Prognostic value of MYC rearrangement in cases of B-cell lymphoma, unclassifiable, with features intermediate between diffuse large B-cell lymphoma and Burkitt lymphoma

BACKGROUND:

B‐cell lymphoma, Unclassifiable with features intermediate between diffuse large B‐cell lymphoma (DLBCL) and Burkitt lymphoma, for convenience referred to here as unclassifiable B‐cell lymphoma, is a category in the 2008 World Health Organization system used for a group of histologically aggressive neoplasms that are difficult to classify definitively. Currently, there is no established standard therapy for these neoplasms.

METHODS:

The authors assessed MYC status and correlated it with treatment response and outcome in a group of 52 patients with unclassifiable B‐cell lymphoma treated with either a standard DLBCL regimen (R‐CHOP [rituximab plus cyclophosphamide, doxorubicin, vincristine, and prednisolone‐related therapy]) or more intensive regimens, such as R‐hyper‐CVAD (rituximab plus hyperfractionated cyclophosphamide, vincristine, doxorubicin, and dexamethasone alternating with high‐dose methotrexate and cytarabine). The regimens were selected by the treating clinicians based on the overall clinical and pathological findings.

RESULTS:

Thirty (58%) unclassifiable B‐cell lymphomas had MYC abnormalities (MYC⁺) including 27 with rearrangement, 2 with amplification, and 1 with both. The MYC⁺ and MYC^? groups were similar in their age distribution and International Prognostic Index scores. Progression‐free survival of patients with MYC⁺ unclassifiable B‐cell lymphoma treated initially with R‐CHOP was significantly worse than patients treated with R‐hyper‐CVAD (P = .0358). In contrast, for the MYC^? unclassifiable B‐cell lymphoma group, some patients responded to R‐CHOP, and others were refractory to R‐hyper‐CVAD.

CONCLUSIONS:

MYC aberrations are common in unclassifiable B‐cell lymphoma. The presence of MYC aberrations identifies a patient subset that requires more aggressive therapy than R‐CHOP. In contrast, MYC^? unclassifiable B‐cell lymphoma patients responded variably to either R‐CHOP or aggressive therapy, and the latter showed no survival advantage. Cancer 2011;. © 2011 American Cancer Society.     

Absolute monocyte count predicts overall survival in mantle cell lymphomas: correlation with tumour‐associated macrophages

Mantle cell lymphoma (MCL) is characterized by a variable clinical course in which patients can experience indolent disease or frequent relapses despite a good initial response to conventional therapy. Risk stratification of MCL is most frequently performed using the MCL International Prognostic Index (MIPI). Recent studies indicate that the peripheral blood absolute monocyte count (AMC) and tumour‐associated macrophages may reflect the state of the tumour microenvironment in lymphomas. The significance of AMC and tumour‐associated macrophages in the clinical course of MCL is unknown. The prognostic impact of the AMC, of CD68 expression and of CD163 expression was retrospectively examined in 103 MCL samples using the receiver operating characteristic curved. Patients with an AMC ≥ 375 cells/μL at diagnosis were more likely to present with advanced‐stage disease (p = 0.026), leukocytosis (p < 0.001), lymphocytosis (p = 0.01) and granulocytosis (p = 0.003). On univariate analysis, a high AMC (≥375 cells/μL) correlated with poorer overall survival (OS) (p = 0.01). Neither CD68 nor CD163 expression was significantly associated with either OS or event‐free survival. Multivariate analysis showed that a high AMC was a prognostic factor for OS, independent of the MIPI [hazards ratio (HR), 1.811; 95% confidence interval, 1.018–3.223; p = 0.043]. This study demonstrates that the AMC at the time of diagnosis is an independent prognostic factor for OS in MCL, which suggests the possibility that AMC may be used in addition to the MIPI to predict outcome in patients with MCL. Copyright © 2013 John Wiley & Sons, Ltd.     

Prognostic impact of extranodal involvement in diffuse large B-cell lymphoma in the rituximab era

BACKGROUND:

Extranodal involvement is considered a poor prognostic factor for patients with diffuse large B‐cell lymphoma (DLBCL); however, the prognostic impact of specific sites of involvement has not been fully elucidated.

METHODS:

The authors retrospectively analyzed 1221 patients treated uniformly with standard R‐CHOP therapy between 2003 and 2006. Patients with distinct forms of DLBCL such as intravascular lymphoma, primary effusion lymphoma, pyothorax‐associated lymphoma, primary central nervous system lymphoma, and intraocular lymphoma were also excluded. The authors evaluated 26 extranodal sites of involvement with respect to prognostic impact. The median age was 64 years (range, 15‐91 years).

