Cyclophosphamide, doxorubicin, vincristine, and prednisone (CHOP) in the treatment of stage IE/IIE extranodal natural killer/T cell lymphoma, nasal type: 13-year follow-up in 135 patients

We conducted a retrospective study of 135 patients of stage IE/IIE extranodal natural killer/T cell lymphoma, nasal type (ENKTL) treated with CHOP as induction chemotherapy to find some valuable prognostic factors and analyze the usefulness of International Prognostic Index (IPI) and Korean Prognostic Index (KPI) in predicting prognosis. Most of the patients were in the low-risk group (IPI score 0?C1). Complete remission (CR) after induction chemotherapy was achieved in 31.8?% of the patients, which increased to 69.6?% after radiotherapy. The 2-, 5-, and 10-year overall survival (OS) rates were 60, 48, and 43?%, respectively. Patients with better performance status (ECOG 0-1), normal serum LDH level, without local invasiveness, low KPI scores, and IPI score of 0 had significantly better overall survival (P?<?0.05) in univariate analysis. Using multivariate analysis, we identified serum LDH level, ECOG PS score and local invasiveness to be independent prognostic factors. In conclusion, ENKTL is an aggressive lymphoma that shows heterogeneity. The IPI and KPI score systems should be improved further to classify patients into different groups, and should be validated in larger prospective trials. Due to the multi-drug resistance mechanism of ENKTL, CHOP is no longer the state of art and novel drugs should be incorporated into future treatments.     

Prognostic impact of beta-2 microglobulin in patients with extranodal natural killer/T cell lymphoma

Although serum beta-2 microglobulin (B2M) has been suggested as an independent prognostic factor for several lymphoproliferative diseases, it has rarely been investigated in extranodal natural killer/T cell lymphoma (ENKTL). From a prospectively collected database, 145 patients with ENKTL were identified. Among them, a total of 101 patients were included in the analysis, with exclusion of patients without baseline serum B2M level and those did not receive anticancer therapy. Serum B2M (<3.0 vs. ≥3.0 mg/L) was analyzed for association with overall survival (OS). Seventy-nine (78 %) patients had nasal ENKTL, and 22 (22 %) had extranasal ENKTL. In overall patients, median OS was 26.7 months (95 % confidence interval (CI), not assessable), with a median follow-up of 32.4 months (range, 0.9–155.2 months). While median OS was not reached in patients with nasal ENKTL, extranasal ENKTL group had median OS of 5.1 months (95 % CI, 1.2–8.9 months; p?<?0.001). Baseline serum B2M was significantly associated with OS in patients with nasal ENKTL (p?<?0.001). This was consistent in limited (stages I and II) nasal ENKTL (p?=?0.002) and disseminated (stages III and IV) nasal ENKTL (p?=?0.02). However, there was no difference of OS in extranasal ENKTL patients (p?=?0.69). In multivariate analysis including other prognostic factors, elevated serum B2M was significantly associated with poor OS (hazard ratio (HR)?=?3.8, 95 % CI 1.7–8.2, p?=?0.001, in a model including Korean Prognostic Index, and HR?=?3.6, 95 % CI 1.6–8.2, p?=?0.002, in a model including International Prognostic Index). In patients with nasal ENKTL, baseline serum B2M is a powerful prognostic factor. The prognostic value of B2M was independent of previously established prognostic models. Further investigations are necessary to validate the role of B2M in ENKTL.     

Intensity-modulated radiation therapy followed by GDP chemotherapy for newly diagnosed stage I/II extranodal natural killer/T cell lymphoma,nasal type

Extranodal natural killer (NK)/T cell lymphoma, nasal type (ENKTL) is an aggressive non-Hodgkin lymphoma and the majority of ENKTL cases are diagnosed at the localized stage. Radiotherapy in combination with chemotherapy has been used for localized ENKTL, but the optimal combination treatment modality and the best first-line chemotherapy regimen have not been defined. In this retrospective study, 44 patients with newly diagnosed, stages I/II ENKTL were enrolled and received intensity-modulated radiation therapy (IMRT, 50–56 Gy) followed by GDP (gemcitabine, dexamethasone, and cisplatin) chemotherapy. The median number of chemotherapy cycles per patient was 4 (range, 2–6 cycles). At the end of treatment, the overall response rate was 95% (42/44), including 39 patients (89%) who attained complete response. Two patients developed systemic progression after IMRT. With a median follow-up of 37.5 months, the 3-year overall survival (OS) rate and progression-free survival (PFS) rate were 85% (95% CI, 74 to 96%) and 77% (95% CI, 64 to 91%), respectively. Locoregional and systemic failure rates for this treatment were 9% (4/44) and 14% (6/44), respectively. The most common grades 3 to 4 adverse events included leukopenia (37%), neutropenia (34%), and mucositis (25%). No treatment-related deaths were observed. This study suggested high efficacy and low toxicity of IMRT followed by GDP regimen chemotherapy for newly diagnosed stage I/II ENKTL patients. These results require further investigation in prospective trials.     

