treatment failure (e.g. within 1–2 years of initial treatment) or multiple relapses have also been treated with either autologous (i.e. stem cells taken from patient) or allogeneic (i.e. stem cells taken from a donor) stem cell bone marrow transplantation. While studies are inconclusive, autologous stem cell bone marrow transplantation appears to prolong survival in early treatment failure patients who are healthy enough to withstand this therapy. Unfit patients may benefit from initial

Immunochemotherapy With Obinutuzumab or Rituximab for Previously Untreated Follicular Lymphoma in the GALLIUM Study: Influence of Chemotherapy on Efficacy and Safety.

Purpose The GALLIUM study ( ClinicalTrials.gov identifier: NCT01332968) showed that obinutuzumab (GA101; G) significantly prolonged progression-free survival (PFS) in previously untreated patients with follicular lymphoma relative to rituximab (R) when combined with cyclophosphamide (C), doxorubicin, vincristine (V), and prednisone (P; CHOP); CVP; or bendamustine. This report focuses on the impact of chemotherapy backbone on efficacy and safety. Patients and Methods A total of 1,202 patients with previously untreated follicular lymphoma (grades 1 to 3a), advanced disease (stage III or IV, or stage II with tumor diameter ≥ 7 cm), Eastern Cooperative Oncology Group performance status 0 to 2, and requiring treatment were randomly assigned 1:1 to G 1,000 mg on days 1, 8, and 15 of cycle 1 and day 1 of subsequent cycles or R 375 mg/m<sup2</sup on day 1 of each cycle, for six to eight cycles, depending on chemotherapy (allocated nonrandomly by center). Responding patients received G or R for 2 years or until disease progression. Results Baseline Follicular Lymphoma International Prognostic Index risk, bulky disease, and comorbidities differed by chemotherapy. After 41.1 months median follow-up, PFS (primary end point) was superior for G plus chemotherapy (overall hazard ratio [HR], 0.68; 95% CI, 0.54 to 0.87; P = .0016), with consistent results across chemotherapy backbones (bendamustine: HR, 0.63; 95% CI, 0.46 to 0.88; CHOP: HR, 0.72; 95% CI, 0.48 to 1.10; CVP: HR, 0.79; 95% CI, 0.42 to 1.47). Grade 3 to 5 adverse events, notably cytopenias, were most frequent with CHOP. Grade 3 to 5 infections and second neoplasms were most frequent with bendamustine, which was associated with marked and prolonged reductions in T-cell counts. Fatal events were more frequent in patients treated with bendamustine, possibly reflecting differences in patient risk profiles. Conclusion Improved PFS was observed for G plus chemotherapy for all three chemotherapy backbones. Safety profiles differed, although comparisons are confounded by nonrandom chemotherapy allocation.

[Nodular lymphocyte-predominant Hodgkin's lymphoma: Principles of diagnosis and treatment].

To describe the clinical and morphological features of the rare Hodgkin's lymphoma (HL) subtype--nodular lymphocyte-predominant HL (NLPHL). Forty-two patients were diagnosed with NLPHL in 2010 to 2014. The male to female ratio was 2.2:1; the median age was 37 years (range 17-68 years). NLPHL was diagnosed on the basis of the histological and immunohistochemical examinations of tumor biopsy specimens; disease stages were determined by standard HL studies. Before NLPHL was detected, 23 (55%) patients were diagnosed as having HL in 13 cases, follicular lymphoma in 2, lymphofollicular hyperplasia in 3, angioimmunoblastic lymphoma in 1, diffuse large B-cell lymphoma in 3, and B-cell lymphoma (non-HL) in 1. Long-term (3-21-year; median 8 years) persistent lymphadenopathy was observed in 16 (38%) patients. Seventeen (40.5%) patients had early (I-II) stages of the disease and 25 (59.5%) had advanced stages. B symptoms were noted in 24% of cases. There was involvement of extranodal sites (salivary gland, tonsil) in 2 patients, spleen in 14 (33%), bone marrow in 8, and bulky disease in 2. Cycles of ABVD ± rituximab ± radiotherapy (RT) were used in early-stage NLPHL; those of R-BEACOPP-14 ± RT were performed in the advanced stages of the disease or its transformation to diffuse large B-cell lymphoma with excessive T cells. When patients have a history of long-term asymptomatic lymphadenopathy, it is necessary to rule out NLPHL, for which purpose an immunohistochemical examination of a biopsy specimen and its reexamination in a laboratory having experience in diagnosing NLPHL must necessarily be done. Lower RT doses and rituximab incorporated into the cycle of treatment are indicated to reduce its toxicity and to preserve therapeutic efficiency.