RESULTS:

Univariate analysis revealed that patients with involvement of specific extranodal sites had significantly worse overall survival (OS) than did patients without such involvement; these sites included nasal cavity, paranasal sinus, lung, pleura, small intestine, peritoneum, liver, pancreas, stomach, spleen, adrenal gland, testis, bone, bone marrow, peripheral blood, skin, and subcutaneous tissue. Patients with Waldeyer ring involvement had significantly better OS. Multivariate analysis revealed that patients with the involvement of the pleura (P < .001), small intestine (P = .015), peritoneum (P = .002), adrenal gland (P < .001), testis (P = .005), bone marrow (P < .001), and peripheral blood (P = .002) had significantly worse OS, whereas those with Waldeyer ring involvement had significantly better OS (P = .038). Subgroup analysis with the nodal and/or Waldeyer patient group also showed prognostic impact of Waldeyer ring by multivariate analysis (relative risk, 0.3; P = .04).

CONCLUSIONS:

Extranodal involvement affects the prognosis of patients undergoing R‐CHOP therapy for DLBCL. Cancer 2012. © 2011 American Cancer Society.     

Burkitt post-transplantation lymphoma in adult solid organ transplant recipients: Sequential immunochemotherapy with rituximab (R) followed by cyclophosphamide, doxorubicin, vincristine, and prednisone (CHOP) or R-CHOP is safe and effective in an analysis of 8 patients

BACKGROUND:

Burkitt lymphoma post‐transplantation lymphoproliferative disorder (Burkitt‐PTLD) is a rare form of monomorphic B‐cell PTLD for which no standard treatment has been established. Currently, the treatment of Burkitt lymphoma outside the post‐transplantation setting involves high doses of alkylating agents, frequent dosing, and intrathecal and/or systemic central nervous system prophylaxis. In PTLD, however, such protocols are associated with considerable toxicity and mortality.

METHODS:

The authors present a retrospective series of 8 adult patients with Burkitt‐PTLD. Six patients were reported to the prospective German PTLD registry or were enrolled in the PTLD‐1 trial, and 2 patients had received treatment before 2000, thus allowing for comparison with the pre‐rituximab era.

RESULTS:

Seven of the 8 patients were men. The median age at presentation was 38 years, and the median time since transplantation was 5.7 years. Five of 8 patients had histologically established, Epstein‐Barr virus‐associated disease, and 7 of 7 patients were positive for a MYC translocation. Five of 8 patients received sequential immunochemotherapy (4 courses of rituximab [R] followed by 4 cycles of cyclophosphamide, doxorubicin, vincristine, and prednisolone [CHOP] or R plus CHOP [R‐CHOP]). In this group, 5 of 5 patients reached complete remission (CR), and their overall survival (OS) was significantly longer (P = .008) compared with the OS for 2 of 8 patients who received first‐line CHOP and did not respond. One of 8 patients (who had stage IV disease with meningiosis) received combination therapy (cyclophosphamide pretreatment, rituximab, intrathecal chemotherapy, whole‐brain irradiation, and radioimmunotherapy) and reached CR. Overall, 6 of 8 patients reached CR; and, after a median follow‐up of 4.7 years (range, 1.7‐4.8 years), the median OS was 36.7 months. There was no treatment‐related mortality under first‐line therapy.

CONCLUSIONS:

In the largest adult case series in Burkitt‐PTLD to date, sequential immunochemotherapy with rituximab followed by standard CHOP or R‐CHOP was a both safe and effective treatment. Cancer 2012. © 2012 American Cancer Society.     

Response and survival benefit with chemoimmunotherapy in Epstein‐Barr virus‐positive diffuse large B‐cell lymphoma

Epstein‐Barr virus (EBV)‐positive diffuse large B‐cell lymphoma (DLBCL) is a haematologic malignancy with poor prognosis when treated with chemotherapy. We evaluated response and survival benefits of chemoimmunotherapy in EBV‐positive DLBCL patients. A total of 117 DLBCL patients were included in our retrospective analysis; 33 were EBV‐positive (17 treated with rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone [R‐CHOP] and 16 with CHOP), and 84 were EBV‐negative (all treated with R‐CHOP). The outcomes of interest were complete response (CR) and overall survival (OS) in EBV‐positive DLBCL patients (R‐CHOP versus CHOP) and in DLBCL patients treated with R‐CHOP (EBV‐positive vs EBV‐negative). There were no differences in the clinical characteristics between EBV‐positive and EBV‐negative DLBCL patients. Among EBV‐positive DLBCL patients, R‐CHOP was associated with higher odds of CR (OR 3.14, 95% CI 0.75‐13.2; P = .10) and better OS (hazard ratio 0.30, 95% confidence interval [CI] 0.09‐0.94; P = .04). There were no differences in CR rate (OR 0.52, 95% CI 0.18‐1.56; P = .25) or OS (hazard ratio 0.93, 95% CI 0.32‐2.67; P = .89) between EBV‐positive and EBV‐negative DLBCL patients treated with R‐CHOP. Based on our study, the addition of rituximab to CHOP is associated with improved response and survival in EBV‐positive DLBCL patients. Epstein‐Barr virus status does not seem to affect response or survival in DLBCL patients treated with R‐CHOP.     