Prognostic analysis and a new risk model for Hodgkin lymphoma in Japan

The Japan Clinical Oncology Group conducted two multicenter phase II trials in 200 patients with advanced Hodgkin lymphoma (HL) in the 1990s. Among 181 patients whose histopathological specimens were available and reviewed by 6 hematopathologists, 167 (92.3%) were diagnosed with HL. Five-year overall survival (OS) among these 167 patients was 88.3%, including 89.2% among nodular sclerosis and 82.2% among mixed cellularity cases. International prognostic score was not closely associated with OS. Seven unfavorable prognostic factors for OS on univariate analysis were male, B symptoms, clinical stage of III or IV, elevated serum LDH, elevated alkaline phosphatase, elevated β2-microglobulin, and pathological subtype (mixed cellularity and lymphocyte depletion). On multivariate analysis, male [HR 3.30 (95% CI 1.15–9.52, p = 0.027)] and elevated serum LDH [HR 2.41 (95% CI 1.07–5.43, p = 0.034)] were independent factors for OS. Based on these prognostic factors, the 5-year OS was 95.7% in the low-risk group (no adverse factor), 87.9% in the intermediate-risk group (1 adverse factor) and 73.3% in the high-risk group (2 adverse factors). This simple prognostic model for HL warrants further validation studies.     

Assessing DcR3 expression in relation to survivin and other prognostic factors in B cell non-Hodgkin’s lymphoma

The soluble decoy receptor 3 (DcR3) is a member of the tumor necrosis factor receptor superfamily whose overexpression has been observed in several human malignancies. Survivin is one of the inhibitors of apoptosis proteins that are thought to play an important role in the pathogenesis of malignancies. We aimed to evaluate the expression of DcR3 in relation to survivin in B cell non-Hodgkin`s lymphoma (NHL) and then we focused on patients with diffuse large B cell non-Hodgkin’s lymphoma (DLBCL) (50 cases) and correlated DcR3 expression with survivin expression and other prognostic parameters. Fifteen subjects with reactive lymphoid hyperplasia were included as controls. The expression of DcR3 and survivin were analyzed by immunohistochemistry on formalin-fixed paraffin-embedded lymph node sections from 80 cases of B cell NHL and 15 controls. Bone marrow biopsy sections of patients were also immunostained with the previous markers. Results: DcR3 expression was found in 32.5 % of B cell NHL patients versus 6.7 % of controls (p <0.001) and was associated with the aggressive/highly aggressive subtypes. DcR3 was strongly expressed in 30 % of DLBCL patients, where it was associated with survivin expression, high international prognostic index (IPI), the presence of extra nodal disease, ECOG performance status >1, reduced remission rates and shorter event-free survival. The expression of survivin was 40 % in B cell NHL patients versus 13.3 % in the control group (p <0.001). The expression of survivin in aggressive/highly aggressive B cell NHL was significantly higher than that in indolent B cell NHL. Survivin expression has been detected in 44 % of the DLBCL patients and was associated with their clinical stage and shorter event-free survival (p?=?0.026). Bone marrow biopsy sections from DLBCL patients showed significant DcR3 and survivin over expressions in sections with infiltration by lymphoma cells than sections with no infiltration. Conclusion: DcR3 expression was associated with other prognostic factors including survivin, reduced remission rates, and shorter event-free survival. Survivin is closely related to aggressive/highly aggressive subtypes of B cell NHL and is associated with shorter event-free survival. Both DcR3 and survivin expressions on bone marrow sections can be of help in diagnosing bone marrow infiltration.     

