Rituximab added to an intensified salvage chemotherapy program followed by autologous stem cell transplantation improved the outcome in relapsed and refractory aggressive non-Hodgkin lymphoma

We investigated the addition of rituximab to an intensified salvage program followed by a myeloablative course with autologous stem cell transplantation (ASCT) in patients with relapsed or refractory aggressive non-Hodgkin lymphoma (NHL). Patients with relapsed or progressive aggressive NHL were treated with two cycles of conventional salvage chemotherapy (DHAP) followed by high-dose sequential chemotherapy (cyclophosphamide, methotrexate with vincristine and etoposide) and a final myeloablative course (BEAM) with ASCT. Rituximab (375 mg/m²) was administered at each treatment cycle. This cohort was compared with a historical control group of patients treated with the same chemotherapy but without rituximab. Patients from both groups were matched by duration of first remission and lactate dehydrogenase serum levels. Forty-five patients were treated with chemotherapy and 22 with immunochemotherapy. The overall response rates (ORR) at the final evaluation were 63% for the immunochemotherapy group and 42% for the chemotherapy group (p = 0.330). In the historical controlled analysis freedom from second failure (FF2F) at 2 years in the immunochemotherapy group was 57% and overall survival (OS) was 77%. FF2F in the chemotherapy group was 18% (p = 0.0051) and OS was 37% (p = 0.0051). In the matched-pair analysis, FF2F was 58% in the immunochemotherapy group compared to 16% in the chemotherapy group (p = 0.0517); OS was 74 vs 33%, respectively (p = 0.0424). The toxicity was tolerable and comparable in both groups. The addition of rituximab to an intensified salvage chemotherapy regimen seems to improve the prognosis. However, only prospective randomized trial can offer sufficient data of the value of rituximab in relapsed and refractory aggressive NHL.     

Autologous stem cell transplantation for follicular lymphoma is of most benefit early in the disease course and can result in durable remissions,irrespective of prior rituximab exposure

The role of autologous stem cell transplantation (ASCT) and the optimal timing of such transplants in patients with follicular lymphoma (FL) remains contentious. We present a single‐centre experience documenting the outcomes of 70 FL patients who underwent BEAM (carmustine, cytarabine, etopside, melphalan)‐conditioned ASCT between 1988 and 2009. With a median follow‐up of 6·8 years (0·1–19·2), the 7‐year overall survival (OS) and progression‐free survival (PFS) from the date of ASCT was 76% and 60%, respectively. A significant difference in OS was found when comparing the patients transplanted in first or second remission versus those transplanted in later remissions (P = 0·02) and this significance was maintained when OS was calculated from the date of diagnosis (P = 0·03). There was a plateau on the PFS curves for patients transplanted in either first or second remissions after 9·3 and 6·4 years respectively, suggesting that these groups may never relapse. No differences were seen in OS or PFS in those treated with rituximab prior to transplant versus those who were not. Our data shows that BEAM ASCT can be a highly effective treatment in patients with FL early in the disease course, and that a proportion of patients experience prolonged disease‐free survival and may be cured.     

Post-autologous stem cell transplantation administration of rituximab improves the outcome of patients with aggressive B cell non-Hodgkin’s lymphoma

The major cause of treatment failure following high-dose therapy with autologous stem cell transplantation (ASCT) for aggressive B cell non-Hodgkin’s lymphoma (NHL) is persistent disease or recurrence. We describe our experience with the administration of rituximab post-ASCT, either as maintenance therapy or for the treatment of relapsed disease in patients with aggressive B cell NHL. Fifty-six patients achieved complete remission post-transplant, and 19 of them received maintenance with rituximab. Maintenance with rituximab resulted in statistically significant superior outcome in terms of progression free (PFS; p = 0.002) and overall survival (OS; p = 0.011). The median PFS and OS of patients in the maintenance arm has not been reached yet, while the median PFS and OS of patients in the control arm were 29 and 42 months, respectively. Fifty-four patients had disease progression or relapsed post-ASCT, and 15 of them received rituximab in combination with chemo- and/or radiotherapy in order to achieve disease remission. Therapeutic administration of rituximab resulted in statistically significant prolongation of OS (p = 0.021). The median OS of patients treated with rituximab was 17 months, while median OS of patients in the control group was 10 months. We consider that the results of our study are promising but need to be verified within large randomized trials.     