Correlation of pretransplant and early post‐transplant response assessment with outcomes after reduced‐intensity allogeneic hematopoietic stem cell transplantation for non‐Hodgkin's lymphoma

BACKGROUND:

Chemotherapy sensitivity, defined simply as at least a partial response to chemotherapy, is an important outcome predictor for non‐Hodgkin lymphoma (NHL) patients undergoing reduced‐intensity allogeneic hematopoietic stem cell transplantation (allo‐HCT). The authors hypothesized that further differentiation of chemotherapy sensitivity by specific response, complete remission (CR) versus partial remission (PR) versus stable disease (SD) versus progression of disease (PD), correlates with post‐transplant outcomes.

METHODS:

The impact of pretransplant and early (28 days) post‐transplant disease response on transplant outcomes was analyzed in 63 NHL patients treated with reduced‐intensity allo‐HCT.

RESULTS:

The 3‐year event‐free survival (EFS) and overall survival (OS) (median potential follow‐up after reduced‐intensity allo‐HCT = 58 months) for all patients was 37% and 47%, respectively. The 3‐year EFS based on pretransplant response was: CR = 50%; PR = 66%; SD = 18%; no patient with PD pretransplant reached 3‐year follow‐up. The 3‐year OS based on pretransplant response was: CR = 63%; PR = 69%; SD = 45%. The 3‐year EFS based on post‐transplant response was: CR = 57%; PR = 32%; SD = 33%; no patient with PD post‐transplant reached 3‐year follow‐up. The 3‐year OS based on post‐transplant response was: CR = 65%; PR = 43%; SD = 50%. In multivariate analyses, pretransplant response was the best predictor of EFS (P < .0001). Pretransplant response (P < .0001) and age (P = .0035) were jointly associated with OS.

CONCLUSIONS:

These data suggest that NHL patients with pretransplant SD, generally considered inappropriate candidates, may benefit from reduced‐intensity allo‐HCT, and patients with pretransplant PD should only receive this therapy in clinical trials. Cancer 2010. © 2010 American Cancer Society.     

Romidepsin treatment for relapsed or refractory peripheral and cutaneous T‐cell lymphoma: Real‐life data from a national multicenter observational study

Romidepsin is a class I selective histone deacetylase (HDAC) inhibitor approved by the Food and Drug Administration (FDA) for relapsed/refractory (R/R) cutaneous T‐cell lymphoma (CTCL) and peripheral T‐cell lymphoma (PTCL), treated with at least one prior systemic therapy. Currently, there is paucity of real‐life data on the efficacy and safety of romidepsin in R/R T‐cell lymphoma. This national, multicenter study presents real‐life data on the efficacy and safety of romidepsin in R/R T‐cell lymphoma. Patients diagnosed and treated with romidepsin for R/R CTCL or PTCL between 2013 and 2018 were retrospectively reviewed. Outcomes included overall survival (OS), event‐free survival (EFS), overall response rate (ORR), complete response (CR), and adverse events. Fifty‐three patients with R/R PTCL (n = 42) or CTCL (n = 11) were included. Among CTCL patients, median OS was not reached, ORR was 25%, and none achieved CR. Among PTCL patients, median OS was 7.1 months, EFS was 1.9 months, ORR rate was 33%, and 12.5% achieved CR. In a univariate analysis, predictors for longer EFS include any response to therapy, number of previous lines, and PTCL subclass (with better results for angioimmunobalstic T‐cell lymphoma). In a univariate and multivariate analysis for OS, treatment response was the only factor predicting OS (OR 4.48; CI 95%, 1.57‐12.79; P = .005). Most grade 3 and 4 adverse events were hematological (35%). Infections were reported in 34% of patients. This real‐life experience with romidepsin confirms the results of the pivotal phase II trials. PTCL subtype and the number of previous lines of therapy have an impact on EFS. In addition, patients who had good response to romidepsin benefited most in terms of both EFS and OS. Efforts should be done to identify those patients.     

Human immunodeficiency virus‐associated plasmablastic lymphoma

BACKGROUND:

Plasmablastic lymphoma (PBL) is a rare and aggressive B‐cell lymphoma strongly associated with human immunodeficiency virus (HIV) infection. The authors conducted a multi‐institutional, retrospective study to describe characteristics and determine prognostic factors in HIV‐associated PBL.

METHODS:

For this study, the investigators included consecutive, HIV‐positive patients diagnosed between the years 2000 and 2010 whose tumors had a plasmablastic morphology, were cluster of differentiation 20 (CD20)‐negative, and expressed markers of plasmacytic differentiation.