Outcome of children with relapsed acute myeloid leukemia following initial therapy under the AML99 protocol

The outcomes of children with relapsed acute myeloid leukemia (AML) are known to be poor, but remain obscure. We retrospectively analyzed 71 patients who had relapsed following first-line treatment under the AML99 protocol. We investigated the time and site of recurrence, response to re-induction therapy, and performance of hematopoietic stem cell transplantation (HSCT) in relapsed cases, and performed a multivariate analysis to identify prognostic factors. The 5-year overall-survival (OS) rate after relapse was 37 %. Of 71 patients, three died without any anti-leukemic therapy and two underwent allogeneic HSCT. The remaining 66 patients received re-induction chemotherapy, and 33 (50 %) achieved second CR (CR2). Twenty-two of 25 (88 %) late relapse patients and 11 of 41 (27 %) early relapse patients achieved CR2 (P < 0.001). Twenty-nine CR2 cases and 35 non-CR2 cases underwent allogeneic HSCT. The 5-year OS rate was significantly higher in patients who underwent HSCT in CR2 than those in non-CR2 (66 vs. 17 %, P < 0.000001). Multivariate analysis indicated that early relapse (P < 0.05) and the positivity of the FMS-like tyrosine kinase 3—internal tandem duplication (P < 0.05) were adverse prognostic factors for survival. In conclusion, the etiology of relapsed pediatric AML needs to be elucidated and effective chemotherapy should be administered to obtain CR2.     

Significance of circulating Epstein-Barr virus DNA monitoring after remission in patients with extranodal natural killer T cell lymphoma

Circulating Epstein-Barr virus (EBV)-DNA has been established as a useful parameter for diagnosis and predicting prognosis in patients with extranodal natural killer T cell lymphoma (ENKTL); however, the role of monitoring of circulating EBV-DNA after complete remission (CR) is not well established. From January 2008 to August 2016, 328 ENKTL patents were enrolled in 2 lymphoma cohorts. Of 171 patients achieved a CR, 81 had available monitoring data for circulating EBV-DNA with negative post-treatment EBV-DNA. Measurement of circulating EBV-DNA was performed from unfractionated whole blood and calculated according to WHO international standards. Median duration of follow-up was 40.4 months. In 31 of the 81 patients (38.8%), circulating EBV-DNA was detected at least once during follow-up, and 16 of these patients (51.6%) experienced relapse. In contrast, only 7 out of 50 (14.0%) patients with consistently undetectable circulating EBV-DNA experienced relapse (p?<?0.001). In multivariate analysis, positive conversion of circulating EBV-DNA was the only independent prognostic factor for occurrence of relapse (HR?=?6.552, p?<?0.001), progression-free survival (HR?=?4.549, p?=?0.01), and overall survival (HR?=?8.726, p?<?0.001). Patients with a higher level of circulating EBV-DNA than 3310 IU/mL (3.52 log₁₀ IU/mL) showed a strong tendency to relapse (73.3 vs. 31.3%, p?=?0.019). In conclusion, positive conversion of circulating EBV-DNA was a valuable indicator of relapse and inferior survival, especially if the level was higher than 3310 IU/mL in ENKTL patients had achieved CR. Close follow-up is necessary for patients developed detectable circulating EBV-DNA after remission.     

ACUTE LEUKEMIAS XVI

Few studies have examined the prognostic impact of blood markers [other than the five factors in the enhanced International Prognostic Index (NCCN-IPI)] in elderly patients with diffuse large B cell lymphoma (DLBCL). We retrospectively analyzed 391 DLBCL patients receiving rituximab plus anthracycline-containing chemotherapy to examine the prognostic impact of simple blood markers. The NCCN-IPI was more accurate for discriminating prognoses than the original IPI. Multivariate analysis identified platelet count (<100,000/μl) and albumin (<3.5 g/dl) levels as significantly associated with lower overall survival (OS), independently of the NCCN-IPI. These parameters stratified patients into three risk groups: platelet–albumin (PA) score low (platelet count ≥100,000/μl, albumin ≥3.5 g/dl, n?=?243); intermediate (platelet count <100,000/μl, albumin ≥3.5 g/dl or platelet count ≥100,000/μl, albumin <3.5 g/dl, n?=?125); and high (platelet count <100,000/μl, albumin <3.5 g/dl, n?=?23). The 5-year OS rates were 81.5, 48.6, and 20.2 %, respectively (p?<?0.001). Notably, most patients with a low platelet count (n?=?30) were stratified into the high-risk subgroup, suggesting that platelet count was prognostic for high-risk patients with a dismal outcome. In elderly patients (n?=?291), the prognostic value of the NCCN-IPI might be diminished because the low-risk category was excluded; however, the PA score was predictive of survival: the 5-year OS rates for PA score low (n?=?171), intermediate (n?=?101), and high (n?=?19) groups were 77.6, 47.9, and 19.0 %, respectively (p?<?0.001). Platelet count and albumin levels are useful prognostic factors, and their combined use can predict survival, even in elderly patients.     