Efficacy and safety of subcutaneous rituximab versus intravenous rituximab for first-line treatment of follicular lymphoma (SABRINA): a randomised, open-label, phase 3 trial.

Intravenous rituximab is the standard of care in B-cell non-Hodgkin lymphoma, and is administered over 1·5-6 h. A subcutaneous formulation could reduce patients' treatment burden and improve resource utilisation in health care. We aimed to show the pharmacokinetic non-inferiority of subcutaneous rituximab to intravenous rituximab in follicular lymphoma and to provide efficacy and safety data. SABRINA is a two-stage, randomised, open-label phase 3 study at 113 centres in 30 countries. Eligible patients were aged 18 years or older and had histologically confirmed, previously untreated, CD20-positive grade 1, 2, or 3a follicular lymphoma; Eastern Co-operative Oncology Group performance statuses of 0-2; bidimensionally measurable disease (by CT or MRI); life expectancy of 6 months or more; adequate haematological function for 28 days or more; and one or more symptoms requiring treatment according to the Groupe d'Etudes des Lymphomes Folliculaires criteria. Patients were randomly assigned (1:1) by investigators or members of the research team via a dynamic randomisation algorithm to 375 mg/m<sup2</sup intravenous rituximab or 1400 mg subcutaneous rituximab, plus chemotherapy (six-to-eight cycles of cyclophosphamide, doxorubicin, vincristine, and prednisone [CHOP] or eight cycles of cyclophosphamide, vincristine, and prednisone [CVP]), every 3 weeks during induction, then rituximab maintenance every 8 weeks. Randomisation was stratified by selected chemotherapy, Follicular Lymphoma International Prognostic Index, and region. The primary endpoint for stage 2 was overall response (ie, confirmed complete response, unconfirmed complete response, and partial response) at the end of induction. Efficacy analyses were done in the intention-to-treat population. Pooled data from stages 1 and 2 are reported on the basis of the clinical cutoff date of the last patient completing the maintenance phase of the study. This trial is registered with ClinicalTrials.gov, number NCT01200758; new patients are no longer being recruited, but some patients are still being followed up. Between Feb 15, 2011, and May 15, 2013, 410 patients were randomly assigned, 205 to intravenous rituximab and 205 to subcutaneous rituximab. Investigator-assessed overall response at the end of induction was 84·9% (95% CI 79·2-89·5) in the intravenous group and 84·4% (78·7-89·1) in the subcutaneous group. The frequency of adverse events was similar in both groups (199 [95%] of 210 in the intravenous group vs 189 [96%] of 197 in the subcutaneous group); the frequency of adverse events of grade 3 or higher was also similar (116 [55%] vs 111 [56%]). The most common grade 3 or higher adverse event was neutropenia, which occurred in 44 patients (21%) in the intravenous group and 52 (26%) in the subcutaneous group. Serious adverse events occurred in 72 patients (34%) in the intravenous group and 73 (37%) in the subcutaneous group. Administration-related reactions occurred in 73 patients (35%) in the intravenous group and 95 (48%) patients in the subcutaneous group (mainly grade 1 or 2 local injection-site reactions). Intravenous and subcutaneous rituximab had similar efficacy and safety profiles, and no new safety concerns were noted. Subcutaneous administration does not compromise the anti-lymphoma activity of rituximab when given with chemotherapy. F Hoffmann-La Roche.

[Clinical course of 8 patients with intravascular large B-cell lymphoma diagnosed while alive].