RESULTS:

Fifty patients from 13 institutions were evaluated. The median age was 43 years, and there was a male predominance. The median count of cells that were positive for CD4 (a glycoprotein expressed on the surface of T‐helper cells, monocytes, macrophages, and dendritic cells) was 206 cells/mm³. At presentation, 90% of patients had extranodal involvement, 69% presented with advanced stage disease, and 27% had oral involvement. Rearrangements of v‐myc myelocytomatosis viral oncogene homolog (MYC) were detected in 41% of the tested patients. Eighty‐five percent of patients received chemotherapy, with 63% receiving cyclophosphamide, doxorubicin, vincristine, and prednisone and 37% receiving more intensive regimens. The complete response (CR) rate was 66%. The median overall survival (OS) was 11 months regardless of the intensity of chemotherapy. In the survival analysis, an Eastern Cooperative Oncology Group performance status ≥2, advanced stage, and MYC rearrangements were associated significantly with a worse outcome, whereas attaining a CR with chemotherapy was associated with a better outcome.

CONCLUSIONS:

The prognosis of PBL in HIV‐infected individuals remains poor in the highly active antiretroviral therapy era. Intensive chemotherapy regimens do not seem to increase survival in patients with HIV‐associated PBL. Cancer 2012. © 2012 American Cancer Society.     

Post-treatment (not interim) positron emission tomography-computed tomography scan status is highly predictive of outcome in mantle cell lymphoma patients treated with R-HyperCVAD

BACKGROUND:

Although convincing data exist regarding the prognostic utility of positron emission tomographic (PET)‐computed tomographic (CT) imaging in Hodgkin lymphoma and diffuse large B‐cell lymphoma, its prognostic utility both during treatment and immediately after treatment have not been systematically evaluated in a large mantle cell lymphoma (MCL) patient cohort to support its use in clinical practice.

METHODS:

The authors conducted a retrospective cohort study to examine the prognostic utility of PET‐CT imaging in a uniform MCL patient cohort undergoing dose‐intensive chemotherapy (R‐HyCVAD) in the frontline setting. The primary study endpoints were progression‐free survival (PFS) and overall survival (OS). PET‐CT images were centrally reviewed for the purposes of this study using standardized response criteria.

RESULTS:

Fifty‐three patients with advanced stage MCL with PET‐CT data were identified. With median follow‐up of 32 months, 3‐year PFS and OS estimates were 76% (95% confidence interval [CI], 64%‐84%) and 84% (95% CI, 72%‐90%), respectively. Interim PET‐CT status was not associated with PFS (hazard ratio [HR], 0.9; 95% CI, 0.3‐2.7; P = .8) or OS (HR, 0.6; 95% CI, 0.1‐2.9; P = .5). Post‐treatment PET‐CT status was statistically significantly associated with PFS (HR, 5.2; 95% CI, 2.0‐13.6; P = .001) and trended toward significant for OS (HR, 2.8; 95% CI, 0.8‐9.6; P = .07).

CONCLUSIONS:

These data do not support the prognostic utility of PET‐CT in pretreatment and interim treatment settings. A positive PET‐CT after the completion of therapy identifies a patient subset with an inferior PFS and a trend toward inferior OS. Cancer 2012;3565–3570. © 2011 American Cancer Society.     

Intravenous methotrexate as central nervous system (CNS) prophylaxis is associated with a low risk of CNS recurrence in high‐risk patients with diffuse large B‐cell lymphoma

BACKGROUND:

The outcome of patients with systemic diffuse large B‐cell lymphoma (DLBCL) had improved over the past decade with the addition of monoclonal antibody therapy. Unfortunately, approximately 5% of these patients still developed a secondary central nervous system (CNS) recurrence followed invariably by rapid death. This rate is substantially increased in patients with certain high‐risk features. Although prophylaxis against CNS recurrence with either intrathecal or intravenous methotrexate is commonly used for such patients, to the authors' knowledge, there is no standard of care. Retrospectively evaluated was the role of high‐dose systemic methotrexate combined with standard cyclophosphamide, doxorubicin, vincristine, and prednisone with rituximab (R‐CHOP) chemotherapy to decrease CNS recurrence in high‐risk patients.

METHODS:

A total of 65 patients with DLBCL and CNS risk factors were identified at the study institution between 2000 and 2008 who received intravenous methotrexate as CNS prophylaxis concurrent with standard systemic therapy with curative intent. CNS recurrence rate, progression‐free survival, and overall survival were calculated.

RESULTS:

Patients received a median of 3 cycles of methotrexate at a dose of 3.5 gm/m² with leucovorin rescue. The complete response rate was 86%, with 6% partial responses. At a median follow‐up of 33 months, there were only 2 CNS recurrences (3%) in this high‐risk population. The 3‐year progression‐free and overall survival rates were 76% and 78%, respectively. Complications associated with methotrexate therapy included transient renal dysfunction in 7 patients and a delay in systemic chemotherapy in 8 patients.

