Primary gastric diffuse large B-cell lymphoma: The role of dose-dense chemotherapy.

OBJECTIVE: To assess if the use of a dose-dense regimen of chemotherapy can improve the prognosis in patients with primary gastric diffuse large B-cell lymphoma in early stages (I-II) but associated with worse prognostic factors. METHODS: One hundred and eight consecutive patients with primary gastric diffuse large B-cell lymphoma in early stages (I-II) with high serum levels of lactic dehydrogenase and beta 2 microglobulin (more than >2 of normal levels), which were associated with a worse prognostic outcome, were treated with a dose-dense chemotherapy: CHOP with increased doses of cyclophosphamide and doxorubicin, was administered every 14 days (instead of 21 days). The end points of this study were to improve outcome measured from progression-free survival and overall survival and to evaluate acute toxicities. RESULTS: Complete response was achieved in 85 patients (78%). Actuarial curves at five years show that progression-free survival was 82% and overall survival was 85%. Hematological toxicities were severe, but no death-related treatment was observed. CONCLUSIONS: We considered that in this setting of patients, the use of a dose-dense regimen could be of benefit because it improves outcome and toxicities were well controlled.

Retracted article: Adjuvant radiotherapy in patients with diffuse large B-cell lymphoma in advanced stage (III/IV) improves the outcome in the rituximab era.

Statement of Retraction: Adjuvant radiotherapy in patients with diffuse large B-cell lymphoma in advanced stage (III/IV) improves the outcome in the rituximab era We, the Editor[s] and Publisher of Hematology, have retracted the following article: Avilès, A, Nambo, M-J, Calva, A, et al. Adjuvant radiotherapy in patients with diffuse large B-cell lymphoma in advanced stage (III/IV) improves the outcome in the rituximab era. Hematology. 2019;24:507-511; DOI: 10.1080/10245332.2018.1423880 The above article has been retracted as a result of concerns regarding the data upon which the presented research has been based. After re-examination and several independent expert reviews the consensus is that the data and results are not reliable and therefore the article must be retracted. The authors have agreed with this decision. We have been informed in our decision-making by our policy on publishing ethics and integrity and the COPE guidelines on retractions. The retracted article will remain online to maintain the scholarly record, but it will be digitally watermarked on each page as "Retracted".

Treatment of Early Stages Hodgkin Lymphoma During Pregnancy.

BACKGROUND: To assess maternal and fetal outcome of women and newborns who received chemotherapy during pregnancy to treat Hodgkin lymphoma (HL)in early stages (IA, IIA), we performed a retrospective analysis of a cohort of 44 pregnant women with HL and early stages, diagnosed and treated between 1988 to 2013, at a tertiary reference cancer center. METHODS: We analyzed data on HL characteristics and treatment, with a particular attention to maternal and fetal complications; in children, we performed a longer follow-up to detect any anomaly in physical development, scholar performance, psychological, cardiac, neurological function, and intelligence tests. RESULTS: Median age was 29.4 (range 21-37) years; Most patients were stage IIA (86%), had M a bulky mediastinal disease (78%) and 60% had > 3 nodal sites involved; thus these patients were considered to have a not favorable condition. Abortion was refused when it was proposed. All patients received chemotherapy during pregnancy; ABVD (adryamicin, bleomycin, vinblastine, and dacarbazine) at standard doses and schedule, even during the first trimester. Radiotherapy, when indicated, was administered after delivery in 39 patients. No obstetrical complications were observed, delivery occurred between 33 to 36 weeks in 10 cases (22%); and >37 weeks in 34 cases (87%). Four newborns were low-weight: 2012 g median (range 1750 - 2350 g). No clinical malformations were observed, and development of newborns was physiological without evidence of cardiac and neurological damage, behavior, intelligence, and scholar attendance were normal. At median follow-up range of 120.4 (48-299) months, the progression-free survival and overall survival of patients were 95% and 93%respectively. CONCLUSION: Combined chemotherapy, as initial therapy appears to be the best approach in this setting of patients, with an excellent outcome to both mothers and children. If radiotherapy is necessary, it could be administered after delivery.

Prolonged Use of Zoledronic Acid (4 Years) Did Not Improve Outcome in Multiple Myeloma Patients.