High-dose radioimmunotherapy versus conventional high-dose therapy and autologous hematopoietic stem cell transplantation for relapsed follicular non-Hodgkin lymphoma: a multivariable cohort analysis

We performed a multivariable comparison of 125 consecutive patients with follicular lymphoma (FL) treated at our centers with either high-dose radioimmunotherapy (HD-RIT) using 131I-anti-CD20 (n = 27) or conventional high-dose therapy (C-HDT) (n = 98) and autologous hematopoietic stem cell transplantation. The groups were similar, although more patients treated with HD-RIT had an elevated pretransplantation level of lactate dehydrogenase (41% versus 20%, P =.03) and elevated international prognostic score (41% versus 19%, P =.02). Patients treated with HD-RIT received individualized therapeutic doses of 131I-tositumomab (median, 19.7 GBq [531 mCi]) to deliver 17 to 31 Gy (median, 27 Gy) to critical organs. Patients treated with C-HDT received total body irradiation plus chemotherapy (70%) or chemotherapy alone (30%). Patients treated with HD-RIT experienced improved overall survival (OS) (unadjusted hazard ratio [HR] for death = 0.4 [95% confidence interval (95% CI), 0.2-0.9], P =.02; adjusted HR, 0.3, P =.004) and progression-free survival (PFS) (unadjusted HR =.6 [95% C.I., 0.3-1.0], P =.06; adjusted HR, 0.5, P =.03) versus patients treated with C-HDT. The estimated 5-year OS and PFS were 67% and 48%, respectively, for HD-RIT and 53% and 29%, respectively, for C-HDT. One hundred-day treatment-related mortality was 3.7% in the HD-RIT group and 11% in the C-HDT group. The probability of secondary myelodysplastic syndrome/acute myeloid leukemia (MDS/AML) was estimated to be.076 at 8 years in the HD-RIT group and.086 at 7 years in the C-HDT group. HD-RIT may improve outcomes versus C-HDT in patients with relapsed FL.     

Clinical significance of metabolic tumor volume by PET/CT in stages II and III of diffuse large B cell lymphoma without extranodal site involvement

The objective of this study was to investigate whether metabolic tumor volume (MTV) by positron emission tomography (PET) can be a potential prognostic tool when compared with Ann Arbor stage, in stages II and III nodal diffuse large B cell lymphoma (DLBCL). We evaluated 169 patients with nodal stages II and III DLBCL who underwent measurements with PET prior to rituximab combined with cyclophosphamide, adriamycin, vincristine, and prednisone (R-CHOP). Cutoff point of MTV was measured using the receiver operating characteristic (ROC) curve. During a median period of 36 months, stage II was 59.2% and III was 40.8%. Using the ROC curve, the MTV of 220 cm³ was the cutoff value. The low MTV group (<220 cm³) had longer progression-free survival (PFS) and overall survival (OS), compared with the high MTV group (≥220 cm³) (p < 0.001, p < 0.001). Stage II patients had longer survival than those in stage III (PFS, p = 0.011; OS, p = 0.001). The high MTV group had lower PFS and OS patterns, regardless of stage, compared with the low MTV group (p < 0.001, p < 0.001). Multivariate analysis revealed an association of the high MTV group with lower PFS and OS (PFS, hazard ratio (HR) = 5.300, p < 0.001; OS, HR = 7.009, p < 0.001), but not stage III (PFS, p = 0.187; OS, p = 0.054). Assessment of MTV by PET had more potential predictive power than Ann Arbor stage in the patients that received R-CHOP.     

Abnormal surface markers expression on bone marrow CD34<Superscript>+</Superscript> cells and correlation with disease activity in patients with systemic lupus erythematosus

Defects of hematopoietic stem cells (HSCs) have been suggested to contribute to the development of systemic lupus erythematosus (SLE). The aim of this study was to investigate the phenotypic characteristics of bone marrow (BM) CD34⁺ cells in patients with SLE and its relationship with SLE disease activity. Ten SLE patients and 10 healthy subjects were recruited and their BM CD34⁺ cells were analyzed by flow cytometric analysis with CD45/SSC gating for the expression of CD90, CD95, CD117, CD123, CD164, CD166, FAS-L, and HLA-DR. The percentage of BM CD34⁺ cells was significantly decreased in active SLE patients (1.48 ± 0.41%, n = 7) compared to the healthy controls (2.31 ± 0.75%, n = 10, p < 0.01), but no significant difference was found between the inactive patients (2.04 ± 0.44%, n = 3) and the controls. The expression of CD95, CD123, and CD166 on BM CD34⁺ cells were significantly increased in SLE patients (48.31 ± 10.59%, 44.9 ± 21.5%, 30.9 ± 19.54%, respectively, n = 10) when compared with the control subjects (24.33 ± 11.1%, 19.5 ± 4.4%, 10.7 ± 5.5%, respectively, n = 10, p < 0.05). The increased CD123 expression was negatively correlated with the number of peripheral white blood cells (r = −0.700, p < 0.05, n = 10). The percentage of CD166 expression was found significantly correlated with the index of SLE disease activity (r = 0.472, p < 0.05, n = 10) and 24 h proteinuria (r = 0.558, p < 0.05, n = 10), but negatively correlated with serum C3 level (r = −0.712, p < 0.01, n = 10). Our study found that the surface marker expression of CD95, CD123, and CD166 on BM CD34⁺ cells were significantly increased in patients. This supports the hypothesis that there are abnormalities of the HSC in SLE. Since CD166 and CD123 correlated with the overall lupus activity, their role as a biomarker of inflammatory disease activity also requires further study.     