We retrospectively evaluated the diagnosis and clinical courses of 8 patients with intravascular large B-cell lymphoma (IVL) diagnosed while they were alive. The median age was 67 years old (range 54 to 82). Most complaints at diagnosis were fever or dyspnea. All patients were in clinical stage IV with B symptoms and 4 patients showed performance status 4. The diagnosis of IVL was confirmed by biopsy specimens from the bone marrow in 4, lung in 2, muscle, adrenal gland, and lymph node in 1 case, respectively. Initial bone marrow involvement was found in 6 patients. Chemotherapy was performed in 7 patients. Rituximab was added to chemotherapy in 5 patients. Though 5 patients are alive at the median follow up of 12.3 months, only 1 patient is in remission. Four of 5 patients treated with Rituximab relapsed. In suspicious cases, it is important to bear IVL in mind and examine bone marrow biopsies for an early diagnosis. In addition, it is suggested that Rituximab may play only a temporary role in the treatment of IVL.

[Clinical analysis of elderly patients with malignant lymphoma].

An epidemiological study on 173 consecutive elderly malignant lymphoma patients age 65 years or over was performed and the clinical outcome of chemotherapy is reported. Of there, 131 patients (75.7%) had non-Hodgkin's lymphoma (NHL) and 21 patients had Hodgkin's disease (HD). As for clinical staging, 58.9% of patients were in stage 3 or 4. The initial sites were nodal in 61.8% of the patients the most common sites of involvement in superficial lymph nodes being cervical, inguinal and axillar. The most frequent site of extranodal involvement was the gastrointestinal tract. The cases were treated with CHOP/COPP, BACOP or COP-BLAM combination chemotherapy. The clinical efficacy of these modalities was similar, with complete remission rates being about 50%. However, the total response rate (CR+partial remission) by the COP-BLAM regimen were 88.1%. The median survival time of cases achieving CR, was longer than 47 months. The most frequent cause of death was infection, especially pneumonia and septicemia. Many elderly ML patients were found and diagnosed when the disease developed to an advanced stage. Therefore it is necessary to make efforts to find early ML patients by screening apparently healthy elderly people. Improvement of the complete remission rate should be obtained if vigorous and intensive chemotherapy is carried out with careful supportive therapy concerning the general condition and complications in patients.

Follicular lymphoma

strongly support its use in localized disease. The use of an immunotherapeutic agent such as Rituximab alone or in combination with a chemotherapeutic regimen such as CVP (i.e. cyclophosphamide, vincristine, prednisone and rituximab) in cases of localized, early-stage disease may be appropriate choices for some of these early-stage patients. However, the latter approach is recommended for cases of localized disease in which the disease extends beyond a single field: 56% of patients treated in this manner had progression-free survival at 10 years while patients treated with other regimens had progression free survivals of 41%. Nonetheless, overall survival did not differ between the two groups.

[The treatment of large-cell non-Hodgkin's lymphomas with the MACOP-B protocol].

To investigate the results of the treatment of large-cell non-Hodgkin's lymphomas (LCNHL) with the MACOP-B chemotherapy protocol. 20 patients with the following inclusion criteria were treated: LCNHL with a definite majority of large lymphoid cells and absence of previous therapy, HIV infection or severe underlying diseases. Three patients died during therapy and 15 (75%) achieved a complete remission. Actuarial survival after 36 months (0.66) was significantly better (p = 0.05) than that of a comparable historical series of LCNHL treated with CHOP (0.28). Age, stages III-IV, B symptoms, large lymphatic mass (LLM) and bone marrow infiltration did not negatively affect survival. The toxicity of the MACOP-B protocol was high: mucositis (65%), cytopenia (55%), neuropathy (40%), complications of steroid therapy (15%), and mortality directly related with therapy in 15%. Residual masses were found after therapy in 7% (70%) with BD, which were localized in lymphoid areas or in parenchyma (spleen and kidney). Surgical exploration showed that the residual masses were not tumoral in three cases, and in another three magnetic resonance suggested inactive disease. The MACOP-B protocol is highly effective for the treatment of LCNHL. The essential prognostic factor for survival in these NHL appears to be the cell composition with a great majority of large cells.

Rituximab plus short-duration chemotherapy as first-line treatment for follicular non-Hodgkin's lymphoma: a phase II trial of the minnie pearl cancer research network.

