[Five year experience in ibrutinib therapy for relapsed and refractory mantle cell lymphoma in real world Russian clinical practice].

BACKGROUND: Mantle cell lymphoma (MCL) is a rare and clinically aggressive lymphoma subtype. Current approaches have greatly improved patients outcomes, but relapse is inevitable. In phase IIIII clinical trials, ibrutinib has shown significant activity in patients with relapsed or refractory (R/R) MCL. AIM: To assess efficacy and toxicity of ibrutinib monotherapy in patients with R/R MCL in routine practice outside of clinical trials. MATERIALS AND METHODS: The study enrolled patients with confirmed R/R MCL who had received at least one line of previous chemotherapy. ECOG 24, cytopenia, infectious complications, hemorrhagic syndrome were not exclusion criteria. Patients received daily oral ibrutinib 560 mg until progression or unacceptable toxicity. RESULTS: From May 2015 to September 2020 ibrutinib therapy was started in 106 patients with R/R MCL in 16 regions of Russia. The median age was 66 years; ECOG2 18%, blastoid variant (or Ki6740% or WBC50109/l) 43%. The median number of previous treatment lines was 2 (111). The ORR was 78.4% (CRR 27.4%). The median PFS was 13.6 months and OS 23.2 months. In the blastoid group the median PFS was 4.4 months vs 36.5 months in the alternative group (p0.001), the median OS 9.0 vs 41.0 (p=0.001). The median OS of patients after progression on ibrutinib was 3.2 months. The common complications are hemorrhages (63%), diarrhea (62%), myalgia and muscle cramps (60%), infections (31%), skin and nail toxicity 15%, arrhythmia 8%. None of recipients had to completely discontinue ibrutinib therapy due to complications. CONCLUSION: Ibrutinib is effective and well tolerated in routine practice of R/R MCL treatment and our results are consistent with international clinical trials. The favorable toxicity profile and the high response rate made it possible to prescribe ibrutinib in severe somatic status, cytopenia, and even in the presence of infectious complications.

[Informativeness of whole-body diffusion-weighted magnetic resonance imaging and positron emission tomography with computed tomography in follicular lymphoma].