Circulating CD133<Superscript>+</Superscript>VEGFR2<Superscript>+</Superscript> and CD34<Superscript>+</Superscript>VEGFR2<Superscript>+</Superscript> cells and arterial function in patients with beta-thalassaemia major

Arterial dysfunction has been documented in patients with beta-thalassaemia major. This study aimed to determine the quantity and proliferative capacity of circulating CD133⁺VEGFR2⁺ and CD34⁺VEGFR2⁺ cells in patients with beta-thalassaemia major and those after haematopoietic stem cell transplantation (HSCT), and their relationships with arterial function. Brachial arterial flow-mediated dilation (FMD), carotid arterial stiffness, the quantity of these circulating cells and their number of colony-forming units (CFUs) were determined in 17 transfusion-dependent thalassaemia patients, 14 patients after HSCT and 11 controls. Compared with controls, both patient groups had significantly lower FMD and greater arterial stiffness. Despite having increased CD133⁺VEGFR2⁺ and CD34⁺VEGFR2⁺ cells, transfusion-dependent patients had significantly reduced CFUs compared with controls (p = 0.002). There was a trend of increasing CFUs across the three groups with decreasing iron load (p = 0.011). The CFUs correlated with brachial FMD (p = 0.029) and arterial stiffness (p = 0.02), but not with serum ferritin level. Multiple linear regression showed that CFU was a significant determinant of FMD (p = 0.043) and arterial stiffness (p = 0.02) after adjustment of age, sex, body mass index, blood pressure and serum ferritin level. In conclusion, arterial dysfunction found in patients with beta-thalassaemia major before and after HSCT may be related to impaired proliferation of CD133⁺VEGFR2⁺ and CD34⁺VEGFR2⁺ cells.     

Dose-escalated CHOP and tailored intensification with IFE according to early response and followed by BEAM/autologous stem-cell transplantation in poor-risk aggressive B-cell lymphoma: a prospective study from the GEL-TAMO Study Group

Objectives: The role of high‐dose therapy and autologous stem‐cell transplantation (HDT/ASCT) in the up‐front treatment of poor‐risk aggressive lymphoma is still unknown. We conducted a prospective multi‐centre trial with dose‐escalated CHOP (MegaCHOP) and tailored intensification prior to HDT/ASCT according to early response assessed by CT and gallium scan (Ga⁶⁷S). Patients and methods: Eighty‐six patients with newly diagnosed and Ga‐67 avid aggressive B‐cell lymphoma received MegaCHOP for three courses and were evaluated for response by CT and Ga⁶⁷S. Patients with CT response and negative Ga⁶⁷S received another MegaCHOP cycle followed by BEAM and ASCT. Those patients with positive Ga⁶⁷S or without CT response received salvage treatment with two courses of ifosfamide and etoposide (IFE) followed, whenever response had been achieved, by BEAM and ASCT. Results: Response rate before HDT/ASCT was 85% and, with 34 months of median follow‐up, progression‐free survival (PFS), overall survival (OS) and treatment‐related mortality were 56%, 64% and 7%, respectively. For transplanted patients (81% of the whole series), PFS and OS were 67% and 74%, respectively. No different outcomes were observed between patients achieving an early negative Ga⁶⁷S response treated with MegaCHOP and BEAM/ASCT and patients with mid‐treatment positive Ga⁶⁷S who received IFE prior BEAM/ASCT. Conclusions: This response‐adapted strategy including early treatment modifications prior HDT/ASCT have yielded encouraging PFS and OS in patients with poor‐risk B aggressive non‐Hodgkin’s lymphoma.     

