ASHAP – an effective salvage therapy for recurrent and refractory malignant lymphomas

Background: This study was performed to examine the efficacy and toxicity of the combination of adriamycin (ADR), methylprednisolone (solumedrol), cytarabine (Ara-C), and cisplatin (CDDP) in patients with recurrent and refractory malignant lymphomas. Patients and methods: Sixty-five patients with Hodgkin's disease (HD) (n=14) or non-Hodgkin's lymphomas (NHL) (n=51) were enrolled in the study. The ASHAP therapy consisted of ADR (40 mg/m² by continuous infusion (CI) over 96 h), methylprednisolone (500 mg i.v., days 1–5), Ara-C (2 g/m² as a 2-h infusion on day 5), and CDDP (100 mg/m² by CI over 96 h). Results: Twenty-five patients (38%) achieved complete remission (CR) and 20 (31%) were taken into partial remission (PR) for an overall response rate of 69%. Thirty-two patients with CR or PR following ASHAP underwent high-dose therapy (HDT) with subsequent hematopoietic stem cell transplantation. After a median follow-up of 52 months, 13 patients are in continuous CR (CCR), the 3-year event-free survival (EFS) was 30% for responders and 21% for all patients. The median overall survival (OS) was 12 months (range 0–70 months), and the OS rate after 3 years was 32%. Unfavorable prognostic factors for EFS and OS by univariate analysis were an elevated value of the serum lactate dehydrogenase and refractory lymphoma. The most frequently observed side effects following ASHAP were leukocytopenia and thrombocytopenia of World Health Organization (WHO) grades III/IV in approximately 80% of all courses. Non-hematological toxicities such as gastrointestinal side effects, infections, mucositis, renal and neurotoxicity occurred more rarely and reached WHO grades III/IV only occasionally. No treatment-related mortality with ASHAP was observed. Conclusions: ASHAP is an effective and moderately toxic salvage therapy for patients with recurrent or refractory HD and NHL. The results in patients responding to ASHAP and afterwards undergoing HDT with stem cell support are comparable with other established protocols and indicate an improvement in survival if HDT is carried out as intensification. Received: 21 July 1999 / Accepted: 24 November 1999     

Effect of rituximab on the long-term outcome after high-dose therapy for relapsed B-cell non-Hodgkin’s lymphoma

To better define the role of rituximab in salvage and high-dose therapy (HDT) for relapsed or refractory non-Hodgkin’s lymphoma (NHL), patients treated before the implementation of rituximab in salvage and HDT (n=57, control group) were compared with patients with rituximab included in this procedure (n=36, study group). All patients had been antibody-naive at this point, and analyses were performed separately for 22 and 31 patients with aggressive, and 14 and 26 patients with indolent NHL, respectively. All patients received two courses of salvage therapy, predominantly dexamethasone, BCNU, etoposide, cytosine arabinoside, melphalan. Conditioning regimens included BCNU, etoposide, cytosine arabinoside, melphalan; BCNU, etoposide, cytosine arabinoside, cyclophosphamide or total body irradiation and cyclophosphamide, with rituximab added for patients in the study group. Despite the absence of differences in stem cell collection, haematopoietic recovery was delayed in patients with aggressive NHL treated in the study group: median days to absolute neutrophil count more than 0.5×10⁹/l, 11 vs 10 (p=0.01), and platelets more than 20×10⁹/l, 14 vs 11 (p=0.0005), with an increased requirement for platelet transfusions. No similar observations were made in indolent lymphoma patients. Remission rates were superior for patients with aggressive NHL in the study group. With a median follow-up of 7.25 and 4.5 years, this resulted in an improvement in OS at 4.5 years: 67 vs 45% (95% confidence interval, 47–87% vs 28–64%; p=0.0468). For patients with indolent lymphoma, no comparable benefit was detectable. Our data support the use of rituximab in HDT for patients with aggressive NHL. For patients with indolent NHL, only longer follow-up and/or randomized trials may help to fully determine the impact of rituximab on the outcome after HDT.     