To evaluate the feasibility and efficacy of rituximab with short-duration chemotherapy in the first-line treatment of patients with follicular non-Hodgkin's lymphoma (NHL). Patients with previously untreated stage II-IV follicular NHL, grade 1 or 2, were eligible for this multicenter phase II trial. All patients received four weekly doses of rituximab (375 mg/m(2) intravenous), followed by three courses of combination chemotherapy (either cyclophosphamide, doxorubicin, vincristine, and prednisone [CHOP], or cyclophosphamide, vincristine, and prednisone [CVP]) plus rituximab. Patients were evaluated for response after completing treatment, and were then followed up at 3-month intervals. Between January 2000 and July 2001, 86 patients were treated. Eight-two patients (95%) completed treatment; no patient was withdrawn due to toxicity. The overall response rate was 93%, with 55% complete responses. After a median follow-up of 42 months, the 3- and 4-year actuarial progression-free survivals were 71% and 62%, respectively. Five patients (6%) died from lymphoma; the overall actuarial survival at 3 years was 95%. Grade 3/4 leukopenia occurred in 53% of patients, but only six patients (7%) had neutropenia or fever. Grade 3/4 nonhematologic toxicities were uncommon. Rituximab plus short-course chemotherapy is well tolerated as first-line treatment for patients with follicular NHL. The overall and complete response rates are similar to those reported with chemotherapy/rituximab combinations of longer duration. The actuarial progression-free survival of 62% at 4 years is encouraging, but further follow-up is necessary. Rituximab plus short-course chemotherapy may prove to be as effective as longer-duration chemotherapy and currently provides an attractive option for first-line treatment of elderly patients and others who tolerate chemotherapy poorly.

[Diagnosis and treatment of 41 cases of head and neck Castleman's disease].

<bObjective:</b To explore the diagnosis and treatment of head and neck Castleman's disease (CD), and to improve the understanding of the disease. <bMethods:</b The clinical data of 41 patients with head and neck CD treated from January 2007 to July 2017 in the First Affiliated Hospital of Zhengzhou University were analyzed retrospectively. The patients were divided into two groups: localized CD (LCD, <in</i=27) and multicentric CD (MCD, <in</i=14). The clinical manifestations, laboratory examinations, operations, pathological findings and follow-up data were analyzed. <bResults:</b LCD was characterized by asymptomatic enlargement of the single lymph node with mild clinical symptoms. The main pathological type was hyaline vascular type, which can be cured by surgical treatment. MCD accompanied by fever 9 cases(64.3%), anemia 8 cases (57.1%), splenomegaly 7 cases (50.0%), respiratory symptoms 6 cases (42.9%), with multiple enlarged superficial and deep lymph nodes with pain, pleural effusion, and edema of lower extremity, C-reaction protein increased in 8 cases (57.1%), hypoproteinemia 8 cases(57.1%), globulin increased 7 cases (50.0%) and neutropenia 6 cases(42.9%). The main pathological type was plasma cell type in 7 cases (50.0%), and also there were 4 cases of hyaline vascular type and 2 cases of mixed type. Chemotherapy with or without rituximab was the main treatment. Most patients received complete or partial remission except for 2 patients who died of lung infection due to chemotherapy. <bConclusions:</b The diagnosis of head and neck CD depends on pathological examination. LCD shows mild symptoms and good prognosis after surgery. However, clinical manifestations of MCD are complex, with relatively poor prognosis after comprehensive treatment.

Transformation of Follicular Lymphoma to a High-Grade B-Cell Lymphoma With MYC and BCL2 Translocations and Overlapping Features of Burkitt Lymphoma and Acute Lymphoblastic Leukemia: A Case Report and Literature Review.