CONCLUSIONS:

Intravenous methotrexate can be safely administered concurrently with R‐CHOP and is associated with a low risk of CNS recurrence in high‐risk patients. Cancer 2010. © 2010 American Cancer Society.     

Phase 2 trial of combined cisplatin,etoposide, gemcitabine,and methylprednisolone (PEGS) in peripheral T‐cell non‐Hodgkin lymphoma

BACKGROUND:

Patients with peripheral T‐cell lymphomas (PTCLs) have inferior progression‐free survival (PFS) and overall survival (OS) compared with patients who have aggressive B‐cell non‐Hodgkin lymphoma. Because PTCLs over express multidrug resistance gene 1/P‐glycoprotein (MDR‐1/P‐gp), we devised platinum, etoposide, gemcitabine, and methylprednisolone (PEGS) with agents that are not substrates of the efflux pump. Gemcitabine was included because of its excellent single‐agent activity in PTCL.

METHODS:

Patients who had PTCL with stage II bulky disease, stage III or IV disease with extra‐nodal, nodal, and transformed cutaneous presentations were eligible. Patients received intravenous cisplatin 25 mg/m² on days 1 through 4, etoposide 40 mg/m² on days 1 through 4, gemcitabine 1000 mg/m² on day 1, and methylprednisolone 250 mg on days 1 through 4 of a 21‐day cycle for 6 cycles.

RESULTS:

In total, 34 patients were enrolled, 33 were eligible, and 79% were newly diagnosed. Histologic types were PTCL not otherwise specified (n = 15), anaplastic lymphoma kinase (ALK)‐negative anaplastic large cell lymphoma (n = 4), angioimmunoblastic T‐cell lymphoma (n = 6), or other T‐cell non‐Hodgkin lymphomas (n = 8). Adverse events included 1 grade 5 infection with grade 3 or 4 neutropenia and 9 grade 4 hematologic toxicities. The overall response rate was 39% (47% in PTCL not otherwise specified, 33% in angioimmunoblastic T‐cell lymphoma, 25% in ALK‐negative and 38% in other T‐cell non‐Hodgkin lymphomas). The PFS rate at 2 years was 12% (95% confidence interval, 0.1%‐31%), and the median PFS was 7 months. The OS rate at 2 years was 30% (95% confidence interval, 8%‐54%), and the median OS was 17 months. Immunohistochemical analysis of P‐gp expression revealed strong positivity in a subset of lymphoma cells (n = 6) and tumor endothelium (n = 25).

CONCLUSIONS:

Overall, PEGS was well tolerated, but OS was not considered promising given the design‐specified targets. These results may serve as a benchmark for future comparisons for non‐CHOP regimens. Cancer 2013. © 2012 American Cancer Society.     

Immune reconstitution of B‐cell lymphoma patients receiving CHOP‐based chemotherapy containing rituximab

Sixty‐six B‐cell lymphoma patients were treated with a CHOP‐based chemotherapy containing rituximab (R‐CHOP‐like regimen). Immune reconstitution was assessed by measuring lymphocyte subsets and immunoglobulins. Fifty‐five patients (83.3%) underwent six cycles of the R‐CHOP‐like regimen. CD19⁺ and CD20⁺ cells were completely eliminated from the peripheral blood after one cycle of the R‐CHOP‐like regimen; they were detected again 6 months after the therapy. One year after the therapy, B‐cell numbers recovered to their level at diagnosis and almost doubled 2 years after the therapy. The lowest numbers of CD3⁺, CD8⁺ and CD56⁺ cells were seen after three cycles of the regimen, but continued to increase until 1 year after the therapy, remaining stable thereafter. CD4⁺ T‐cells were at their lowest after six cycles of the regimen and recovered slowly for 2 years after the therapy; however, their numbers were still lower than that at diagnosis. Immunoglobulins decreased over six cycles of the R‐CHOP‐like regimen and then recovered gradually for 2 years after the therapy. The percentage of IgG, IgA and IgM 2 years after the therapy compared with those at diagnosis was 93.9%, 90.1%, 76.3%, respectively. Twelve infectious complications occurred which consisted of three febrile neutropenia, three Herpes Zoster, two tympanitis, two Pneumocystis jiroveci pneumonia and two hepatitis B virus reactivation. B‐cells required 1 year and CD4⁺ T‐cells and immunoglobulins needed 2 years to recover after the therapy. Copyright © 2010 John Wiley & Sons, Ltd.     

Total lesion glycolysis in positron emission tomography is a better predictor of outcome than the International Prognostic Index for patients with diffuse large B cell lymphoma

BACKGROUND:

This study was undertaken to evaluate the prognostic value of quantitative metabolic parameters in [¹⁸F]2‐fluoro‐2‐deoxyglucose (FDG)‐positron emission tomography (PET) for diffuse large B cell lymphoma (DLBCL).

