ALBERT

Description: Background: Rituximab (R) plus CHOP (R-CHOP) is the standard of care for patients with diffuse large B-cell lymphoma (DLBCL). The International Prognostic Index (IPI) and revised IPI were reported as prognostic indicators for DLBCL in 1993 and 2007, respectively. Although they are widely accepted, the performance status (PS) factor is sometimes ambiguous or subjective. Therefore, we developed a new prognostic index, the SIL, that includes only three objective prognostic factors: the clinical stage (S), a soluble interleukin-2 receptor level 〉2,500 U/mL (I), and an elevated lactate dehydrogenase level (L) (Cancer Sci. 2012). This study was conducted to confirm the value of the SIL index in a larger cohort and in each risk stratification of patients and to validate the SIL index in an independent patient cohort. Methods: Between 2003 and 2012, we registered and treated 781 consecutive patients with DLBCL, excluding those with mediastinal large B-cell lymphoma, intravascular large B-cell lymphoma, and primary effusion lymphoma. All the included patients were scheduled to undergo primary therapy with six cycles of full-dose R-CHOP. Patients in whom the initial therapy dose was reduced by 〉20% were excluded. Finally, 572 of 781 patients were retrospectively analyzed. Patients with partial remission (PR) after the initial four cycles underwent eight R-CHOP cycles in total, whereas those who did not achieve PR after the initial four R-CHOP cycles or those who exhibited disease progression at any given time received salvage therapy. If deemed necessary by the attending physician, additional local irradiation was performed in patients with PR or complete remission.Furthermore, we verified the value of the SIL index in an independent cohort of 89 DLBCL patients. Results: The median age at diagnosis was 63 years (range, 18-89 years). The median number of therapy cycles was 6 (range, 1-8), and 90% of patients received 〉6 cycles. Sixty-one patients (11%) received radiation therapy as primary treatment, which was often used to treat sites of residual masses at the end of chemotherapy. The median observation time for survivors was 55 months (range, 1-131 months). For 572 patients, the 5-year progression-free survival (PFS) and 5-year overall survival (OS) rates were 70% and 81%, respectively. The 5-year PFS rate was significantly different as 86%, 73%, 63%, and 41% for 0, 1, 2, and 3 of SIL index, respectively (Fig 1; P 〈 0.0001). The 5-year OS rate was also significantly different as 92%, 87%, 78%, and 52% for 0, 1, 2, and 3 of SIL index, respectively (P 〈 0.0001). According to the SIL index, 367 (64%) and 205 patients (36%) were classified as having standard (SIL index: 0 or 1) and high (SIL index: 2 or 3) risks, respectively. In patients with a low/low-intermediate risk on the IPI, 84% were categorized as having standard risk according to the SIL index, whereas in patients with a high-intermediate/high risk on the IPI, 82% were categorized as having high risk according to the SIL index. Five-year PFS rates in the standard and high risk groups according to the SIL index were 79% and 53%, respectively (Fig 2; P 〈 0.0001). Five-year OS rates in the standard risk and high risk groups were 90% and 66%, respectively (P 〈 0.0001). Cox regression analysis of the SIL index, age (〉60 years), PS (2-4), sites of extranodal involvement (〉1), and sex showed that the SIL index (P 1), and sex, the SIL index was still a good prognostic indicator for PFS and OS in both groups. Lastly, when they were divided by the PS (0-1 and 2-4), the SIL index was effective in the good PS group. However, in the poor PS group, the SIL index showed a statistically significant difference in the OS, but not in the PFS. In the validation cohort analysis, 5-year PFS rates in the standard and high risk groups were 81% and 49%, respectively (Fig 3; P = 0.001). Five-year OS rates in the standard risk and high risk groups were 87% and 59%, respectively (P = 0.003). Conclusion: The SIL index is a simple and objective prognostic indicator for DLBCL patients treated with R-CHOP. Disclosures Fujita: Chugai Pharmaceutical CO.,LTD.: Honoraria.