Tandem high-dose therapy in relapsed and refractory B-cell lymphoma: results of a prospective phase II trial of myeloablative chemotherapy,followed by escalated radioimmunotherapy with <Superscript>131</Superscript>I-anti-CD20 antibody and stem cell rescue

A phase II trial evaluated safety, feasibility and efficacy of a sequential tandem approach combining myeloablative BEAM chemotherapy and autologous stem cell transplantation (ASCT) with myeloablative radioimmunotherapy (HD-RIT), with ¹³¹I-anti-CD20 antibody (¹³¹I-rituximab), followed by a second ASCT in patients with relapsed or refractory CD20+ B-cell lymphoma. According to protocol, 16 patients with relapsed (n = 14) and refractory (n = 2) CD20+ B-cell lymphoma received salvage therapy with rituximab and Dexa-BEAM, followed by BEAM (HD chemotherapy) and high-dose myeloablative radioimmunotherapy 2–6 months after BEAM. Nine of 16 patients received HD-RIT; seven patients were excluded before HD-RIT because of toxicity or progressive disease. Disease histologies were follicular lymphoma (FL) grades 1 and 2 (n = 4), transformed follicular (FL 3b; n = 6), diffuse large B-cell (DLBCL; n = 4), mantle cell (n = 1) and marginal zone lymphoma (n = 1). After a median follow-up of 50.4 months for OS and 39.7 months for progression-free survival (PFS), estimated 4-year OS and PFS were 67% and 64%, respectively. The estimated 4-year OS and PFS for patients with FL were 80% and 78%, respectively. Toxicity was significant, including one fatal outcome due to pneumonitis. Tandem transplants consisting of HD chemotherapy followed by HD-RIT with ¹³¹I-coupled anti-CD20 are manageable and effective but toxic treatment modalities for relapsed poor prognosis CD20+ B-NHL.     

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.     

High-dose therapy with peripheral blood stem cell transplantation for patients with relapsed or refractory Hodgkin's disease: long-term outcome and prognostic factors

 From March 1986 to March 1998, 82 patients with relapsed or refractory Hodgkin's disease underwent high-dose chemotherapy (HDCT) with peripheral blood stem cell (PBSC) transplantation in our center. This is a retrospective analysis of the long-term clinical outcome. There were 52 males and 30 females with a median age of 32 years (range 18–59 years). Prior to transplantation, 36 patients were in complete remission (CR), 34 in partial remission (PR), and 12 had refractory disease after salvage therapy. For HDCT, 78 patients were treated with CBV (cyclophosphamide, 6.0–6.8 g/m²; etoposide, 1.0–1.6 g/m²; carmustine, 0.45–0.8 g/m²), while four patients received different regimens. Probability of freedom from progression (FFP), overall survival (OS), and event-free survival (EFS) at 5 years of the entire group was 63%, 61%, and 54%, respectively. Early mortality rate (≤100 days) declined from 17% to 6% after 1992. Five patients died of late transplant-related complications (>100 days), including secondary lymphoma and leukemia in two patients. None of the refractory patients survived beyond 3.5 years. Multivariate analyses identified extranodal sites of disease at relapse and refractory disease status prior to transplantation as significant prognostic factors for FFP, EFS, and OS. As we have shown in our study, remarkable progress was achieved in reducing early morbidity and mortality over time, but this was associated with only a slight, not significant improvement of long-term outcome (OS 66% vs 57% at 5 years for patients undergoing PBSC transplantation before and after 1992, P=0.26). Although the results as a whole are encouraging for chemosensitive patients, new therapeutic strategies are needed to reduce toxicity and improve the clinical outcome of patients, especially of those with a less favorable prognosis. Received: 12 October 1999 / Accepted: 29 February 2000     

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 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.     