METHODS:

A total of 140 DLBCL patients underwent FDG‐PET scans before rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisolone (R‐CHOP) chemotherapy. The maximal standardized uptake value (SUV_max) and total lesion glycolysis (TLG) were calculated, with the margin thresholds as 25%, 50%, and 75% of SUV_max of all lesions. Treatment outcomes were compared between groups according to metabolic parameters and the International Prognostic Index (IPI).

RESULTS:

After a median follow‐up of 28.5 months (range, 5‐81 months), the 2‐year progression‐free survival (PFS) and overall survival (OS) were 83% and 87%, respectively. Among metabolic parameters, TLG at the threshold of 50% (TLG₅₀) was significantly associated with treatment outcomes. High TLG₅₀ values (>415.5) were associated with reduced survivals compared with low TLG₅₀ values (≤415.5) (2‐year PFS of 73% versus 92%, P = .007; and 2‐year OS of 81% versus 93%, P = .031). High IPI score (≥3) significantly reduced OS (2‐year OS of 79% versus 90%, P = .049). Ann Arbor stage III/IV adversely affected PFS (P = .013). However, high IPI score and Ann Arbor stage of III/V did not significantly shorten PFS (P = .200) and OS (P = .921), respectively. High TLG₅₀ values independently predicted survivals by multivariate analysis (hazard ratio = 4.4; 95% confidence interval = 1.5‐13.1; P = .008 for PFS and hazard ratio = 3.1; 95% confidence interval = 1.0‐9.6; P = .049 for OS).

CONCLUSIONS:

Combined assessment of volume and metabolism (ie, TLG) is predictive of survivals in DLBCL patients who are treated with R‐CHOP. Cancer 2013. © 2012 American Cancer Society.     

CHOP or THP‐COP regimens in the treatment of newly diagnosed peripheral T‐cell lymphoma,not otherwise specified: a comparison of doxorubicin and pirarubicin

The CHOP regimen consisting of cyclophosphamide, doxorubicin (DOX), vincristine and prednisolone has been the most used regimen for peripheral T‐cell lymphoma, not otherwise specified (PTCL‐NOS). Pirarubicin [tetrahydropyranyladriamycin (THP)], a derivative of DOX, is an anthracycline with reportedly less cardiotoxicity than DOX. Here, we confirmed the efficacy of THP‐COP using THP instead of DOX in the treatment of PTCL‐NOS. The study protocol employed a retrospective, consecutive entry design. We retrospectively analysed 56 patients with PTCL‐NOS who had received THP‐COP or CHOP. These regimens were performed every 21 days. Twenty‐nine patients received THP‐COP, and 27 received CHOP. There were no significant differences in known prognostic factors, including in the International Prognostic Index (IPI) and the prognostic index for T‐cell lymphoma (PIT), between the two groups. Complete remission rates in patients with THP‐COP and CHOP were 52% in both groups; the 3‐year overall survival (OS) rates were 67% and 52% (p = 0.074), and the 3‐year progression‐free survival (PFS) rates were 51% and 29% (p = 0.070), respectively. In patients with low IPI (low or low‐intermediate), THP‐COP had significantly better 3‐year OS (100% vs. 64%; p < 0.001) and 3‐year PFS (75% vs. 33%; p < 0.05) than CHOP. Similar differences between THP‐COP and CHOP were observed in patients with a low PIT (groups 1 or 2). Our study showed that THP‐COP produced results equivalent to CHOP regarding efficacy and safety in patients with PTCL‐NOS. In patients with low IPI or PIT, THP‐COP resulted in significantly better prognosis. Copyright © 2015 John Wiley & Sons, Ltd.     

Expression of eukaryotic initiation factor 4E predicts clinical outcome in patients with mantle cell lymphoma treated with hyper‐CVAD and rituximab,alternating with rituximab,high‐dose methotrexate,and cytarabine

BACKGROUND:

Oncogenic AKT/mammalian target of rapamycin (mTOR) signaling has recently been shown to contribute to tumor survival and proliferation in mantle cell lymphoma (MCL) through its downstream effector eukaryotic initiation factor 4E (eIF4E), which may control cyclin D1 protein levels. However, the clinical significance of eIF4E expression in MCL is unknown.

METHODS:

The authors investigated the prognostic significance of eIF4E expression in 70 MCL patients uniformly treated with hyper‐CVAD and rituximab, alternating with the rituximab, high‐dose methotrexate, and cytarabine regimen (R‐hyper‐CVAD). eIF4E expression was assessed using tissue biopsy specimens obtained before treatment, immunohistochemical methods, and a highly specific monoclonal antibody. Failure‐free (FFS) and overall (OS) survival were used as endpoints in univariate and multivariate survival analysis.