Description: Abstract 1620 Few randomized prospective studies have been conducted on patients with localized DLBCL in the rituximab era. The SWOG 0014 study examined DLBCL patients treated with 3 cycles of R-CHOP followed by involved-field radiotherapy. Each of the patients had at least 1 of the 4 risk factors (nonbulky stage II, over 60 years of age, WHO performance status [PS] of 2, or elevated LDH), but showed 4-year progression-free survival (PFS) and 4-year overall survival (OS) rates of 88% and 92%, respectively. However, long-term observations showed that the PFS and OS curves did not plateau (Persky DO, et al. J Clin Oncol 2008). We retrospectively analyzed a series of patients with localized DLBCL treated with R-CHOP therapy alone. This study included 190 consecutive, untreated patients with localized DLBCL seen between 2003 and 2009 in 1 of the 7 participating hospitals. All the patients were scheduled to undergo primary therapy with 6 cycles of full-dose R-CHOP in 1 of the hospitals. Patients who required a dose reduction of more than 20% were excluded from the study, as were patients with special forms of DLBCL, such as intravascular lymphoma, primary mediastinal large B-cell lymphoma, and T-cell-rich B-cell lymphoma. Patients who achieved partial remission (PR) after the 4 initial cycles underwent a total of 8 R-CHOP cycles. Patients who did not achieve PR after the 4 initial cycles or those with disease progression at any time during the study underwent salvage therapy, and that time point was designated as the point at which the disease progression began. Additional local irradiation was allowed in patients with PR. Patients who received additional radiotherapy following CR in the decision of attending physicians were excluded from this study. Patients who achieved CR but who were initially at risk of central nervous system (CNS) involvement received 4 intrathecal doses of methotrexate (15 mg) and hydrocortisone (25 mg) for CNS prophylaxis. Central pathological reviews were not performed; only the individual institutional diagnoses were used. The study included 111 men and 79 women, with a median age at diagnosis of 63 years (range, 18–80 years). According to the IPI, 133 patients were classified as L; 49, as LI; 5, as HI; and 3, as H. Five patients received additional local irradiation after PR at the end of the R-CHOP therapy. CNS prophylaxis was performed in 15 patients who had an initial CNS risk and achieved CR. The median observation period for the living patients was 52 months. The responses to therapy were 180 CR, 8 PR, and 2 progression of disease (PD). The 5-year PFS and 5-year OS rates were 84% and 90%, respectively, and both plateaued (Figure 1). None of the patients experienced PD after 4 years of observation. Multivariate analysis revealed that the presence of bulky mass, which was evident in 18 patients, was an independent risk factor for PFS (P = 0.007, relative risk [RR] 3.5) and OS (P = 0.003, RR 5.8), along with poor performance status. During the observation period, 29 patients experienced PD. The progression sites included the primary sites in 15 patients, outside the primary sites in 10, and undetermined in 4. There were 16 deaths, 14 of which were due to the lymphoma. In 149 patients with at least one of the 4 risk factors used in the SWOG 0014 study, the 5-year PFS and 5-year OS rates were 86% and 94%, respectively. Six cycles of R-CHOP therapy alone were observed to be highly effective in attaining good survival results with plateaus. These results suggest that the “standard” strategy of 3 cycles of R-CHOP followed by involved-field radiotherapy for localized DLBCL should be replaced by R-CHOP alone. Disclosures: No relevant conflicts of interest to declare.