Salvage chemotherapy with mitoxantrone, fludarabine, cytarabine, and cisplatin (MIFAP) in relapsing and refractory lymphoma

Purpose: The aim of the study was to evaluate the feasibility and efficacy of the combination of mitoxantrone, fludarabine, cytarabine, and cisplatin (MIFAP) in patients with prognostically unfavorable recurrent and refractory Hodgkin's disease (HD) and non-Hodgkin's lymphoma (NHL). Methods: Forty-six patients (median age 43 years, range 18–63) with relapsed (n=15) or refractory (n=31) malignant lymphoma were enrolled (HD, n=13; low-grade/transformed NHL, n=4; high-grade NHL, n=29). A total of 39 patients (85%) showed multiply relapsed diseases with a duration of prior remission of <12 months (n=8) or had lymphoma being resistant to prior chemotherapy (n=31). The MIFAP therapy consisted of fludarabine (15 mg/m², q. 12 h, day 1–4), cytarabine (50 mg/m² by continuous infusion (CI) over 22 h, day 1–4), cisplatin (25 or 30 mg/m² by CI over 24 h, day 1–4), and mitoxantrone (4 mg/m², day 2–5). Results: Thirteen patients (28%) achieved complete remission (CR) and 15 patients (33%) partial remission (PR), for an overall response (OR) rate of 61%. Twenty-two patients responding to MIFAP (10 CR, 12 PR) have been consolidated by high-dose therapy (HDT) with hematopoietic stem cell transplantation (SCT). After a median follow-up of 12 months, 16 patients are in continuous CR (CCR) (n=14) or CCRu (unconfirmed) (n=2). The median duration of event-free survival (EFS) and overall survival (OS) were 6.5 and 19.3 months, respectively. Probabilities of EFS and OS after 3 years were 19% and 40%. Responders consolidated by subsequent HDT showed rates for 3-year EFS and OS of 40% and 66%, respectively. Unfavorable prognostic factors for EFS by univariate analysis were refractory lymphoma and the presence of B-symptoms. Significant prognostic factors for OS were NHL, refractory lymphoma, B-symptoms, and bone marrow involvement. The major toxicities were leukocytopenia and thrombocytopenia of the World Health Organization (WHO) grade IV in nearly all courses (median duration 10 and 11 days). In contrast, non-hematological side effects were moderate, predominantly of WHO grades I and II. Treatment-related mortality with MIFAP was 4% (two patients with septicemia by Aspergillus fumigatus). Conclusions: MIFAP is an effective salvage protocol for patients with poor-risk recurrent or refractory HD and NHL. The observed toxicity seems to be acceptable considering the unfavorable prognosis and intensive pretreatment. The results in patients responding to MIFAP and afterwards undergoing HDT with autologous stem cell support are even comparable to those published in patients with prognostically more favorable diseases. Received: 12 October 2000 / Accepted: 8 November 2000     

Positron emission tomography derived metrics in relapsed or refractory large B-cell lymphoma with residual disease before autologous stem cell transplant

Salvage chemotherapy followed by high-dose chemotherapy and autologous stem cell transplantation (ASCT) is a potentially curative treatment for patients with relapsed or refractory large B-cell lymphoma (rrLBCL) with chemosensitive disease. A¹⁸F-fluorodeoxyglucose positron emission tomography (PET) scan after salvage chemotherapy is used to assess response and eligibility for ASCT, but metrics for chemosensitivity in patients with residual disease are not well defined. We performed a single-centre retrospective analysis of 92 patients with a partial response or stable disease after salvage chemotherapy for rrLBCL who received ASCT to investigate PET-derived parameters and their prognostic utility. The Deauville 5-point Scale (D-5PS) score, maximum standardised uptake value (SUV_max), total metabolic tumour volume (TMTV), and total lesion glycolysis (TLG) were calculated from the post-salvage/pre-ASCT PET scan. The 5-year progression-free survival (PFS) and overall survival (OS) rates were 40% and 54% respectively. A D-5PS score of 5 (p = 0.0082, hazard ratio [HR] 2.09), high SUV_max (p = 0.0015, HR 2.48), TMTV (p = 0.035, HR 1.83) and TLG (p = 0.0036, HR 2.27) were associated with inferior PFS. A D-5PS score of 5 (p = 0.030, HR 1.98) and high SUV_max (p = 0.0025, HR 2.55) were associated with inferior OS. PET-derived parameters may help prognosticate outcomes after ASCT in patients with rrLBCL with residual disease after salvage chemotherapy.     

High-dose chemotherapy and autologous stem cell transplantation for peripheral T-cell lymphoma: complete response at transplant predicts survival