Most commonly, histologic transformation (HT) from follicular lymphoma (FL) manifests as a diffuse large B-cell lymphoma, not otherwise specified (DLBCL, NOS). Less frequently, HT may result in a high-grade B-cell lymphoma (HGBL) with MYC and B-cell lymphoma protein 2 (BCL2) and/or BCL6 gene rearrangements, also known as "double-hit" or "triple-hit" lymphomas. In the 2016 revision of the World Health Organization (WHO) classification of lymphoid neoplasms, the category B-cell lymphoma, unclassifiable was eliminated due to its vague criteria and limiting diagnostic benefit. Instead, the WHO introduced the HGBL category, characterized by MYC and BCL2 and/or BCL6 rearrangements. Cases that present as an intermediate phenotype of DLBCL and Burkitt lymphoma (BL) will fall within this HGBL category. Very rarely, HT results in both the intermediate DLBCL and BL phenotypes and exhibits lymphoblastic features, in which case the WHO recommends that this morphologic appearance should be noted. In comparison with de novo patients with DLBCL, NOS, those with MYC and BCL2 and/or BCL6 gene rearrangements have a worse prognosis. A 63-year-old woman presented with left neck adenopathy. Laboratory assessments, including complete blood count, complete metabolic panel, serum lactate dehydrogenase, and β<sub2</sub-microglobulin, were all normal. A whole-body computerized tomographic (CT) scan revealed diffuse adenopathy above and below the diaphragm. An excisional node biopsy showed grade 3A nodular FL. The Ki67 labeling index was 40% to 50%. A bone marrow biopsy showed a small focus of paratrabecular CD20+ lymphoid aggregates. She received 6 cycles of bendamustine (90 mg/m2 on days +1 and +2) and rituximab (375 mg/m2 on day +2), with each cycle delivered every 4 weeks. A follow-up CT scan at completion of therapy showed a partial response with resolution of axillary adenopathy and a dramatic shrinkage of the large retroperitoneal nodes. After 18 months, she had crampy abdominal pain in the absence of B symptoms. Positron emission tomography with 2-deoxy-2-[fluorine-18] fluoro-d-glucose integrated with CT (18F-FDG PET/CT) scan showed widespread adenopathy, diffuse splenic involvement, and substantial marrow involvement. Biopsy of a 2.4-cm right axillary node (SUVmax of 16.1) showed involvement by grade 3A FL with a predominant nodular pattern of growth. A bone marrow biopsy once again showed only a small focus of FL. She received idelalisib (150 mg twice daily) and rituximab (375 mg/m2, monthly) beginning May 2015. After 4 cycles, a repeat CT scan showed a complete radiographic response. Idelalisib was subsequently held while she received corticosteroids for immune-mediated colitis. A month later, she restarted idelalisib with a 50% dose reduction. After 2 weeks, she returned to clinic complaining of bilateral hip and low lumbar discomfort but no B symptoms. A restaging 18F-FDG PET/CT in January 2016 showed dramatic marrow uptake. A bone marrow aspirate showed sheets of tumor cells representing a spectrum from intermediate-sized cells with lymphoblastic features to very large atypical cells with multiple nucleoli. Two distinct histologies were present; one remained consistent with the patient's known FL with a predominant nodular pattern and the other consistent with HT (the large atypical cells expressed PAX5, CD10, BCL2, and c-MYC and were negative for CD20, MPO, CD34, CD30, and BCL6). Focal areas showed faint, heterogeneous expression of terminal deoxynucleotidyl transferase best seen on the clot section. Ki67 proliferation index was high (4+/4). Fluorescence in situ hybridization analysis showed 2 populations with MYC amplification and/or rearrangement and no evidence of BCL6 rearrangement; a karyotype analysis showed a complex abnormal female karyotype with t(14;18) and multiple structural and numerical abnormalities. She started dose-adjusted rituximab, etoposide, prednisone, vincristine, cyclophosphamide, and doxorubicin with concomitant prophylactic intrathecal methotrexate and cytarabine. She had but a short-lived response before dying in hospice from progressive lymphoma. Whether idelalisib could provide a microenvironment for selection of more aggressive clones needs to be addressed. Our patient's clinical course is confounded by the incorporation of idelalisib while being further complicated by the complexity of HT and the mechanisms in which first-line chemotherapy regimens affect double-hit lymphoma.

[Low-grade non-Hodgkin's lymphomas. Study of 73 cases].