RESULTS:

High eIF4E expression was found in 28 (40%) MCL tumors. After a median follow‐up of 51 months for survivors, the 5‐year FFS was 20.6% for patients with high eIF4E expression, compared with 63.5% for patients with low or no eIF4E expression (P = .01, log‐rank). Similarly, the 5‐year OS was 40.1% for patients with high eIF4E expression, compared with 73.8% for patients with low or no eIF4E expression (P = .018, log‐rank). In multivariate analysis, eIF4E expression was associated with poorer FFS and OS, along with age >60 years and high β₂–microglobulin in the final prognostic model.

CONCLUSIONS:

In summary, eIF4E, which seems to recapitulate most of the biologic effects of mTOR signaling in MCL, is an independent predictor of clinical outcome in MCL patients uniformly treated with the R‐hyper‐CVAD regimen. Cancer 2009. © 2009 American Cancer Society.     

The ratio of the absolute lymphocyte count to the absolute monocyte count is associated with prognosis in Hodgkin's lymphoma: correlation with tumor-associated macrophages

Background.

Although most patients with classical Hodgkin''s lymphoma (cHL) have a long survival duration, the current risk stratification is imperfect. A recent study suggested a prognostic role for the peripheral blood absolute lymphocyte count/absolute monocyte count (ALC/AMC) ratio at diagnosis in cHL. It is intriguing to investigate the significance of the ALC/AMC ratio in relation to tumor-associated macrophages (TAMs), yet another prognostic factor for cHL.

Methods.

We examined the prognostic impact of the ALC, AMC, and ALC/AMC ratio in 312 cHL patients (median age, 37 years) using receiver operating characteristic curve analysis for optimal cutoff values, and compared these with TAM content.

Results.

The median follow-up was 65 months (range, 0.1–245 months). On univariate analysis, a low ALC/AMC ratio (<2.9) was correlated with a poorer overall survival (OS) outcome. A subgroup analysis of patients with limited-stage disease showed that the ALC/AMC ratio was significantly correlated with the OS time. Multivariate analysis showed the ALC/AMC ratio to be an independent prognostic factor for OS outcome. A Spearman correlation test of TAM content showed a negative correlation with the ALC/AMC ratio and a positive correlation with the peripheral blood macrophage percentage.

Conclusions.

This study suggests that the ALC/AMC ratio may be a simple, inexpensive, and independent prognostic factor for OS outcome in patients with cHL and may have a role in the stratification of cHL patients in addition to the International Prognostic Score and TAM content.     

A phase 1 dose escalation study of bortezomib combined with rituximab, cyclophosphamide, doxorubicin, modified vincristine, and prednisone for untreated follicular lymphoma and other low-grade B-cell lymphomas

BACKGROUND:

Bortezomib has demonstrated efficacy in patients with relapsed B‐cell non‐Hodgkin lymphoma (NHL) both alone and in combination with other agents; however, limited data exist regarding its toxicity in combination with common frontline therapies for indolent NHL. A phase 1 study of bortezomib combined with rituximab, cyclophosphamide, doxorubicin, modified vincristine, and prednisone (R‐CHOP) was conducted in patients with untreated follicular lymphoma (FL) and other indolent NHLs.

METHODS:

Nineteen patients, including 10 patients with FL, were enrolled. The median patient age was 59 years (range, 29‐71 years). Seven patients had a FL International Prognostic Index score ≥3. R‐CHOP with the vincristine dose capped at 1.5 mg was administered on a 21‐day cycle for 6 to 8 cycles, and 1 of 3 dose levels of bortezomib (1.0 mg/m² [n = 1], 1.3 mg/m² [n = 6], or 1.6 mg/m² [n = 12]) was administered on days 1 and 8 of each cycle using a Bayesian algorithm for dose escalation.

RESULTS:

The maximum tolerated dose (MTD) of bortezomib with modified R‐CHOP was reached at 1.6 mg/m². Dose‐limiting toxicity was observed in 5 patients (1 patient at a bortezomib dose of 1.0 mg/m², 1 patient at a bortezomib dose of 1.3 mg/m², and 3 patients at a bortezomib dose of 1.6 mg/m²). Neuropathy occurred in 16 patients (84%), including 2 patients (11%) who experienced grade 3 sensory neuropathy. Grade 4 hematologic toxicity occurred in 4 patients. Of 19 evaluable patients, 100% responded, and the complete response rate was 68%. At a median follow‐up of 32 months, the 3‐year progression‐free survival rate was 89.5%.

CONCLUSIONS:

Bortezomib combined with modified R‐CHOP produced high response rates without substantial increases in toxicity. A phase 2 study of R‐CHOP and bortezomib given at this established MTD is currently ongoing. Cancer 2012;3538–3548. © 2012 American Cancer Society.     

Midtreatment 18F-fluorodeoxyglucose positron-emission tomography in aggressive non-Hodgkin lymphoma

BACKGROUND:

The use of ¹⁸F‐fluorodeoxyglucose positron‐emission tomography (PET) scan has increased considerably in the clinical management of non‐Hodgkin lymphoma patients, and its role as a prognostic factor during chemotherapy has been established recently.