FDG-PET/CT predicts outcome in patients with aggressive non-Hodgkin’s lymphoma and Hodgkin’s disease

Early therapy response assessment with metabolic imaging is potentially useful to determine prognosis in aggressive lymphoma and, thus, can guide first-line therapy. Forty-eight patients with aggressive lymphoma [24 Hodgkin’s disease (HD); 24 non-Hodgkin’s lymphoma (NHL)] underwent fluoro-deoxyglucose positron emission tomography (FDG-PET) before chemotherapy (PET1) and at mid-treatment (PET2). Therapeutic response was evaluated using conventional methods at mid-treatment. PET2 results were related to event-free survival (EFS) and overall survival (OS) using Kaplan–Meier analyses. PET1 was positive in all patients. PET2 was negative in 38 patients (18 NHL-20 HD) and positive in 10 (6 NHL-4 HD). Of the PET-negative patients, 61 and 65% achieved complete remission, and only 50 and 25% of PET-positive patients, respectively, for NHL and HD, achieved complete remission. Significant associations were found between PET2 and EFS (p=0.0006) and OS (p=0.04) for NHL, and EFS (p<0.0001) for HD (but not for OS, because no HD patient died). FDG-PET at mid-treatment can predict the outcome of patients with aggressive lymphoma and should be a useful tool to modify an ineffective therapy.     

The combined evaluation of interim contrast-enhanced computerized tomography (CT) and FDG-PET/CT predicts the clinical outcomes and may impact on the therapeutic plans in patients with aggressive non-Hodgkin’s lymphoma

We investigated the concomitant interim response of patients with aggressive non-Hodgkin’s lymphoma (NHL) using multi-detector row computerized tomography (CT) and ¹⁸F-fluoro-2-deoxy-d-glucose-positron emission tomography (PET)/CT for prediction of clinical outcomes. One hundred six newly diagnosed patients with aggressive NHL were enrolled. Both the CT and PET/CT were serially performed at the time of diagnosis and after three to four cycles of chemotherapy (interim). The patients were categorized into four different responsive groups according to the interim PET/CT and CT: (1) complete metabolic response (CMR)–complete response unconfirmed (CRu), (2) CMR–partial response (PR), (3) partial metabolic response (PMR)–Cru, and (4) PMR–PR. Fifty-five patients with CMR–CRu, 20 patients with CMR–PR, seven patients with PMR–Cru, and 23 patients with PMR–PR were distributed. In addition, one patient experienced a disease progression. There was a significant difference in relapse rates between PET/CT-positive (67.3%) and PET/CT-negative patients (17.3%; P < 0.01). Also, there was a significant difference between patients with PMR–PR (32.0% and 26.1%) and CMR–CRu (89.3% and 80.0%) for 3-year overall survival (OS) and event-free survival (EFS), respectively. A multivariate analysis revealed that high international prognostic index (≥3) at diagnosis, T-cell phenotype, and PMR–PR in interim PET/CT and CT were independent prognostic significances for OS. Moreover, bulky disease (>10 cm), T-cell phenotype, and PMR–PR showed significant associations for EFS. PMR–PR in interim response was the predictive prognostic determinant for both OS and EFS, with a hazard ratio of 3.93 (1.61–9.60) and 3.60 (1.62–7.98), respectively. The combined evaluation of interim PET/CT and CT was found to be a significant predictor of disease progression, OS, and EFS.     

Study of conditioning regimens with or without high-dose radiotherapy before autologous stem cell transplantation for treating aggressive lymphoma