To analyse the clinico-biologic features at diagnosis and the response to therapy and survival of a group of patients with low-grade non-Hodgkin's lymphoma (NHL). The study comprises 73 NHL patients diagnosed between 1974 and 1989 in the Covadonga Hospital and classified as low-grade in accordance with the international Working Formulation. The first-line treatment regimens used were cyclophosphamide-vincristine-prednisone (CVP), chlorambucil-prednisone (CBL-PRED), radiotherapy, and other combinations. The statistical study was performed by comparative statistics (Student's tests, chi-square), univariate analysis (Cox Mantel method) and multivariate analysis (Cox proportional risks); the BMDP pack was used for the study. The median age of the group was 63 years. Stages III and IV were seen at first in 75% of the patients, and 22% of the series had extranodal involvement. CVP was used in 69% of the cases, 7.6 received CBL-PRED, 11% were given radiotherapy, and other combinations were given to 11% of the patients. As a whole, responses were seen in 46 cases (73%), of whom complete remission (CR) was achieved in 49% and partial remission (PR) or minor responses (MR) were attained in 24% of instances. The factors influencing upon CR were: stage (p less than 0.0005), B-symptoms (p 0.004), splenomegaly (p less than 0.801), platelet count and haemoglobin rate (p less than 0.01). The total survival at 10 years was 53%, and the disease-free survival for those attaining CR was 48%, with disease-free median of 81 months. The univariate analysis was influenced in a negative fashion by the following: peripheral blood lymphocyte count below 2 x 10(9)/L, B-symptoms (p less than 0.002), bulky tumoural mass (p less than 0.007), advanced stage (p less than 0.003) and, chiefly, response to treatment (p less than 0.0001). The 10-year survival of the patients achieving CR was 86%, that of both types of response (PR and MR) was 20%, and it was 0% for the failures. 1) Patients in low stages have high possibilities of curation with radiotherapy. 2) CVP for advanced stages provides moderate percentage of response, with CR rate lower than 50%. It is necessary to select those patients with unfavourable prognostic factors in order to use aggressive treatment to achieve CR. 3) Patients attaining CR have better prognosis in spite of the frequent relapses (63% at 10 years).

Rituximab: a review of its use in non-Hodgkin's lymphoma and chronic lymphocytic leukaemia.