Description: Background: Since the introduction of rituximab, an anti-CD20 monoclonal antibody, the prognosis of patients with CD20-positive non-Hodgkin lymphoma has significantly improved. Recent reports have shown a gender-associated difference in rituximab clearance and clinical response, suggesting that rituximab may be more effective in female patients. However, the prognostic impact of gender with regard to rituximab clearance in diffuse large B-cell lymphoma (DLBCL) patients has not been elucidated thus far. Methods: We retrospectively analyzed data from 576 consecutive DLBCL patients, uniformly treated with standard rituximab plus cyclophosphamide, doxorubicin, vincristine, and prednisone (R-CHOP-21) therapy in 9 institutions in Japan, between 2001 and 2012. Patients with a dose reduction greater than 20%, mainly elderly patients with low performance status, were excluded from this study. The median age of the cohort was 63 years (range, 18–89 years), and 331 (57%) of the patients were male. Results: With respect to the International Prognostic Index (IPI) factors, a significantly higher proportion of female patients had elevated serum lactate dehydrogenase (sLDH) levels than male patients (57% vs. 48%, P = 0.03). A difference was also observed in the frequency of bone marrow (BM) involvement, which was primarily observed in male patients (8% in female vs. 15% in male, P= 0.006).No difference was observed between sexes in other baseline factors (other IPI factors, bulky mass over 10 cm, B symptoms). Complete remission rate for R-CHOP-21 was 86% in female patients and 85% in male patients (P = NS). After a median follow-up of 48 months, the 3-year progression-free survival (PFS) and overall survival (OS) rates were 73.7% and 84.3%, respectively. The IPI on diagnosis was low for 238 (41.3%) patients, low-intermediate for 152 (26.4%) patients, high-intermediate for 94 (16.3%) patients, and high for 92 16.0%) patients, with significant differences in survival among the 4 groups (3-year OS: 93.2%, 85.1%, 81.1%, and 63.6%, respectively, P 〈 0.001). Univariate analysis revealed that advanced clinical stage, poor performance status (PS 2-4), elevated sLDH, more than 1 extranodal involvement, BM involvement, bulky mass over 10 cm, and B symptoms had prognostic impact for both PFS and OS (all P

Description: Background: In lymphoma patients, it is believed that serum lactate dehydrogenase (LDH) reflects the tumor mass and that soluble interleukin-2 receptor (sIL-2R) is indicative of activated T-cell reaction. Although it is important to characterize the pattern of LDH and sIL-2R in each subtype of lymphoma, limited information is available on this topic. We investigated LDH and sIL-2R in patients with representative subtypes of lymphoma. Patients and Methods: In the Yokohama City University Hematology Group Lymphoma Database, 3,484 untreated patients were registered between 1996 and 2014. We extracted the data of 3,005 patients with the 8 following subtypes: follicular lymphoma (FL), mucosa-associated lymphoid tissue lymphoma (MALT), mantle cell lymphoma (MCL), diffuse large B-cell lymphoma (DLBCL), Burkitt lymphoma (BL), Hodgkin lymphoma (HL), peripheral T-cell lymphoma (PTCL), and extranodal NK/T cell lymphoma (ENKL). In this retrospective study, we included 2,889 patients in whom both LDH and sIL-2R were recorded. We used the Kruskal-Wallis test to compare LDH and to compare sIL-2R in all 8 subtypes. Each subtype was compared using the Dwass, Steel, Critchlow-Fligner test (multiple comparison test). Results: The 2,889 patients consisted of 1,630 men and 1,259 women, with a median age of 65 years (range, 15-95 years). The median LDH was 1.0 x upper normal limit (N) (range, 0.1 N–53.9 N). The median sIL-2R was 1,150 U/ml (range, 53-142,000 U/ml). The distribution of lymphoma subtypes was as follows: 584 FL (20%), 219 MALT (8%), 82 MCL (3%), 1,579 DLBCL (54%), 39 BL (1%), 162 HL (6%), 162 PTCL (6%), and 62 ENKL (2%). Overall, LDH as well as sIL-2R showed significant difference in the 8 subtypes (P 〈 .0001 for both). The median values of LDH and sIL-2R in each subtype were as follows: 0.9 N and 1,114 U/ml in FL, 0.8 N and 467 U/ml in MALT, 1.15 N and 4,460 U/ml in MCL, 1.1 N and 1,230 U/ml in DLBCL, 2.4 N and 1,700 in BL, 1.0 N and 1,460 U/ml in HL, 1.2 N and 3,193 U/ml in PTCL, and 1.0 N and 679 U/ml in ENKL, respectively. In LDH analysis, BL showed higher value than any other subtypes and MALT showed lower value than any other subtypes. In sIL-2R analysis, MCL showed a higher value than any other B-cell lymphomas, except for BL, and MALT showed lower value than any other subtypes. In the comparison of the most frequent subtypes of FL and DLBCL, LDH was significantly higher in DLBCL (P 〈 .0001); however, sIL-2R was not significantly different (P = 0.31). The correlation between LDH and sIL-2R in each subtype was depicted in the Figure. The diameter of the circle indicated the number of patients. Conclusion: Our findings suggested that the tumor mass was greatest in BL and that T-cell reaction was greater in MCL. Furthermore, both tumor mass and T-cell reaction were lowest in MALT. Figure 1 Figure 1. Disclosures No relevant conflicts of interest to declare.