AIM: This study conducted the possibilities of diffusion-weighted magnetic resonance imaging of the whole body diffusion WB-MRI (in comparison with positron emission tomography with computed tomography PET/CT) in assessing the volume and prevalence of the tumor, as well as determining bone marrow (BM) damage (for various cytological types) in the diagnosis and staging of the disease in patients with FL. MATERIALS AND METHODS: A prospective comparative search study included 15 patients (4 men and 11 women, with a median age of 53 years) with newly diagnosed FL. Patients have not received antitumor chemotherapy previously. After the diagnosis was established, all patients (with the blindness of both the cases themselves and some specialists regarding the results of other specialists) were examined by PET/CT and diffusion WB-MRI, after which a BM examination was performed (histological examination and determination of B-cell clonality in BM puncture by PCR). Using the diffusion WB-MRI method, the prevalence of tumor lesion (nodal and extranodal foci) in each patient was estimated, and the total tumor volume was calculated, BM lesion was detected, and BM lesion volume was calculated. For lesions of different localization, the measured diffusion coefficient (DC) of the diffusion WB-MRI and the standardized rate of accumulation of the radiopharmaceutical in tissues (SUV) of the PET/CT method were determined and compared with each other (for the same areas). Statistical analysis was performed using the estimate of agreement (by Cohens kappa coefficient and asymptotic test) of the results of the compared methods. RESULTS: Estimates of the prevalence of tumor damage (lymph nodes and extranodal foci) using the diffusion WB-MRI and PET/CT methods were the same. High DC and SUV were observed in the peripheral lymph nodes, extranodal foci and bulky, low DC and SUV in the foci of BM. All 4 methods successfully determined BM damage, however, the diffusion WB-MRI had comparatively less negative results. The highest values of SUV and CD were noted in cases of the 3 grade of FL. Using the diffusion WB-MRI method, the prevalence of tumor lesion was assessed in each patient (nodal and extranodal foci were detected) and the total tumor volume was calculated, BM lesion detection was performed, and the volume of BM lesion was calculated. It is important to note that with the help of diffusion WB-MRI, it was possible to measure separately the total tumor volume (462025 cm3) and separately the volume of bulky (251358 cm3). The diffusion WB-MRI allowed us to differentiate the volume of tumor tissue (reduced as a result of treatment) and residual (fibrous-adipose) tissue in residual formations (which averaged 21% of the initial volume). The predictors of a poor antitumor response were the maximum SUV values (more than 14.0) and the minimum DC values (0.510-3mm2/s) in the BM foci. CONCLUSION: The diffusion WB-MRI allows for detailed visualization of BM lesions and surrounding soft tissues both in the debut of the FL and in the process of tracking the effectiveness of chemotherapy, which makes it possible to use it along with PET/CT. Diffusion WB-MRI allows to separately evaluate the volume of true tumor tissue and residual tissue. Cases of the 3 grade of FL (including the transformation of FL into diffuse B-large cell lymphoma) are isolated due to low DC values (and high SUV values) in the tumor tissue. BM foci of FL lesion also have (in comparison with nodal and extranodal foci) lower DC values. The predictors of a poor antitumor response were high (from 14.0 or more) SUV valuesin the tumor (and especially in bulky), and low (about 0.5103mm2/s) DC values of BM foci. The PET/CT and diffusion WB-MRI have proven to be reliable diagnostic tools for establishing the stage of FL and detecting BM damage. Diffusion WB-MRI for FL is an informative first-line diagnostic method that allows regular monitoring of the disease and early detection of foci of relapse and disease progression.