Although the role of high dose chemotherapy (HDT) and autologous stem cell transplantation (ASCT) in the treatment of aggressive lymphoma has been established in several large prospective studies, its effectiveness in patients with peripheral T cell lymphoma (PTCL) has not been defined. We aimed to evaluate the efficacy of HDT and ASCT and prognostic factors for survival in patients with PTCL. We retrospectively analyzed the results of 40 PTCL patients treated with HDT and ASCT at Asan Medical Center between January 1995 and December 2005. Twenty patients had PTCL-U (peripheral T cell lymphoma, unspecified), 10 had extranodal natural killer/T cell lymphoma, 5 had anaplastic large cell lymphoma, 3 had angioimmunoblastic T cell lymphoma, 1 had hepatosplenic γσ T cell lymphoma, and 1 had disseminated mycosis fungoides. Disease status at transplant was complete response (CR)1 in 3 patients, CR2 or greater in 8, partial remission in 25, and refractory in 4. At a median follow-up of 16 months (range, 5 to 135 months) for surviving patients, the median overall survival (OS) was 11.5 months and the 1-year probability of survival was 46.1%. The median event free survival (EFS) was 3.6 months (95% confidence interval, 2.5 to 4.8 months). Ten patients (25%) remain alive without evidence of disease. The median OS of 11 patients with CR at ASCT was not reached; of these, 7 patients (63.6%) were alive with CR. In multivariate analysis, CR at ASCT was a prognostic factor for EFS (P = 0.025) and OS (P = 0.027) and normal lactate dehydrogenase (LDH) at ASCT was a prognostic factor for improved OS (P = 0.025). Chemosensitive patients with PTCL who achieved CR before ASCT seem to benefit from HDT and ASCT. Pretransplant values of LDH had potential to predict the survival.     

A randomized phase II study of standard‐dose versus high‐dose rituximab with BEAM in autologous stem cell transplantation for relapsed aggressive B‐cell non‐hodgkin lymphomas: long term results

High‐dose rituximab (HD‐R) combined with carmustine, cytarabine, etoposide and melphalan (BEAM) and autologous stem cell transplant (ASCT) was effective and tolerable in a single‐arm prospective study of relapsed aggressive B‐cell non‐Hodgkin lymphoma (R‐NHL). We performed a randomized phase 2 study comparing HD‐R versus standard‐dose rituximab (SD‐R) in R‐NHL. Ninety‐three patients were randomized to HD‐R (1000 mg/m²) (n = 42) or SD‐R (375 mg/m²) (n = 51) administered on post‐transplant days +1 and +8, using a Bayesian adaptive algorithm. The 2 treatment arms were balanced in regards to patient demographic and clinical characteristics. At a median follow‐up of 7·92 years, the 5‐year disease‐free survival (DFS) and overall survival (OS) were 40% and 48%, respectively. We found no statistically significant differences between HD‐R and SD‐R in 5‐year DFS (36% vs. 43%; P = 0·205) and OS (43% vs. 52%; P = 0·392). In multivariate analyses, only disease status before ASCT [residual disease versus complete remission (CR)] (hazard ratio [HR] 1·79, 95% confidence interval [CI]: 1·08–2·95) and number of prior treatments received (>2 vs. ≤2 lines of treatment) (HR 1·89, 95% CI: 1·13–3·18) were associated with worse DFS and OS. Patients who had SCT while in CR or who received ≤2 lines of treatment prior to SCT had better 5‐year OS (57% vs. 35%; P = 0·02 and 54% vs. 30%, P = 0·001, respectively) in both arms. No differences in engraftments or adverse events were noted in the 2 arms. When combined with BEAM and ASCT in relapsed aggressive B‐cell NHL, HD‐R provided no DFS or OS advantage over SD‐R. In patients who have been exposed to rituximab in the frontline or salvage setting, the addition of rituximab in the peri‐transplant setting remains controversial.     

Improved outcomes of high-risk relapsed Hodgkin lymphoma patients after high-dose chemotherapy: a 15-year analysis

High-dose chemotherapy and autologous stem-cell transplant (HDC/ASCT) is standard treatment for chemosensitive relapsed classical Hodgkin lymphoma, although outcomes of high-risk relapse (HRR) patients remain suboptimal. We retrospectively analyzed all HRR classical Hodgkin lymphoma patients treated with HDC/ASCT at our institution between 01/01/2005 and 12/31/2019. HRR criteria included primary refractory disease/relapse within 1 year, extranodal extension, B symptoms, requiring more than one salvage line, or positron emission tomography (PET)-positive disease at ASCT. All patients met the same ASCT eligibility criteria. We treated 501 patients with BEAM (n=146), busulphan/melphalan (BuMel) (n=38), gemcitabine (Gem)/BuMel (n=189) and vorinostat/Gem/BuMel (n=128). The Gem/BuMel and vorinostat/Gem/BuMel cohorts had more HRR criteria and more patients with PET-positive disease at ASCT. Treatment with brentuximab vedotin (BV) or anti-PD1 prior to ASCT, PET-negative disease at ASCT, and maintenance BV increased over time. BEAM and BuMel predominated in earlier years (2005-2007), GemBuMel and BEAM in middle years (2008-2015), and vorinostat/GemBuMel and BEAM in later years (2016-2019). The median follow-up is 50 months (range, 6-186). Outcomes improved over time, with 2-year progressionfree survival (PFS)/overall survival (OS) rates of 58%/82% (2005-2007), 59%/83% (2008-2011), 71%/94% (2012-2015) and 86%/99% (2016-2019) (P<0.0001). Five-year PFS/OS rates were 72%/87% after vorinostat/ GemBuMel, 55%/75% after GemBuMel, 45%/61% after BEAM, and 39%/57% after BuMel (PFS: P=0.0003; OS: P<0.0001). These differences persisted within the PET-negative and PET-positive subgroups. Prior BV and vorinostat/GemBuMel were independent predictors of more favorable outcome, whereas primary refractory disease, ≥2 salvage lines, bulky relapse, B symptoms and PET-positivity at ASCT correlated independently with unfavorable outcomes. In conclusion, post-HDC/ASCT outcomes of patients with HRR classic Hodgkin lymphoma have improved over the last 15 years. Pre-ASCT BV treatment and optimized synergistic HDC (vorinostat/GemBuMel) were associated with this improvement.     