Description: Background Peripheral T-cell lymphoma (PTCL) is known to have an aggressive clinical course and be associated with poor survival. The International Prognostic Index (IPI) score and the Prognostic Index for T-cell lymphoma (PIT) have been suggested as methods to predict the prognosis of PTCL. Ferritin, the iron storage protein, is associated with chronic inflammation. Although higher levels of serum ferritin are detected in many cancer patients, the significance of elevated serum ferritin as a prognostic factor for lymphoma has yet to be established. Thus, our retrospective study aimed to examine the prognostic value of serum ferritin levels in PTCL. Patients and Methods Serum ferritin levels were evaluated in 78 patients with PTCL, who were treated with anthracycline-containing regimens in 8 institutions affiliated to the Yokohama City University Hematology Group between 1998 and 2011. Fourteen patients received cyclophosphamide, doxorubicin, vincristine, and prednisone (CHOP); 44 receivedpirarubicin, cyclophosphamide, vincristine, and prednisone (THP-COP); 3 received THP-COP followed by radiotherapy; 3 received up-front autologous peripheral blood stem cell transplantation; and 14 received THP-COP at 2-week intervals in a clinical trial. Results The study population comprised 50 male and 28 female patients with a median age of 64 years at the time of diagnosis (range, 16–83 years). With regard to the PTCL subtype, 39 patients had PTCL, not otherwise specified, and 39 had angioimmunoblastic T-cell lymphoma. Twelve patients had localized disease and 66 patients had advanced Ann Arbor stage lymphoma. Twenty-three patients had a poor Eastern Cooperative Oncology Group performance status (PS) of 2–4. B symptoms were present in 34 patients. Risk stratification according to the IPI was as follows: low risk, 9 patients; low–intermediate risk, 20 patients; high–intermediate (HI) risk, 30 patients; and high (H) risk, 19 patients. According to the PIT, 4 patients were categorized into group 1, 25 into, group 2 , 28 into, group 3, 21 into, as group 4. The median observation period for the surviving patients was 50 months. The median serum ferritin level was 183 ng/ml (range, 5–14,622 ng/ml). Factors associated with a poor overall survival (OS) in univariate analysis were HI and H risk status with regard to IPI (P = 0.024), assignment to group 3 or 4 with regard to PIT (P = 0.017), poor performance status (P〈 0.001), and ferritin levels ≥ 300 ng/ml (P〈 0.001). The 4-year OS rate of all 78 patients was 54%. The 4-year OS rate was poorer in patients with serum ferritin levels ≥300 ng/ml (n = 21) than in those with serum ferritin levels〈 300ng/ml (n = 57; 22% vs. 65%; P〈 0.001) (Figure). Multivariate analysis including each factor comprising the IPI (age, lactate dehydrogenase level, PS, Ann Arbor stage, and number of extranodal lesions), gender, bone marrow involvement, and serum ferritin level showed that poor PS (P = 0.002, relative risk [RR] 3.6) and a serum ferritin level ≥300 ng/ml (P = 0.014, RR 2.7) were independent risk factors for poor OS. Conclusion The serum ferritin level is a useful prognostic marker for PTCL. Disclosures: No relevant conflicts of interest to declare.