[Risk - adapted intensive induction therapy, autologous stem cell transplantation, and rituximab maintenance allow to reach a high 7-year survival rate in patients with mantle cell lymphoma].

Mantle cell lymphoma (MCL) is aggressive B-cell neoplasm diagnosed predominantly among older men. R-CHOP-like regimens allow to achieve high response rate, but the overall survival (OS) are disappointingly short - 3-4 years. An addition of high - dose cytarabine to the upfront therapy and autoSCT significantly improved outcomes but remain feasible largely for medically fit patients. Based on the activity and good tolerance of gemcitabine - oxaliplatin schemes in relapsed and refractory MCL patients, we developed an alternative first - line course for patients who are not eligible for R-HD-MTX-AraC. AIM: Assess toxicity and efficacy of R-DA-EPOCH/ R-HD-MTX-AraC and R-DA-EPOCH/R-GIDIOX schemes, autoSCT and R-maintenance in untreated MCL patients. MATERIALS AND METHODS: 47 untreated MCL patients from 6 centers were enrolled in prospective study between April 2008 and September 2013. All patients have stage II-V; ECOG 0-3; median age 55 years (29-64); Male/Female 76%/24%. MIPIb: 28% low, 33% intermediate and 39% high risk. Following 1st R-EPOCH patients were assigned to receive either R-DA-EPOCH/ R-HD-MTX-AraC or R-DA-EPOCH/ R-GIDIOX regimen. In the absence of renal failure, hematological toxicity grade 4 more than 3 days and severe infections patients received R-HD-MTX-AraC scheme (R 375 mg/m2 Day 0, Methotrexate 1000 mg/m2/24 hours Day 1, AraC 3000 mg/m2 q 12 hrs Days 2-3). Patients who had at least one of these complications received R-GIDIOX scheme (R 375 mg/m2 day 0, gemcitabine 800 mg/m2 days 1 and 4, ifosfamide 1000 mg/m2 days 1-5, dexamethasone 10 mg/m2 IV days 1-5, irinotecan 100 mg/m2 day 3, oxaliplatin 120 mg/m2 day 2). Subsequently these courses were alternating with R-DA-EPOCH in each arm of the protocol. Depending on the time of achieving CR patients received 6 or 8 courses, unless they progressed on therapy. Those patients who achieved PR/CR/CRu underwent autoSCT (BEAM-R). Post - transplant R-maintenance was administered for 3 years (R - 375 mg/m2 every 3 months). RESULTS: 29/47 patients were treated on R-HD-MTX-AraC arm (median 50 years; MIPIb: 35.7% low, 28.6% intermediate, 35.7% high risk) and 18/47 patients were on R-GIDIOX arm (median 60 years; MIPIb: 16.7% low, 38.9% intermediate, 44.4% high risk). In R-HD-MTX-AraC arm CR rate was 96.5%. In R-GIDIOX arm OR and CR rates were 94.4% and 77.7% respectively. Main hematological toxicity of R-GIDIOX was leukopenia gr. 4 occurred in 74.1%. With median follow - up of 76 months, the estimated 7-years OS and EFS in R-HD-MTX-AraC arm are 76% and 57% respectively. In R-GIDIOX arm the estimated 7-years OS and EFS are 59% and 44%, respectively. There are no statistical differences in EFS (p=0.47) and OS (p=0.06) between two arms. CONCLUSIONS: The use of a risk - adapted strategy allowed 95.7% of patients achieve PR/CR/CRu, performed autoSCT and begun R-maintenance therapy with rituximab. None of the patients needed a premature discontinuation of therapy because of unacceptable toxicity. The performance of autoSCT and R-maintenance apparently allowed to partially offset differences in the intensity of induction therapy and to maintain comparable results of therapy in both induction arms.