Rituximab is an anti-CD20 monoclonal antibody that has demonstrated efficacy in patients with various lymphoid malignancies, including indolent and aggressive forms of B-cell non-Hodgkin's lymphoma (NHL) and B-cell chronic lymphocytic leukaemia (CLL). While the optimal use of the drug in many clinical settings has yet to be clarified, two pivotal trials have established rituximab as a viable treatment option in patients with relapsed or refractory indolent NHL, and as a standard first-line treatment option when combined with cyclophosphamide, doxorubicin, vincristine and prednisone (CHOP) chemotherapy in elderly patients with diffuse large B-cell lymphoma (the most common type of aggressive NHL). The former was a noncomparative trial in relapsed indolent NHL (follicular and small lymphocytic subtypes) with clinical responses achieved in about half of patients treated with rituximab 375 mg/m(2) intravenously once weekly for 4 weeks, which was similar to some of the most encouraging results reported with traditional chemotherapeutic agents. The latter was a randomised comparison of eight cycles of CHOP plus rituximab 375 mg/m(2) intravenously (one dose per cycle) versus CHOP alone in previously untreated elderly patients (60 to 80 years of age) with diffuse large B-cell lymphoma. In this pivotal trial, 2-year event-free and overall survival were significantly higher with rituximab plus CHOP, and there was no increase in clinically significant adverse effects compared with CHOP alone. Treatment with rituximab is generally well tolerated, particularly in terms of adverse haematological effects and serious or opportunistic infections relative to standard chemotherapy. Infusion-related reactions occur in the majority of patients treated with rituximab; these are usually mild to moderate flu-like symptoms that decrease in frequency with subsequent infusions. In approximately 10% of patients, however, severe infusion-related reactions develop (e.g. bronchospasm, hypotension). These reactions are usually reversible with appropriate interventions and supportive care but there have been rare reports of fatalities. Clinical trials with rituximab indicate that the drug has broad application to B-cell malignancies, although further clarification is needed to determine its optimal use in many of these clinical settings. Importantly, rituximab in combination with CHOP chemotherapy has emerged as a new treatment standard for previously untreated diffuse large B-cell lymphoma, at least in elderly patients. Compared with conventional chemotherapy, rituximab is associated with markedly reduced haematological events such as severe neutropenia, as well as associated infections. Rituximab may be particularly suitable for elderly patients or those with poor performance status, and its tolerability profile facilitates its use in combination with cytotoxic drugs. Rituximab is a mouse/human chimaeric IgG(1)-kappa monoclonal antibody that targets the CD20 antigen found on the surface of malignant and normal B lymphocytes. Although treatment with rituximab induces lymphopenia in most patients, typically lasting about 6 months, a full recovery of B lymphocytes in the peripheral blood is usually seen 9-12 months after therapy, as CD20 is not expressed on haematopoietic stem cells. CD20 is, however, expressed on >90% of B-cell non-Hodgkin's lymphomas (NHL) and to a lesser degree on B-cell chronic lymphocytic leukaemia (CLL) cells. Although not fully elucidated, the cytotoxic effects of rituximab on CD20-positive malignant B cells appears to involve complement-dependent cytotoxicity, complement-dependent cellular cytotoxicity, antibody-dependent cellular cytotoxicity and induction of apoptosis. In addition, in vitro data indicate that rituximab sensitises tumour cells to the effects of conventional chemotherapeutic drugs. Serum rituximab concentrations increased in proportion to dose across a wide range of single- and multiple-dose intravenous regimens in patients with B-cell NHL. When administll NHL. When administered at a dose of 375 mg/m(2) once weekly for 4 weeks in a pivotal trial in patients with relapsed or refractory indolent B-cell NHL (follicular or small lymphocytic subtypes), peak serum concentrations essentially doubled from the first (239.1 mg/L) to the fourth (460.7 mg/L) infusion, while elimination half-life (t(1/2)) increased from 76.3 to 205.8 hours (3.2 to 8.6 days). The concomitant increase in serum rituximab concentrations and t(1/2) with each successive infusion may be due, at least in part, to the elimination of circulating CD20-positive B cells and reduction or saturation of CD20-binding sites after the initial infusions of rituximab. The pharmacokinetic properties of rituximab are also characterised by wide inter-individual variability, and serum drug concentrations that are correlated with clinical response. Although pharmacokinetic data are limited in patients with aggressive forms of NHL, such as diffuse large B-cell lymphoma, rituximab appears to have a similar pharmacokinetic profile in these patients to that in patients with indolent B-cell NHL. The pharmacokinetics of rituximab are also reported to be similar whether the drug is administered with or without cyclophosphamide, doxorubicin, vincristine and prednisone (CHOP) chemotherapy. A number of studies have demonstrated efficacy of intravenous rituximab in patients with various lymphoid malignancies of B-cell origin, including indolent (e.g. follicular lymphoma) and aggressive (e.g. diffuse large B-cell lymphoma) forms of NHL, and CLL, but the drug has not yet been approved for use in CLL, and approved indications in NHL vary between countries. In the US, for example, rituximab is available for the treatment of patients with low-grade or follicular, relapsed or refractory, CD20-positive B-cell NHL. In Europe, the drug has similar approval for relapsed or refractory follicular NHL as in the US, but has also been approved for use in combination with CHOP chemotherapy for the most common aggressive form of NHL (CD20-positive, diffuse large B-cell lymphoma). Rituximab was approved for these indications primarily on the basis of results from two pivotal trials. In Japan, rituximab has been approved for indolent B-cell NHL and mantle cell lymphoma (an aggressive form of B-cell NHL), primarily on the basis of results of a Japanese phase II trial. Indolent NHL: Results of several studies evaluating rituximab 375 mg/m(2) once weekly for 4 weeks in patients with indolent forms of B-cell NHL (primarily follicular and small lymphocytic lymphomas) showed objective response (OR) rates ranging from approximately 40-60% in those receiving the drug for relapsed or refractory indolent B-cell NHL, and slightly higher (50-70%) for those receiving rituximab as first-line therapy. In a pivotal trial in 166 patients with relapsed or refractory low-grade or follicular B-cell NHL, intent-to-treat (ITT) analysis showed an OR rate of 48%, and a projected median time to progression of 13 months. Encouraging data are also emerging on the use of rituximab in combination with chemotherapeutic agents (e.g. CHOP, fludarabine-containing regimens) or other drugs (e.g. interferon-alpha2a) in previously untreated patients with indolent forms of B-cell NHL (primarily follicular and small lymphocytic subtypes). Rates for OR were consistently around 95%, with the majority being complete responses (CRs). Follow-up data from a study in 40 patients with low-grade or follicular B-cell NHL treated with rituximab plus CHOP as first-line therapy showed that responses were durable with a progression-free survival and median duration of response >5 years.Bcl-2 gene rearrangement (t14;18) occurs in malignant cells in up to 85% of patients with follicular lymphoma, and minimal residual disease in peripheral blood and bone marrow can be monitored using polymerase chain reaction (PCR). In several studies assessing blood and/or bone marrow, rituximab has achieved molecular response (conversion from PCR-positive to PCR-negative bcl-2 status) in at least half of the patients. Aggressive NHL: Studies with rituximab as monotherapy in aggressive B-cell NHL, a potentially curable disorder, have generally been restricted to patients with relapsed or recurrent disease, since CHOP has traditionally been the standard first-line treatment regimen. However, promising results from phase II monotherapy studies prompted further clinical investigation of rituximab in conjunction with chemotherapy. Thus, most studies with rituximab in patients with aggressive forms of B-cell NHL have involved combination therapy, including a pivotal randomised trial comparing eight cycles of standard CHOP therapy plus rituximab 375 mg/m(2) (one dose per cycle) versus CHOP alone in 399 previously untreated elderly patients (60-80 years of age) with diffuse large B-cell lymphoma. Results of the pivotal trial showed a clear advantage for rituximab plus CHOP versus CHOP in terms of event-free survival (primary endpoint) at 2 years (57% vs 38%, p < 0.001). Overall survival at 2 years (70% vs 57%, p < 0.01) and CR rate (76% vs 63%, p < 0.01) were also higher with the rituximab-CHOP combination. Other, smaller trials with rituximab in combination with CHOP or other chemotherapeutic regimens, either as first-line therapy or for patients with relapsed or refractory aggressive B-cell NHL, have also shown promising results in terms of clinical response rates.CLL: In relatively small trials (n < 40) conducted primarily in patients with relapsed or refractory B-cell CLL, rituximab monotherapy (various regimens) achieved OR rates of 23-45%, with median duration of response ranging from approximately 3-10 months. (ABSTRACT TRUNCATED)