Description: Abstract 2644 Background: Extranodal NK/T-cell lymphoma, nasal type (ENKL) is a rare subtype in Western countries but is more frequent in East Asia or in Central and South America. The response to conventional chemotherapy is not good, generally resulting in a poor prognosis. Several Asian investigators reported that the International Prognostic Index (IPI) score, Prognostic Index for PTCL-U (PIT) and Korean index, including regional lymph node involvement, clinical stage, presence of B symptom and serum lactate dehydrogenase (LDH) levels, are good indicators for prognosis. We retrospectively analyzed the prognostic factors of our patients with ENKL. Patients and methods: A total of forty-two patients were diagnosed as having ENKL from April 1998 to May 2011 at Yokohama City University Hematology Group, consisting of eight hospitals in Japan. Central pathological review was not performed; only the individual institutional diagnoses were used. Overall survival (OS) was measured from the date of diagnosis to the date of death or the last follow-up. This study was approved by the Yokohama City University Hospital Clinical Research Ethics Board. The procedures used in this study were in accordance with the Helsinki Declaration. Results: The study included 27 males and 15 females, with the median age at diagnosis of 63 years (range, 18–82 years). Twenty-five patients had localized while 17 patients had advanced Ann Arbor stages of lymphoma. Thirty-two patients had a good ECOG performance status of 0–1. B symptoms were present in 18 patients. Thirty patients presented with nasal and/or paranasal lesions. Twelve patients showed no nasal/paranasal involvement. Of these patients, seven (7/12) had skin involvement, and one each (1/12) with involvement of the gingiva, liver, intestines, testis and lymph node, respectively. According to IPI, 17 patients were classified as low, 9 as low-intermediate, 6 as high-intermediate (HI), and 10 as high (H) risk. According to PIT, 10 patients were categorized as group 1, 16 as group 2, 10 as group 3, and 6 as group 4. According to the Korean index, 11 patients were classified as group 1, 9 as group 2, 10 as group 3, and 12 as group 4. Combined radiotherapy-chemotherapy was administered to 23 patients, 11 patients were treated with chemotherapy alone, 6 patients received radiotherapy alone, and two could not be treated due to their poor condition. After a median follow-up duration among all patients of 12 months (range 1–93 months), and a median follow-up duration among patients still alive at their last follow-up of 47 months (range 8–93 months), 3-year OS rate was 46.7%. Factors associated with a worse overall survival in a univariate analysis were IPI score of HI or H (p

Description: Background : The International Prognostic Index (IPI) is useful for prognostic prediction in patients with diffuse large B-cell lymphoma (DLBCL). Besides the IPI, previous reports demonstrated that some biomarkers (e.g., thymidine kinase [TK] activity and soluble interleukin-2 receptor [sIL-2R] levels) were useful for prognostic prediction in patients with DLBCL. However, few studies have analyzed many biomarkers together. This retrospective study aimed to determine a biomarker that would predict the prognosis of patients with DLBCL most strongly. Patients and Methods : A total of 781 patients were newly diagnosed with DLBCL at 9 institutions of the Yokohama City University Hematology Group between 2003 and 2012. We analyzed 319 of these 781 patients who were treated with rituximab plus cyclophosphamide, doxorubicin, vincristine, and prednisone (R-CHOP) therapy (median 6 cycles) with curative intent, and evaluated 6 biomarkers before R-CHOP treatment. We excluded patients from this study for whom reduction of the initial therapy dose by more than 20% was required owing to any major comorbidities, or who were not evaluated any one of 6 biomarkers, or who were stopped observation during R-CHOP therapy. Using univariate and multivariate analyses, we assessed the association between progression free survival (PFS) and the serum levels of the following 6 biomarkers: lactate dehydrogenase (LDH), sIL-2R, TK activity, beta-2 microglobulin (b2MG), C-reactive protein (CRP), and ferritin. The cut-off values for the 6 biomarkers analyzed were decided by using the receiver operating characteristic curves to determine the association between the values of the biomarkers and PFS. In addition, we assessed the association of the PFS with clinical characteristics including age, sex, presence of B symptoms, presence of bulky masses, Ann Arbor stage, performance status, and presence of extra-nodular lesions. Multivariate analysis includes both 6 biomarkers and clinical characteristics. Results : The analyzed patients included 181 men and 138 women, with a median age of 63 years (range, 22–89 years). The median PFS was 40.1 months (range, 0.1–130.8 months). The 3-year PFS rate of the 319 patients analyzed in this study was 77.7% (95% confidence interval [CI], 72.6–82.1%). The cut-off for LDH , sIL-2R, TK activity, b2MG, CRP, and ferritin levels were defined as 1.4 times the upper normal limit, 1660 U/mL, 19 U/L, 1.75 µg/mL, 2.3 µg/mL, and 179 ng/mL, respectively. On univariate analysis, the patients with serum b2MG levels 〉 1.75 µg/mL showed inferior PFS (n = 210; 3-year PFS rate, 71.2% [95% CI, 64.3–77.0]) compared to those with serum b2MG levels ≤ 1.75 µg/mL (n = 109; 3-year PFS rate, 90.0% [95% CI, 82.1–94.6]). In addition, patients with high levels of LDH, sIL-2R, and CRP as well as high TK activity showed inferior PFS rates compared to patients with low levels of these markers. On multivariate analysis, serum b2MG levels were most strongly correlated with poor PFS (hazard ratio [HR], 2.11; 95% CI, 1.04–4.31; P = 0.04). TK activity as well as CRP, sIL-2R, and ferritin levels did not predict the prognosis of patients with DLBCL. Conclusion : The serum b2MG level at diagnosis is a useful prognostic marker for patients with DLBCL. Figure 1 Figure 1. Disclosures No relevant conflicts of interest to declare.