[Follicular lymphoma: first - line selection criteria of treatment].

Follicular lymphoma (FL) is a tumor that develops from the B cells of the germinal center; characterized by recurrent and remitting course of the disease, the transformation of a tumor into diffuse large B-cell lymphoma (DLBCL) is possible. In generalized lesions and progression of FL, the most commonly used courses are R-CHOP and R-B. The choice of therapy for different cytological types, clinical and laboratory parameters remains disputable. AIM: To analyze the clinical, laboratory, morphological parameters of patients with FL, who got R-B and R-CHOP therapy; determine the criteria for selecting induction therapy. MATERIALS AND METHODS: The study included 203 patients with FL from 2000 to 2018. R-CHOP treatment was initiated in 126 patients, 14 of whom later received high - dose therapy (HDT) (R-DHAP: rituximab, dexamethasone, cisplatin, cytarabine) without autologous stem cell transplantation (autoSCT), 21 - HDT with autoSCT; treatment of 89 patients was limited to courses of R-CHOP and maintenance therapy with rituximab, two patients (in whom the disease progressed, despite R-CHOP therapy) were assigned the mNHL-BFM-90 program. The efficacy of treatment on various treatment regimens was evaluated primarily by overall survival. RESULTS AND DISCUSSION: R-B. 77 patients received R-B therapy. Complete remission of the disease was achieved in 47/77 (61%) patients (3 of them later developed a relapse of the disease), partial remission was achieved in 15/77 (19%) patients, in 13/77 (17%) cases progression was recorded tumors. 70 patients had 1-2 cytological type of tumor, 6 patients - 3A cytological type. In cases of progression, 3 of 13 patients (46%) were diagnosed with 3A cytological type FL. Median observation (at the time of analysis) - 34 months. R-CHOP. 89 patients with FL received high - dose therapy with R-CHOP (6-8 courses) and maintenance therapy with rituximab. In 39 (44%) patients, the disease remained in remission, and in 50 (56%), a relapse of the disease developed. 50 patients had 1-2 cytological types, 39 - 3 cytological types. In cases of recurrence of FL, a 3A cytologic type (36%) was diagnosed in 18/50 patients. Median observation - 93 months. R-CHOP + HDT and autoSCT. 21 patients after the R-CHOP courses continued (due to insufficient antitumor response) high - dose chemotherapy (HDT) and auto-SCT were performed. In 18/21 (86%) cases, complete remission of the disease was achieved and maintained, in 3 (14%) cases relapse developed. 16 patients had 1-2 cytological types, 5 - 3 cytological types. Median observation - 81 months. R-CHOP + HDT without autoSCT. 14 patients started therapy under the R-CHOP program as induction therapy, but then (due to insufficient antitumor response), the treatment was continued according to the HDT without autoSCT. 11 (79%) patients are currently in remission of the disease, in 3 (21%) - there was a relapse. 10 patients had 2 cytological types of PL, 4 - 3 cytological types. 11 (79%) patients are currently in remission of the disease, in 3 (21%) - there was a relapse. Median observation - 80 months. 7-year OS of patients with FL on RB therapy was 89% (95% CI 75-99), on R-CHOP therapy - 85% (95% CI 73-90), on R-CHOP + HDT and autoSCT - 87% (95% CI 57-100), on R-CHOP + HDT without autoSCT - 82%. 7-year PFS of FL patients on RB therapy was 70% (95% CI 75-99), on R-CHOP therapy - 44% (95% CI 73-90), on R-CHOP + HDT and autoSCT - 74% (95% CI 57-100), on R-CHOP + HDT without autoSCT - 80%. CONCLUSION: The R-B is most effective in FL 1 and 2 cytological types. The cytological type does not correspond to the type of tumor growth: at 3A and 3A + 3B cytological types, nodular / nodular - diffuse and diffuse types of growth are found. When choosing an induction course, one should look at the cytological type of FL. A high proliferative activity index (according to Ki67) is a predictor of resistance to R-B therapy. The absence of an interfollicular T-cell reaction in tumor tissue FL is associated with tumor chemoresistance. The presence of the bulky factor is associated (in most patients) with the FLIPI index with values from 3 to 5, and is a predictor of a poor response to therapy. Patients with bulky, high (more than 35%) Ki67 index and FLIPI from 3 to 5 in the debut of the disease as the first line therapy, it is preferable to choose the R-CHOP mode, and in the absence of (after 4-6 courses) to complete or partial remission to continue conducting the HDT.

[Leukemization of follicular lymphoma: The features of diagnostic and clinical course of a rare form of the disease]. / Leikemizatsiia follikuliarnoi limfomy: osobennosti diagnostiki i klinicheskogo techeniia redkoi formy zabolevaniia.

AIM: To characterize a group of patients with follicular lymphoma (FL) with leukemization and to evaluate the efficiency of different therapy options (R-CHOP/R-FMC/high-dose chemotherapy (HDCT)). SUBJECTS AND METHODS: 18 (7.2%) out of 250 patients diagnosed with FL, who were examined and treated at the National Research Center for Hematology, Ministry of Health of the Russian Federation, were found to have leukemic FL (tumor cells in the peripheral blood smears were detected by cytology and flow cytofluorometry. Eight of the 18 patients had extranodal foci of involvement: lung, stomach, spleen, lumbar muscles, upper jaw, and vertebrae. Bone marrow was involved in 17 of the 18 patients. Tumor biopsy specimens displayed a morphological pattern of indolent FL in the majority of patients (10 of the 18 patients had cytological grade 1-2 tumors and 14 patients had a nodular or nodular-diffuse tumor growth pattern). The patients underwent R-CHOP/R-FMC) or HDCT cycles as first-line therapy, followed by autologous stem cell transplantation (auto-SCT). RESULTS: The median follow-up was 66 months (range 12-217 months). The 5-year overall survival (OS) and progression-free survival (PFS) rates were 70% (10% SEM) and 35% (15% SEM), respectively. The median OS was not reached; the median PFS was 3 years. CONCLUSION: Leukemic FL is characterized by low OS and PFS rates. The most effective chemotherapy regimens were R-CHOP, followed by HDCT and auto-SCT in first remission or R-FMC. These cycles can to a greater extent achieve a complete eradication of the bone marrow tumor clone. Due to the relapsing course of FL and the aggressiveness of leukemic FL, it is expedient to carry out auto-SCT in first remission.