A study on nm23-H1 expression in diffuse large B-cell lymphoma that was treated with CyclOBEAP plus rituximab therapy

In our previous study on nm23-H1 expression with diffuse large B-cell lymphoma (DLBCL), we found that patients with positive nm23-H1 had significantly poorer prognosis than patients with negative nm23-H1. We examined whether nm23-H1 is a prognostic factor of DLBCL in the rituximab era. The subjects were 101 DLBCL patients who underwent R-CyclOBEAP (rituximab, cyclophosphamide, vincristine, bleomycin, etoposide, doxorubicin, and prednisolone) therapy and in whom markers could be analyzed. We evaluated CD5, CD10, BCL2, BCL6, MUM1, and nm23-H1 expression by immunohistochemistry. Ninety-four DLBCL patients who underwent CyclOBEAP therapy were assumed as historical controls. Among DLBCL patients who underwent CyclOBEAP therapy, BCL2 positivity, MUM1 positivity, non-germinal center B-cell (non-GCB), and nm23-H1 positivity were associated with significantly shorter overall survival (OS) and progression-free survival (PFS). On the other hand, among DLBCL patients who underwent R-CyclOBEAP therapy, the 5-year OS rates of the nm23-H1-positive DLBCL (n = 32) and nm23-H1-negative DLBCL groups (n = 69) were 65% and 97%, respectively (p = 0.001), with 5-year PFS rates of 51% and 89%, respectively (p = 0.001). In the rituximab era, BCL2, MUM1, and non-GCB were not prognostic factors. We demonstrated that among patients with DLBCL who underwent R-CyclOBEAP therapy, patients with nm23-H1 expression had a significantly poorer prognosis than patients without nm23-H1 expression. These results suggest an important role for nm23-H1 in malignant progression and a potential therapeutic target for DLBCL.     

Autologous hematopoietic stem cell transplantation—what determines the outcome: an experience from North India

Limited information is available from developing countries about complications, pattern of infections, and long-term outcome of patients following high-dose chemotherapy (HDCT) and autologous blood stem cell transplantation (ASCT). Between April, 1990 and December 2009, 228 patients underwent ASCT. Patients’ median age was 48 years, ranging from 11 to 68 years. There were 158 males and 70 females. Indications for transplant included multiple myeloma, n = 143; lymphoma, n = 44 (Hodgkin’s, n = 25 and non-Hodgkin’s, n = 19); leukemia, n = 22; and solid tumors, n = 18. Patients received HDCT as per standard protocols. Following ASCT, 175 (76.7%) patients responded; complete, 98 (43%); very good partial response, 37 (16.2%); and partial response, 40 (17.5%). Response rate was higher for patients with good Eastern Cooperative Oncology Group (ECOG) performance status (0–2 vs. 3–4, p < 0.001), pretransplant chemo-sensitive disease (p < 0.001) and those with diagnosis of hematological malignancies (p < 0.003). Mucositis, gastrointestinal, renal, and liver dysfunctions were major nonhematologic toxicities, 3.1% of patients died of regimen-related toxicities. Infections accounted for 5.3% of deaths seen before day 30. At a median follow-up of 66 months (range, 9–234 months), median overall (OS) and event-free survival (EFS) were 72 months (95% CI 52.4–91.6) and 24 months (95% CI 17.15–30.9), respectively. For myeloma, OS and EFS were 79 months (95% CI 52.3–105.7) and 30 months (95% CI 22.6–37.4), respectively. Pretransplant good performance status and achievement of significant response following transplant were major predictors of survival. Our analysis demonstrates that such procedure can be successfully performed in a developing country with results comparable to developed countries.     