Description: The treatment of acute leukemia with myelosuppressive chemotherapy usually requires the transfusions of blood and blood products. For religious reasons, Jehovah’s Witnesses (JW) do not consent to the transfusion of blood. We describe here six cases of JW with acute leukemia, who received induction chemotherapy without blood support. From January 1996 to March 2006, six JW with newly diagnosed acute leukemia received remission induction chemotherapy at Shizuoka Red Cross Hospital or Kanagawa Cancer Center (acute myeloid leukemia (AML) n=5, acute lymphoblastic leukemia (ALL) n=1). All patients refused the consent for transfusions of packed red cells and platelet units and they were never forced accept them. Remission induction therapy: One patient with M3 received all-trans retinoic acid alone. One ALL patient received prednisolone alone. Three AML patients received the following LVP regimen: L-asparaginase 5000U/sqm div from day 8 to day 21 + vincristine 1.4mg/sqm div day1, 6, 11, 16, 21, 26 + prednisolone 40mg/sqm div from day 1 to day 28, and one AML patient received a low dose of Ara-C regimen (20mg/sqm continuous div from day 1 to day 14). Results (see Table): Four out of six patients achieved complete remission and two paitents died from cardiac arrest due to severe anemia before hematological recovery. No patients developed fatal bleeding complications, not even long lasting severe thrombocytopenia. Conclusion: We have demonstrated the feasibility of remission induction therapy for JW with leukemia. This LVP regimen, or steroid based regimen, may be suitable for JW with acute leukemia because myelosuppression is relatively mild. While two patients experienced cardiac arrest due to severe anemia of under 3g/dL of hemoglobin, severe thrombocytopenia can be managed without prophylactic platelet transfusion. Clinical characteristics of patients Pt#:Age/Sex/FAB/ Karyotype Induction therapy Epo use Nadir in Induction therapy (day) Out come Follow-up from Induction therapy WBC(×109/L) Hb(g/dL) PLT(×109/L) ATRA: All-trans retinoic acid, PSL: Prednisolone, , LDAC: Low dose of Ara-C regimen, Epo: Erythropoietin, CR: Complete Remisson, ED: Early Death, RLPs: Relapse 1: 28/F/M3/t(15;17) ATRA Yes 0.9 (day2) 3.6 (day3) 20 (day2) CR 10Y6M+, 2ndCR 2: 29/F/M1/normal PSL+LVP No 0.6 (day4) 2.4 (day19) 16 (day6) CR 2Y6M, dead in 2nd RLPs 3: 45/F/M2/normal LVP No 0.9 (day22) 3.0 (day30) 8 (day25) CR 2Y1M+, in 1st CR 4: 25/M/M2/t(8;21) LVP Yes 1.2 (day25) 1.5 (day31) 17 (day31) ED 31days 5: 15/F/L1/complex PSL Yes 1.3 (day5) 3.8 (day7) 1 (day4) CR 10M+, in 1st CR 6: 64/M/M2/complex LDAC Yes 0.6 (day6) 2.7 (day21) 1 (day21) ED 23days