[Therapy for primary mediastinal large B-cell lymphoma in accordance with the R-DA-EPOCH-21 program: The first results]. / Pervye rezul'taty terapii pervichnoi mediastinal'noi V-krupnokletochnoi limfomy po programme R-DA-EPOCH - 21.

AIM: to evaluate the efficiency of the R-DA-EPOCH-21 + R-DHAP protocol and autologous hematopoietic stem cell transplantation (a BEAM conditioning mode) in first-line therapy for primary mediastinal large B-cell lymphoma (PMBCL). SUBJECTS AND METHODS: In 2013 to 2016, the investigation enrolled 57 patients with newly diagnosed PMBCL (according to the 2008 WHO criteria). The results were analyzed in 40 patients who had completed their treatment. RESULTS: All the 40 patients (14 men and 26 women) (median age, 27 years (19 to 67 years)) received 6 cycles of polychemotherapy (PCT) in accordance with the R-DA-EPOCH-21 regimen. After induction PCT cycles, 32/40 (80%) patients achieved complete remission. Partial remission was stated in 8/40 (20%) patients who had further 2 cycles of chemotherapy using the R-DHAP program and autologous hematopoietic stem cell transplantation (a BEAM conditioning mode). Two-year overall and relapse-free survival rates were 100% and 96%, respectively; the median follow-up was 17 months. CONCLUSION: The R-DA-EPOCH regimen allows complete remission in 80% of the cases and two-year survival in 100%. If there are unfavorable factors at onset and in partial remission, it is appropriate to intensify treatment at early stages, by using high-dose chemotherapy and autologous hematopoietic stem transplantation.

[Follicular lymphoma. High-dose immunochemotherapy with autologous blood stem cell transplantation: Results of the first prospective study in Russia]. / Follikulyarnaya limfoma. Vysokodoznaya immunokhimioterapiya s transplantatsiei autologichnykh stvolovykh kletok krovi: rezul'taty pervogo prospektivnogo issledovaniya v Rossii.

AIM: to evaluate the efficiency of high-dose chemotherapy (HDCT) with further autologous blood stem cell transplantation (auto-BSCT) in the first-line therapy of patients with follicular lymphoma (FL) and poor prognostic factors. SUBJECTS AND METHODS: In 2000 to 2015, the National Research Center for Hematology, Ministry of Health of the Russian Federation, performed therapy in 39 patients with FL and poor prognostic factors (a total of 215 patients with FL). The R-CHOP treatment was done as induction therapy. Sequential HCT and further auto-BSCT were performed in 29 (74%) of the 39 patients, who had shown a partial tumor response to the induction therapy or achieved partial remission after 4-6 cycles of CT, but had poor prognostic factors. 22 of the 29 patients underwent auto-BSCT in first-line therapy after induction R-CHOP regimens. Among them, there were 17 men with a median age of 46 years (31-68 years). 21 of the 22 patients were recorded to have Stage IV by the Ann Arbor staging classification. Bulky peritoneal and retroperitoneal tumors larger than 7 cm were detectable at disease onset in 14 of the 22 cases. Two patients were noted to have phenomena of leukemization. 16 patients had bone marrow (BM) involvement. According to the Follicular Lymphoma International Prognostic Index-1 (FLIPI-1), the patients were divided into 3 groups: 1) a low risk (n=5); 2) an intermediate risk (n=3); a high risk (n=14). B-symptoms were observed in 16 cases. 16 patients were diagnosed with cytological grade I-II FL and 6 had grade IIIA. According to the tumor proliferative pattern, the distribution turned out to be as follows: nodular (n=6), nodular-diffuse (n=13), and diffuse (n=3). The proliferative activity index averaged 30% (8-90%). Serum and urine proteins were immmunochemically assayed in 18 cases, out of them 8 patients were diagnosed as having serum ß2-microglobulin concentrations above normal as a poor prognostic factor. In 14 of the 22 patients, the activity of lactate dehydrogenase was greater than normal (266-7806 U/l). RESULTS: Out of the 22 patients, 20 who have undergone auto-BSCT in first-line therapy are survivors and have remission of the underlying disease: 18 and 2 patients achieved complete and partial remission, respectively. The follow-up period was 7 to 178 months (median, 32 months). After auto-BSCT in the first remission, 2 patients developed disease recurrences: an early recurrence after 9 months in one case and a late recurrence 6 years after completion of therapy in the other. CONCLUSION: The first prospective study of intensive therapy for FL in Russia has demonstrated that HDCT with further auto-BSCT in first-line therapy allows complete remission in patients with poor prognostic factors and higher overall and progression-free survival rates.