The aim and objective of the study is to compare the efficacy of conditioning regimens with or without high-dose radiotherapy for treating aggressive non-Hodgkin’s lymphoma (NHL). Eighty-nine aggressive NHL patients who underwent high-dose therapy in combination with autologous stem cell transplantation (HDT/ASCT) between 1993 and 2006 were retrospectively studied. HDT was either high-dose chemotherapy alone (CT) or high-dose chemoradiotherapy (CRT). Overall, 37 patients in CT group and 52 in CRT group. The median radiotherapy DT in CRT group was 8 Gy. The median count of reinfused CD34+ cells was 6.26 × 10⁶ and 22.16 × 10⁶ cells/kg, respectively (p < 0.001). The median time of leukocyte engraftment was 11 days in CT group and 13 days in CRT group (p = 0.003), and the median platelet engraftment time was 12 days in CT group and 11 days in CRT group (p = 0.305). The median event-free survival (EFS) was 102 and 84 months in CT and CRT groups, respectively (p = 0.783), and the median overall survival (OS) was 102 and 121 months in CT and CRT groups, respectively (p = 0.857). Prolonged hospitalization favored EFS (p = 0.013) and OS (p = 0.011). In conclusion, when compared with CT, high-dose CRT does not improve prognosis.     

Outpatient reduced-intensity allogeneic stem cell transplantation for patients with refractory or relapsed lymphomas compared with autologous stem cell transplantation using a simplified method

The effectiveness of reduced-intensity conditioning allogeneic stem cell transplantation (allo- RIC) compared with high-dose chemotherapy followed by autologous stem cell transplantation (auto-SCT) in Hodgkin’s disease (HD) and in non-Hodgkin’s lymphoma (NHL) patients remains poorly defined. The purpose of the study was to demonstrate the usefulness of auto-SCT or allo-SCT, employing a RIC regimen in refractory or relapsed NHL or HD patients. We analyzed the outcome of 71 patients with advanced disease. Twenty-three NHL and 14 HD patients received an allo-RIC using fludarabine, cyclophosphamide, and low-dose busulfan as the conditioning regimen. Sixteen NHL and 18 HD patients received auto-SCT using cyclophosphamide and etoposide as conditioning regimen. All hematopoietic stem cells products were not cryopreserved and the majority of grafts were done on an outpatient basis, including conditioning and post-stem cell infusion care (auto-SCT, 62% and allo-RIC procedure, 91%). The median OS was 45.5 months for the allo-RIC recipients and 53.3 months for auto-SCT recipients. Acute/chronic GVHD incidence in NHL and HL groups was 38%/31% and 14%/7%, respectively. We found no significant difference in overall survival between allo-RIC group and auto-SCT group for NHL patients (P = 0.43) but better OS was observed for auto-SCT group than for allo-SCT group in HL patients (P < 0.001). The relapse rate was higher in autografted patients, both in NHL and HD. Both auto-SCT and allo-RIC appear to be valid treatments for poor-risk patients with relapsed or refractory lymphoma who could not otherwise be cured with conventional salvage regimens.     

Gemcitabine, vinorelbine and prednisone for refractory or relapsed aggressive lymphoma,results of a phase II single center study

The optimum therapy for patients with relapsed or refractory aggressive non-Hodgkin’s lymphomas (NHL) not qualifying for platinum-based and/or high-dose chemotherapy is not known. We conducted a prospective phase II study evaluating a regimen consisting of gemcitabine (1 g/m², days 1 and 8), vinorelbine (30 mg/m², days 1 and 8) and prednisone (100 mg/day, days 1–8) (GVP) given every 21 days. Fifteen patients with a median age of 68 years and a median of three previous therapies were enrolled. Diagnoses included B lymphoblastic (n=1), diffuse large B cell (n=10), anaplastic large T cell (n=2) and peripheral T-cell NHL (n=2). The median international prognostic index score was 3 (six patients with a score of 4 or 5). Five patients achieved a complete remission and three patients a partial remission. The median overall survival was 13.8 months, and the median time to next treatment was 4.4 months. Haematological toxicities of World Health Organisation grades 3/4 were leucopenia in 58%, thrombocytopenia in 33% and anaemia in 17% of all courses. Three patients had grade 3 infections. There was no treatment-related mortality. GVP shows substantial activity in poor prognosis relapsed or refractory aggressive lymphomas and is generally well tolerated, but haematological toxicity is dose limiting.     