Autologous hematopoietic stem cell transplantation in adult acute lymphoblastic leukemia: still not out of fashion

The role of autologous hematopoietic stem cell transplantation (autoHSCT) in adult acute lymphoblastic leukemia (ALL) is still unclear. We retrospectively analyzed the results of the autoHSCT and maintenance therapy, with oral 6-mercaptopurine and methotrexate, in comparison to conventional-dose chemotherapy in the consolidation treatment of adult ALL and lymphoblastic lymphoma (LBL). The patients, with HLA identical sibling donor, underwent allogeneic transplantation, while the others were treated with autoHSCT and maintenance therapy with oral 6-mercaptopurine and methotrexate, or by conventional-dose chemotherapy (patient’s decision, no autologous hematopoietic stem cells harvest). Sixty consecutive adult patients (median age 35.2 years; range 17.3 to 70.7) with ALL (n = 52), LBL (n = 7), and acute biphenotypic leukemia (n = 1) were treated in our center from 1997 to 2007. Patients treated with chemotherapy alone (n = 35) had a shorter median progression-free survival (PFS) compared to patients who underwent autoHSCT plus maintenance therapy (n = 18), 8.4 and 46.8 months, respectively (p = 0.017). Patients treated with chemotherapy alone had also a shorter median overall survival (OS) compared to patients treated with autoHSCT: 13.0 vs. 46.8 months (p = 0.046). The differences remained statistically significant even after excluding patients with Ph positivity. We can conclude that, in our case, autoHSCT followed by maintenance chemotherapy is a good option for adult patients with ALL and, in standard-risk and high-risk patients, provides more favorable OS and PFS rates compared to patients treated by chemotherapy alone. However, we are aware of the fact that our analysis may have been distorted by the fact that the analysis is retrospective, that treatment with autoHSCT was based on patient’s decision, and that chemotherapy may have been administered to negatively selected patients.     

Outcomes in 370 patients with mantle cell lymphoma treated with ibrutinib: a pooled analysis from three open‐label studies

Ibrutinib is highly active in treating mantle cell lymphoma (MCL), an aggressive B‐cell lymphoma. We pooled data from three ibrutinib studies to explore the impact of baseline patient characteristics on treatment response. Patients with relapsed/refractory MCL (n = 370) treated with ibrutinib had an objective response rate (ORR) of 66% (20% complete response; 46% partial response); median duration of response (DOR), progression‐free survival (PFS) and overall survival (OS) were 18·6, 12·8 and 25·0 months, respectively. Univariate analyses showed patients with one versus >one prior line of therapy had longer OS. Multivariate analyses identified that one prior line of therapy affected PFS; Eastern Cooperative Oncology Group (ECOG) performance status, simplified MCL international prognostic index (sMIPI) score, bulky disease, and blastoid histology affected OS and PFS. Patients with blastoid versus non‐blastoid histology had similar time to best response, but lower ORR, DOR, PFS and OS. OS and PFS were longer in patients with better sMIPI, patients with ECOG performance status 0–1, non‐bulky disease and non‐blastoid histology. Additionally, the proportion of patients with poor prognostic factors increased with increasing lines of therapy. Together, results suggest that patient outcomes following treatment failure with ibrutinib are related to the natural biological evolution of the disease.     

A phase II trial evaluating the efficacy of high-dose Radioiodinated Tositumomab (Anti-CD20) antibody,etoposide and cyclophosphamide followed by autologous transplantation,for high-risk relapsed or refractory non-hodgkin lymphoma

Radiation is the most effective treatment for localized lymphoma, but treatment of multifocal disease is limited by toxicity. Radioimmunotherapy (RIT) delivers tumoricidal radiation to multifocal sites, further augmenting response by dose-escalation. This phase II trial evaluated high-dose RIT and chemotherapy prior to autologous stem-cell transplant (ASCT) for high-risk, relapsed or refractory (R/R) B-cell non-Hodgkin lymphoma (NHL). The primary endpoint was progression free survival (PFS). Secondary endpoints were overall survival (OS), toxicity, and tolerability. Patients age < 60 years with R/R NHL expressing CD20 were eligible. Mantle cell lymphoma (MCL) patients could proceed to transplant in first remission. Patients received I-131-tositumomab delivered at ≤25Gy to critical normal organs, followed by etoposide, cyclophosphamide and ASCT. A group of 107 patients were treated including aggressive lymphoma (N = 29), indolent lymphoma (N = 45), and MCL (N = 33). After a median follow-up of 10.1 years, the 10-year PFS for the aggressive, indolent, and MCL groups were 62%, 64%, 43% respectively. The 10-year OS for the aggressive, indolent, and MCL groups were 61%, 71%, 48% respectively. Toxicities were similar to standard conditioning regimens and non-relapse mortality at 100 days was 2.8%. Late myeloid malignancies were seen in 6% of patients. High-dose I-131-tositumomab, etoposide and cyclophosphamide followed by ASCT appeared feasible, safe, and effective in treating NHL, with estimated PFS at 10-years of 43%-64%. In light of novel cellular therapies for R/R NHL, high-dose RIT-containing regimens yield comparable efficacy and safety and could be prospectively compared.     