[Therapy for Burkitt's lymphoma according to the BL-M-04 protocol: 12-year experience].

AIM: To evaluate the efficiency and toxicity of the intensive Burkitt's lymphoma (BL) therapy protocol BL-M-04. SUBJECTS AND METHODS: A total of 70 patients diagnosed with BL, including 45 men and 25 women whose age was 15 to 62 years (median age 31 years), were followed up in 2003 to 2014. Stage I (according to S. Murphy) was diagnosed in 4 (5.7%) patients; II in 9 (12.9%), III in 25 (35.7%), IV in 11 (15.7%), and Burkitt's leukemia in 21 (30%). There were tumor involvements of the bone marrow and central nervous system in 23 (32.9%) and 15 (21.4%) patients, respectively. B symptoms were detected in 56 (80%) patients; enhanced lactate dehydrogenase (LDH) activity was found in 50 (78.1%) out of 64 patients; moreover, in 34 (56.2%) out of 64 patients, LDH activity was more than twice as high as the reference values. The median LDH activity was 2398 (238-20,300) U/I. Acute renal failure at disease onset was identified in 17 (24.2%) patients; chemotherapy was initiated in 8 patients during renal replacement therapy. The treatment was performed using the BL-M-04±R protocol (4 successive blocks of A-C-A-C±R). Six blocks of A-C-A-C-A-C with rituximab has been carried out in patients with bone marrow involvement since 2011. RESULTS: Sixty-two (89%) patients achieved complete remission. At this time, 6 patients died from therapy complications during remission induction; 2 patients were observed to have disease progression; 3 developed disease recurrence (2 patients had early recurrence; 1 patient developed recurrence 2 years after treatment). Five-year overall survival (OS) was 85%; 5-year relapse-free survival (RFS) was 95%. The Cox multivariate regression analysis revealed that Burkitt's leukemia and bone marrow involvement were independent factors that influenced OS and RFS. The poor somatic status (3-4 ECOC scores versus 0-2 scores) proved to be statistically significant for OS rather than RFS. CONCLUSION: Despite the optimistic results obtained by our study group, there is a need to further improve BL treatment protocols and to elaborate novel approaches to therapy particularly for older patients and patients with Burkitt's leukemia.

[Experience with high-dose chemotherapy in patients with testicular diffuse large B-cell lymphoma].