Mechanisms of resistance to methotrexate in childhood acute lymphoblastic leukemia: circumvention of thymidylate synthase inhibition

Purpose: In about 25% of patients suffering from acute lymphoblastic leukemia (ALL) treatment failures occur that are most likely due to development of resistance to methotrexate (MTX). Blasts from patients with ALL were evaluated for MTX uptake, formation of long-chain MTX polyglutamates (MTX-Glu₅₊₆), cytotoxicity and thymidylate synthase inhibition by MTX and compared to blasts from patients with acute myelogenous leukemia (AML). Methods: Radioactively labeled MTX-Glu _n were analyzed by means of HPLC. Thymidylate synthase activity was measured by a tritium-release assay. Cytotoxicity was determined by trypan blue exclusion. Results: In most ALL blasts (n = 9) large amounts of MTX-Glu₅₊₆ (1.06–7.03 pmol/10⁷cells) and high cytotoxicity (43.5%–92.7%) were found, while in others small amounts of MTX-Glu₅₊₆ (0.0–0.39 pmol/10⁷cells) caused only weak cytotoxicity (6.0%–27.9%) (n = 5, 2 relapsed patients). Resistance to MTX in blasts from AML patients (n = 5) was also caused by reduced synthesis of MTX-Glu₅₊₆ (0.0–0.42 pmol/10⁷cells). In contrast, some ALL blasts (n = 7, 4 relapsed patients) were able to survive MTX treatment despite large amounts of MTX-Glu₅₊₆ (1.5–5.05 pmol/10⁷cells) and extensive thymidylate synthase inhibition. Conclusions: Since the majority of ALL patients were examined at first diagnosis, an inherent mechanism of resistance seems most likely. We propose a mechanism based on the switch of thymidylate synthesis to the salvage pathway. Received: 30 October 1998 / Accepted: 6 April 1999     

Primary localized stages I and II non-Hodgkin’s lymphoma of the nasopharynx: a retrospective 17-year single institutional experience

The aim of this retrospective study was to define the natural history, clinicopathological findings, prognostic factors, and treatment outcome of 43 patients with localized stages I and II primary non-Hodgkin’s lymphoma (NHL) of the nasopharynx, followed up in a single institution over a 17-year period. Forty-three (13 women and 30 men) consecutive patients with localized stages I (N = 12) and II (N = 31) primary nasopharyngeal NHL were treated in our institution between 1990 and 2007. The pathologic reports were classified according to the International Working Formulation (N = 22) or Revised European-American Lymphoma classification (N = 21). The vast majority of patients (88%) were managed with a sequential combination of chemotherapy and radiation therapy. Chemotherapy mainly consisted of 4–8 (median 6) cycles of CHOP regimen (cyclophosphamide, doxorubicin, vincristine and prednisolone). Involved-field radiation therapy with a median dose of 44 Gy was delivered to the primary site and entire cervical lymph nodes. The median age of the patients was 53 years (range, 6 to 86 years). The majority of the patients (70%) had high-grade histology. B-cell types represented 67% of the cases, among which diffuse large B cell was the most common histological subtype. After a median follow-up of 70 months, the 5-year disease-free survival and overall survival were 58.8% and 70.6%, respectively. In multivariate analysis, age less than or equal to 30 years (hazard ratio (HR) = 5.32, 95% confidence interval (CI) = 1.69–16.76), elevated serum lactate dehydrogenase level (HR = 3.69, 95% CI = 1.43–9.51), and modified International Prognostic Index with more than or equal to two risk factors (HR = 17.99, 95% CI = 2.32–139.30) retained statistical significance. Our limited data suggest that primary nasopharyngeal NHL tends to have aggressive histology and unfavorable clinical course with poor outcome, despite a considerably localized disease at the time of presentation and high frequency of complete initial response rates. Combined modality therapy should be considered for the majority of patients with primary localized nasopharyngeal NHL.     