Peripheral blood lymphocyte/monocyte ratio predicts outcome for patients with diffuse large B cell lymphoma after standard first-line regimens

To determine whether peripheral blood absolute lymphocyte/absolute monocyte counts ratio (ALC/AMC ratio) at diagnosis predicts survival of diffuse large B cell lymphoma (DLBCL) patients treated with standard first-line regimens, we retrospectively analyzed 244 patients with DLBCL who were treated with standard cyclophosphamide, hydroxydaunorubicin, vincristine, and prednisone, or rituximab–cyclophosphamide, hydroxydaunorubicin, vincristine, and prednisone. Progression-free survival and overall survival (PFS and OS) were estimated using the Kaplan–Meier method and two-tailed log-rank; The Cox proportional hazards model was used to evaluate ALC/AMC ratio as prognostic factors when adjusting for the International Prognostic Index (IPI). On univariate and multivariate analyses performed with factors included in the IPI, the ALC/AMC ratio at diagnosis remained an independent predictor of OS and PFS (OS: P?<?0.001; PFS: P?<?0.001). Patients with lower ALC/AMC ratio (<3.8) seemed to have lower complete remission rate, 2-year PFS and 3-year OS when compared to patients with ALC/AMC ratio ≥3.8, respectively (26 versus 90 %, P?<?0.001; 18 versus 82 %, P?<?0.001; 24 versus 86 %; P?<?0.001, respectively). Moreover, the ALC/AMC ratio was able to further risk-stratify IPI 0-2 and three–five risk patient groups, respectively. The ALC/AMC ratio at the time of diagnosis may provide additional prognostic information beyond that of the IPI for patients with DLBCL who receive standard first-line regimens.     

Improved prognostic stratification power of CIBMTR risk score with the addition of absolute lymphocyte and eosinophil counts at the onset of chronic GVHD

The CIBMTR chronic graft-versus-host disease (cGVHD) risk score can be refined and improved for better prognostic stratification. Three hundred and seven consecutive patients diagnosed with cGVHD by the NIH consensus criteria were retrospectively reviewed and had the CIBMTR risk score applied and analyzed. The CIBMTR risk score was successfully validated in our cohort (n = 307). The 3-year overall survival (OS) rates in each risk group (RG) were 82.5 ± 11.3% (RG1), 79.4 ± 3.0% (RG2), 71.8 ± 6.3% (RG3), and 27.3 ± 13.4% (RG4). A significantly lower OS rate and higher non-relapse mortality (NRM) were noted in RG4 compared to the other RGs. However, there were no differences in OS or NRM among RG1 to 3. To improve prognostic stratification power of the CIBMTR risk score, we incorporated the absolute lymphocyte (ALC) and eosinophil count (EC) at time of cGVHD into the CIBMTR risk score. Lower ALC (<1.0 × 10⁹/L, HR 1.94, p = 0.014) and lower EC (<0.5 × 10⁹/L, HR 3.27, p = 0.014) were confirmed as adverse risk factors for OS. Patients were stratified into four revised risk groups (rRG). The 3-year OS rates were 93.3 ± 6.4% (rRG1, score 0–3), 84.9 ± 3.4% (rRG2, score 4–6), 70.9 ± 4.4% (rRG3, score 7–9), and 32.0 ± 1.1% (rRG4, score ≥ 10) (p < 0.001). The 3-year NRM rates were 0.0% (rRG1), 6.7 ± 0.4% (rRG2), 18.4 ± 0.7% (rRG3), and 57.7 ± 5.1% (rRG4) (p < 0.001). The revised CIBMTR risk score was superior to the original CIBMTR risk score for OS (p < 0.001). The revised CIBMTR risk score including ALC and EC at the onset of cGVHD improved the prognostic stratification power of the CIBMTR risk score for long-term outcomes.