AIM: To evaluate the efficiency of high-dose therapy according to the DLBL-CNS-2007 protocol in patients with testicular diffuse large B-cell lymphoma (DLBL). SUBJECTS AND METHODS: Out of 408 male patients with non-Hodgkin lymphoma, 8 patients aged 50 to 69 years (median age 55.5 years) with primary testicular (n=3) or with generalized-stage testicular DLBL (n=5) were included in the study. These patients were followed up at the Hematology Research Center, Ministry of Health of the Russian Federation, in 2007 to 2013. Systemic chemotherapy was performed in accordance with the DLBL-CNS-2007 protocol. RESULTS: The DLBL-CNS-2007 protocol was implemented in first-line therapy in 7 patients. At the first diagnostic stage, one patient was found to have anaplastic seminoma; in this connection right orchifuniculectomy was carried out, followed by radiotherapy applied to the scrotal region in a total focal dose of 34 Gy. This patient with disease recurrence was included in the DLBL-CNS-2007 treatment protocol. The number of polychemotherapy (PCT) cycles (n=4 or 6) was determined by the time to achieve complete remission. After completion of DLBL-CNS-2007 PCT, 6 patients achieved complete remission; the primary resistant disease was noted in 2 cases. At this moment 6 patients are alive in first complete remission during the median follow-up of 50 months (10-54 months). CONCLUSION: The findings suggest that high-dose therapy according to the DLBL-CNS-2007 protocol in patients with testicular DLBL can achieve complete remission and increase overall and event-free survival rates. This fact should be borne out by a large number of observations.

[Evaluation of tumor vascularization and microenvironment in follicular lymphoma].

AIM: To characterize the degree of follicular lymphoma (FL) vascularization and microenvironment by immunohistochemical studies (IHCS) of lymph node biopsy paraffin-embedded sections in 2 different disease pattern groups. SUBJECTS AND METHODS: The investigation included 59 patients: 39 (67%) women and 20 (33%) men whose age was 27 to 83 years (median age 53 years) treated at the Hematology Research Center, Ministry of Health of the Russian Federation (n=49), and the N.N. Blokhin Russian Cancer Research Center, Russian Academy of Medical Sciences (n=10), in April 2001 to May 2011. In accordance with the clinical features of the disease, the authors identified 2 patient groups: 1) 31 patients with the good results of FL treatment and 2) 28 patients with its poor results. IHCS was performed on lymph node tumor biopsy paraffin-embedded sections prior to treatment using antibodies to CD34, D2-40, CD68, and granzyme B. Morphometric analysis was made applying microscopy and a Leica x400 digital camera. The images of histological specimens were processed by the computer program VideoTesT-Morphology 5.2: the specific vessel area (%) in relation with tumor tissue was estimated under visual guidance of an investigator. Cytotoxic lymphocytes (CTL) and macrophages were quantitatively characterized using 1 mm2 of tumor tissue (12 fields of vision with the objective lens magnifying x400). Immunohistochemical specimens to be examined were chosen randomly, by using the random number table. RESULTS: In Group 2, the specific area of blood vessels was statistically significantly higher than in Group 1: 0.04% (95% confidence interval (CI), 0.03 to 0.05%) versus 0.02% (95% CI, 0.01 to 0.03%; p=0.05). In Group 2, that of lymphatic vessels was significantly higher than in Group 1: 0.06% (95% CI, 0.04 to 0.07%) versus 0.03% (95% CI, 0.01 to 4%; p=0.03). With a nodular diffuse growth, Group 2 showed a significantly more CD68-positive macrophages than did Group 1: 800 (95% CI, 380 to 1222) versus 79 (95% CI, 10 to 566; p=0.01). In Group 1, the count of CTL was statistically significantly (p=0.05) higher than in Group 2 in both the nodule (with a nodular growth pattern: 14 (5-27) versus 5 (1-11)) and the internodular space (with a nodular growth pattern: 158 (118-410) versus 35 (5-287) and with a nodular diffuse growth pattern: 126 (102-360) versus 35 (3-120)). CONCLUSION: Increased tumor vascularization (estimated by the specific density of tumor vasculature) and a pronounced macrophageal reaction are associated with the poor outcomes of FL; the marked cytotoxic component in tumor tissue is linked to the favorable outcomes of the disease.