Ile<Superscript>105</Superscript>Val <Emphasis Type="Italic">GSTP1</Emphasis> polymorphism and susceptibility to colorectal carcinoma in Bulgarian population

Background and aims Etiologically, the sporadic colorectal cancer (CRC) is a complex and multifactorial disease that is linked to both exogenic and endogenic factors. Accumulating evidence indicates that susceptibility to cancers, including CRC, is mediated by genetically determined differences in the effectiveness of detoxification of potential carcinogens. A member of the glutathione-S-transferase (GST) family, GSTP1, is an important candidate for involvement in susceptibility to carcinogen-associated CRC. An A→G transition in exon 5 of the GSTP1 gene resulting in Ile¹⁰⁵Val amino acid substitution has been identified. This change leads to alteration in catalytic efficiency of variant enzyme. The aim of the current study was to evaluate the influence of Ile¹⁰⁵Val GSTP1 polymorphism on susceptibility to CRC. Materials and methods The GSTP1 genotyping was conducted in a case-control study of 80 ethnic Bulgarian CRC patients and 126 unaffected controls using polymerase chain reaction restriction fragment length polymorphism method. Results A statistically significant case-control difference in genotype frequencies was observed: 0.69 vs 0.54 for Ile/Ile, 0.22 vs 0.39 for Ile/Val, and 0.09 vs 0.07 for Val/Val (p = 0.049). The odds ratio (OR) for Val/Val was close to 1 (0.96, 95%CI: 0.35–2.66, p = 0.942), whereas the OR for Ile/Val was significantly lower, 0.45 (95%CI: 0.24–0.86, p = 0.016), compared to the referent Ile/Ile genotype. Although a prevalence of the GSTP1 variant allele-containing genotypes (Ile/Val or Val/Val) was found in controls than in patients (OR = 0.53, 95%CI: 0.30–0.96, p = 0.035), the allele frequencies did not show significant difference between cases and controls (p = 0.127). Conclusions Based on the obtained protective effect of Ile/Val GSTP1 genotype, we could suggest that Ile¹⁰⁵Val GSTP1 polymorphism may play some role in susceptibility to CRC.     

Survival Stratification Panel of Colorectal Carcinoma with Combined Expression of Carcinoembryonic Antigen,Matrix Metalloproteinases-2, and p27<Superscript>kip1</Superscript>

Purpose The prognosis varies greatly in colorectal carcinoma patients, even in the same stage. We examined the association between the expression of matrix metalloproteinases-2, carcinoembryonic antigen, p27^kip1, and clinicopathologic features in patients with colorectal carcinoma to identify a possible panel of tumor markers in predicting prognosis of colorectal carcinoma. Methods The expressions of three individual markers in 127 colorectal carcinoma cases were analyzed by immunohistochemistry method. Univariate and multivariate analysis were performed to analyze the expression with the disease-free survival time in colorectal carcinoma. Results High expression of matrix metalloproteinases-2, carcinoembryonic antigen, and low expression of p27^kip1 were related to poor prognosis in univariate analysis (P = 0.0002; P < 0.0001; P = 0.0008). The expression of matrix metalloproteinases-2, carcinoembryonic antigen, p27^kip1, and tumor differentiation were independent prognostic factors for disease-free survival by Cox regression analysis. The coexpression panel of matrix metalloproteinases-2, carcinoembryonic antigen, and p27^kip had significant prognostic value in all patients (P_AB = 0.0103; P_BC = 0.0068; P_CD = 0.0117). Multivariate analysis with Cox regression reveals that coexpression of matrix metalloproteinases-2, carcinoembryonic antigen, and p27^kip1 were independent prognostic factors as tumor differentiation in colorectal carcinoma. In different stages, coexpression tumor markers functioned in Stages II and III but not in the 19 cases of Stage I. The reason might be the number of patients was too small. Conclusions The results of this study provided further evidence that the combination of tumor markers of matrix metalloproteinases-2, carcinoembryonic antigen, and p27^kip1 was more informative than any single tumor marker alone for the disease-free survival stratification of colorectal carcinoma. Coexpression of matrix metalloproteinases-2, carcinoembryonic antigen, and p27^kip1 might be a useful survival stratification panel for clinical management. Supported by the Research fund of the Beijing Municipal Science & Technology Commission (Grant H020920030390); Beijing New Star Project on Science & Technology (Grant 2006B55). Poster presentation at Digestive Disease Week, Los Angeles, California, May 20 to 25, 2006.