[Late cardiotoxicity of high-dose chemotherapy according to the modified NHL-BFM-90 program in adult patients with diffuse large B-cell lymphoma].

To evaluate the late cardiotoxicity (CT) of high-dose chemotherapy (CT) according to the modified NHL-BFM-90 (mNHL-BFM-90) protocol in adult patients with diffuse large B-cell lymphoma (DLBCL). The results of electrocardiography (ECG) and echocardiography (echoCG) were analyzed in 40 DLBCL patients treated according to the mNHL-BFM-90 program in the Hematology Research Center (HRC), Russian Academy of Medical Sciences (RAMS), in 2002 to 2009. A study group consisted of 20 men and 20 women whose age was 31 to 76 years; median age was 56.5 years at the time of their examination and the median follow-up time after therapy was 6 years. The individual cumulative dose of doxorubicin was 150-300 mg/M2. A comparison group included 19 patients receiving CHOP/R-CHOP CT in HRC, RAMS, in 2002 to 2009. Out of them, there were 8 men and 11 women whose age was 39 to 78 years median age was 70 years at the time of their examination. The individual cumulative dose of doxorubicin was 200-400 mg/M2. ECG and echoCG were carried out before and 5 years or more after CT. Out of the 40 patients with DLBCL, the signs of subclinical cardiomyopathy (CMP) were detected in 24 (60%) patients; no clinical manifestations of congestive heart failure (CHF) were found in any patient. In the comparison group of 19 patients receiving CHOP/R-CHOP CT, 14 (74%) patients were found to have signs of subclinical CMP and no clinical signs of CHF. The summary toxicity index significantly depended on age (p=0.03) and a history of heart disease (p=0.3); it was significantly higher after CHOP/R-CHOP CT (p=0.05). There was a statistically significant relationship of the risk of subclinical CMP to the history of heart diseases (p=0.05). Late cardiotoxicity of the mNHL-BFM-90 program does not exceed the toxicity of standard CHOP/R-CHOP therapy. Post-CT Echo-CG and ECG findings showed that the patients with the most marked subclinical signs of CMP in both groups had cardiotoxicity risk factors, such as coronary heart disease, hypertensive disease, or diabetes in their history. No clinically significant CHF was identified in any patient.