METHODS:

Between May 2003 and May 2009, 91 newly diagnosed patients with primary mediastinal large B‐cell lymphoma (PMLBCL) and diffuse large B‐cell lymphoma (DLBCL) were treated with 12 weekly cycles of rituximab‐MACOP‐B (n = 12 patients with PMLBCL), 6 cycles of rituximab‐CHOP21 (n = 65 patients with DLBCL, aged < 60 years and 1 patient with PMLBCL), or 8 weekly cycles of rituximab‐VNCOP‐B (n = 13 DLBCL patients, aged ≥ 60 years). All patients underwent a staging PET examination at baseline and a midtreatment (interim) PET examination after 6 weeks of rituximab‐MACOP‐B treatment, 3 cycles of rituximab‐CHOP21 treatment, or 4 weeks of rituximab‐VNCOP‐B treatment and again at the end of the chemo‐immunotherapy regimen.

RESULTS:

At midtreatment evaluation, 35 patients showed a persistently positive PET scan; only 6 (17%) of these patients achieved a continuous complete response (CCR). However, 56 patients presented with a negative interim PET, and 50 (89%) of these patients achieved and maintained a CCR. Comparison between the 2 PET groups indicated a statistically significant association between PET findings and event‐free survival (P = .0001) and overall survival (P = .0001).

CONCLUSIONS:

The results of this study indicated that midtreatment PET may represent a significant step forward in helping physicians make crucial decisions on further treatment. Cancer 2011. © 2010 American Cancer Society.     

Increasing incidence of enteropathy-associated T-cell lymphoma in the United States, 1973-2008

BACKGROUND:

Enteropathy‐associated T‐cell lymphoma (EATL) is a rare lymphoma subtype that is strongly associated with celiac disease (CD), an autoimmune disease triggered by the ingestion of gluten. Because CD rates are increasing in the United States, the authors sought to determine whether the incidence rates of EATL also are increasing.

METHODS:

The authors identified patients with primary, pathologically confirmed lymphoma in the Surveillance, Epidemiology, and End Results database registries from 1973 to 2008. To ensure capture of all cases of EATL, the following lymphoma subtypes, limited to the small bowel, were included: non‐Hodgkin lymphoma not otherwise specified (NOS) T‐cell, peripheral T‐cell lymphoma NOS, and enteropathy type T‐cell lymphoma, and their age‐adjusted and sex‐adjusted incidence rates were calculated over time. Survival was estimated using Kaplan‐Meier curves.

RESULTS:

In total, the authors identified 161 small bowel lymphomas that were diagnosed between 1973 and 2008. The overall age‐adjusted and sex‐adjusted annual incidence for all bowel lymphomas was 0.016 per 100,000 population, which increased over the study period from 0.006 to 0.024 per 100,000 population. These tumors were most common in men (age‐adjusted incidence rate, 0.021 per 100,000) with the highest incidence rate in Hispanics (age‐adjusted incidence rate, 0.033 per 100,000). The median overall survival was 7 months. There was no difference in survival by race/ethnicity (P = .09) or sex (P = .06).

CONCLUSIONS:

The current results indicated a significant increase in the incidence of EATL in the United States, which may reflect the increasing seroprevalence of CD and better recognition of rare types of T‐cell lymphomas. The incidence may continue to rise given the large ratio of undiagnosed‐to‐diagnosed individuals with CD in the United States. Cancer 2012. © 2011 American Cancer Society.     

Negative prognostic impact of low absolute CD4+ T cell counts in peripheral blood in mantle cell lymphoma

Tumor microenvironment and host immunity are closely related to outcome in patients with mantle cell lymphoma (MCL). However, few researchers have focused on the prognostic value of peripheral blood lymphocyte subsets counts. The purpose of this study was to investigate the prognostic value of lymphocyte subsets and absolute monocyte counts. Sixty‐eight patients were analyzed retrospectively. Absolute CD4⁺ T cell counts (ACD4C), CD8⁺ T cell counts, nature killer cell counts, and CD4/CD8 ratios were assessed by peripheral blood flow cytometry and correlated with clinical parameters and long‐term outcomes. The median follow‐up for all patients was 21 months and the median survival time was 44 months. The overall survival (OS) rate at 1, 3, and 5 years was 80%, 51%, and 41%, respectively. In our cohort, high absolute monocyte count, and low ACD4C and CD4/CD8 ratio were associated with unfavorable OS (P = 0.029, P = 0.027, and P = 0.045, respectively) by univariate analysis. Multivariate analysis indicated that low ACD4C was a significant predictor of unfavorable OS (P = 0.004) independent of the simplified MCL International Prognostic Index (P = 0.048) in patients treated with or without rituximab (P = 0.011). Low CD4⁺ T cell counts proved to be a significant predictor of unfavorable OS in patients with MCL.