Autologous peripheral blood stem cell transplantation in children with non-Hodgkin’s lymphoma: a report from the Korean society of pediatric hematology-oncology

Recent development of stratified chemotherapeutic regimens has rapidly improved the survival rate of non-Hodgkin’s lymphoma (NHL) of childhood. Despite these improvements, the outcome for children with recurrent or refractory NHL remains dismal. We explored the use of high-dose chemotherapy followed by autologous peripheral blood stem cell transplantation (HDC/PBSCT) for children with either refractory or recurrent NHL, and we evaluated various factors influencing outcome of HDC/PBSCT. Thirty-three patients underwent HDC/PBSCT in 11 institutes were enrolled. All patients had refractory or recurrent NHL. Sex, stage at diagnosis, histologic subtype (lymphoblastic, Burkitt’s, and large-cell lymphoma), LDH level at diagnosis, disease status at transplantation, and preparative regimens for HDC/PBSCT were explored. In regard to the patients, six had Burkitt’s lymphoma, 13 had lymphoblastic lymphoma, and 14 had large-cell lymphoma. The 2-year event-free survival (EFS) was 59.1±9.3%. The EFS for Burkitt’s, lymphoblastic, and large-cell lymphoma was 66.7±27.2, 50.5±14.8, and 82.1±11.7%, respectively. In comparison with lymphoblastic and non-lymphoblastic lymphoma, the relative risk for lymphoblastic lymphoma was higher than the others (P=0.037). EFS between anaplastic large-cell and diffuse large-cell lymphoma was 100 and 55.6±24.9%, respectively (P=0.106). Status at transplantation was the most predictive factor for the survival after HDC/PBSCT (EFS for CR 70.8±9.5% vs non-CR 20.0±17.9%, P=0.008). Transplantation-related complications were minimal, and infection was the most prevalent complication. HDC/PBSCT is considered applicable to recurrent or refractory pediatric NHL patients safely and it could replace conventional chemotherapy. In this study, children with CR status at the time of HDC/PBSCT showed higher survival rate. However, refractory or recurrent lymphoblastic lymphoma patients showed dismal results. Therefore, new therapeutic modalities may be needed for this group of NHL patients.An erratum to this article can be found at     

Replacement of conventional doxorubicin by pegylated liposomal doxorubicin is a safe and effective alternative in the treatment of non-Hodgkin's lymphoma patients with cardiac risk factors

Anthracyclines are a major component in the therapy of non-Hodgkin's lymphoma. However, due to their cardiac toxicity potential, curative and palliative treatment is often limited in patients with preexisting cardiac dysfunction. Liposomal doxorubicin formulations have been described to be less cardiotoxic than conventional doxorubicin. In the current study, we analyzed the efficacy and toxicity of pegylated liposomal doxorubicin (PLD) as constituent of the cyclophosphamide, doxorubicin, vincristine, and prednisone (CHOP) regimen replacing conventional doxorubicin in 21 patients with impaired cardiac left ventricular ejection fraction or preexisting cardiac risk factors and established diagnosis of diffuse large B cell lymphoma (n = 15), mantle cell lymphoma (n = 3), follicular lymphoma (n = 1), and T cell lymphoma (n = 2). Overall and complete response rate were 85% and 40%, respectively. Event-free survival and overall survival after 2 years were 58%. One lethal event of acute cardiac death occurred during the first cycle in a patient with transposition of the big arteries, atrial flutter, and mitral valve regurgitation. In the remaining 20 patients, no deterioration of myocardial function was observed in echocardiography performed before and after treatment. Seven cases of grade III–IV hematological toxicity were observed as well as four episodes of neutropenic fever leading to hospitalization. No infection-related death occurred. However, 25% of patients developed a hand–foot syndrome (HFS) leading to discontinuation of treatment. Importantly, the incidence of HFS increased considerably when PLD doses of 15 mg/m²/week were exceeded. We conclude that replacing conventional doxorubicin with PLD in polychemotherapy regimens such as CHOP is an efficient alternative in the treatment of patients with preexisting cardiac dysfunction. However, we recommend that PLD dose should not exceed 15 mg/m²/week. The rationale for the use of non-pegylated liposomal doxorubicin formulations should be evaluated in further studies.     

A systematic review and meta-analysis of rituximab-based immunochemotherapy for subtypes of diffuse large B cell lymphoma

Addition of rituximab to chemotherapy (R-chemo) has been shown to improve overall survival (OS) in patients with diffuse large B cell lymphoma (DLBCL). Germinal center B cell-like (GCB) subtype of DLBCL has a significantly better clinical outcome than those with non-germinal center B cell-like (non-GCB) subtype. Further research is needed to confirm this difference between those two subtypes treated with R-chemo. We searched for randomized controlled trials that compared R-chemo with identical chemotherapy alone in patients with newly diagnosed or relapsed DLBCL. A random versus fixed effects model was selected according to heterogeneity. Six eligible trials involving 748 adult patients were included in this meta-analysis. Fixed-effects analysis showed OS to be superior for the GCB patients treated with R-chemo (relative risk (RR) = 1.16, 95% confidence interval (CI) = 1.03–1.31, P = 0.02). Superiority was also observed for the GCB subtype under R-chemo with respect to disease control (RR = 1.16, 95% CI = 0.99–1.36) and overall response (RR = 1.19, 95% CI = 0.99–1.99). Both subtypes showed an increased OS (RR = 1.30, 95% CI = 1.11–1.51; RR = 1.89, 95% CI = 1.52–2.35, respectively) and disease control rate (RR = 1.27, 95% CI = 1.05–1.54, P = 0.01; RR = 2.21, 95% CI = 1.68–2.90, respectively) following R-chemo. Therefore, treated with R-chemo, GCB patients still has a significantly better clinical outcome than those with non-GCB subtype.     

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.     

Daunorubicin,cytarabine and fludarabine (DAF) for remission induction in relapsed or refractory acute myeloid leukemia. Evaluation of safety,tolerance and early outcome—Polish Adult Leukemia Group (PALG) pilot study

In 1992–1993, synergistic interaction of ribonucleotide reductase inhibitors (fludarabine, cladribine) and cytarabine (Ara-C) increasing Ara-CTP concentration in myeloblasts was proved. Based on these findings and encouraging results of the addition of cladribine to standard daunorubicin+Ara-C induction regimen (DAC) in acute myeloid leukemia (AML), the Polish Adult Leukemia Group (PALG) conducted a pilot study on the administration of cytarabine, daunorubicin, and fludarabine (DAF) as a reinduction treatment of AML to assess tolerance, toxicity, and early outcome. The DAF regimen consisted of daunorubicine 60 mg m⁻² day⁻¹ iv on days 1–3 and fludarabine 25 mg m⁻² day⁻¹ iv on days 1–5 given before cytarabine 200 mg m⁻² day⁻¹ in ci on days 1–7. Thirty-four AML patients with median age 39, 24% relapsed and 76% refractory, were included into the study between September 2003 and August 2004. Achieved response rate in the whole study population was 56%; n = 16 patients with complete remission (CR), and n = 3 patients with partial remission (PR). Fifteen of 16 patients achieved CR after the first course of therapy. Only 9% of total population died before the assessment of remission. All patients developed severe neutropenia. Serious infections were observed in 47% of the cases. Severe thrombocytopenia was observed in 72% of the patients. All patients required substitution of platelet concentrates (median 4), and PRBC (median 5). Severe alopecia, mucositis, vomiting were of low frequency. Liver, kidney, or circulatory failure, diarrhea, or polyneuropathy were not observed. The probability of overall survival (OS) for 1 year for the whole study population (34 patients) and the group of 16 patients in CR was: 44% (95% confidence interval [CI] 36–52%) and 69% (95% CI 55–83%), respectively. The probability of leukemia-free survival (LFS) for 1 year was 38% (95% CI 22–54%). Summarizing, DAF regimen used as the induction therapy in relapsed/refractory AML was well tolerated with acceptable toxicity and early efficacy.