BACKGROUND: Bisphosphonates, especially zoledronic acid (ZA), show antitumor effects in multiple myeloma (MM) and other neoplasms. The standard time for ZA administration has been 2 years. However, with improvement in overall survival (OS) in MM with new agents, it unclear whether ZA could be administered for a prolonged time to improve OS. PATIENTS AND METHODS: A total of 170 patients with untreated, symptomatic MM were randomly divided into a group to receive ZA for 4 years, with a control group to receive ZA for 2 years. All patients were treated with the same induction therapy and stem-cell transplantation. RESULTS: Actuarial curves at 5 years, showed that progression-free survival was 75% (95% confidence interval [CI], 64%-82%) and OS was 68% (95% CI, 60%-76%) in the 4-year group, which was not statistically significantly different compared with the control group: 72% (95% CI, 62%-78%) and 68% (95% CI, 60%-75%; P = .67). However, the 4-year group showed reduced skeletal events (21% occurrence rate); this was statistically significant compared with the control group: 43% (P < .001). CONCLUSION: Although ZA did not improve OS in patients with MM; it continued to be useful to reduce skeletal events, and thus improve better quality of life for patients.

Speckle-Tracking Echocardiography to Detect Cardiac Toxicity in Children Who Received Anthracyclines During Pregnancy.

Cardiac toxicities remain a possible risk to fetuses that received anthracyclines during pregnancy. The introduction of new echocardiographic techniques will improve the detection of early cardiac damage. Thus, we began a observational study using speckle-tracking echocardiography (STE) in children who had received anthracyclines during pregnancy, including the first trimester. From 2009 to 2013, we performed STE on patients > 5 years old, whose mothers had received anthracyclines during pregnancy. Siblings or cousins of equivalent age and gender were used as the control group. A total of 90 children fulfilled the entry criteria. Our results with STE were normal in all echocardiography parameters and did not show any differences when compared with the findings from the control group. We consider that the use of anthracyclines during pregnancy does not produce cardiac damage in newborns and can be safely administered, because no cardiac toxicity was evident in these children and it is of benefit to the mother.

Rituximab as consolidation therapy did not improve outcome in patients with diffuse large B-cell lymphoma at complete response after dose-dense chemotherapy (CHOP-14).

The authors started a clinical trial to assess the efficacy and toxicity of rituximab (R) as consolidation in patients with diffuse large B-cell lymphoma, with poor prognostic factors, who were in complete response (CR) after dose-dense chemotherapy (CHOP-14). Four hundred sixty-five untreated patients, with advanced stages (III and IV), older (median age >60 years old), and high clinical risk, were treated with dose-dense CHOP-14 (cyclophosphamide 1500 mg/m(2), i.v., day 1; vincristine 2 mg, i.v., standard dose, day 1; epirubicin 120 mg/m(2), i.v., day 1; and prednisone 60 mg/m(2), p.o., days 1-5) every 14 days for six cycles. If CR was achieved, the patients were allocated to receive R (375 mg/m(2), days 1, 8, 15, and 22) at 3 and 9 months after chemotherapy. Three hundred twenty-five patients achieved CR (70%) and were allocated to receive R (151 patients) or not (174 patients). Actuarial curves at 5 years showed that progression-free survival (PFS) was 51% (95% confidence interval [CI]: 44%-58%) in the R group and 53% (95% CI: 47%-59%) in the observation group (p=0.8). Overall survival (OS) was 65% (95% CI: 58%-71%) and 66% (95% CI: 59%-72%), respectively (p=0.78). Late toxicities were more frequent in the R group. The authors showed that the use of R as a consolidation treatment was not useful to improve PFS and OS and toxicity secondary to R was frequent. They did not recommend the use of R as consolidation in this patient setting.

Interferon and low doses of methotrexate versus interferon and retinoids in the treatment of refractory/relapsed cutaneous T-cell lymphoma.

OBJECTIVES: Treatment of refractory/relapsed cutaneous T-cell lymphoma (CTCL) remains controversial, most studies included a few patients with a short follow-up. Previously, we performed two small studies employing interferon alpha 2b (IFN) combined with low doses of methotrexate (MTX) or retinoids. Thus, we conducted an open-label clinical trial to assess the benefit and toxicity of the two mentioned regimens in a large number of patients with a longer follow-up of the treatment of refractory/relapsed CTCL. PATIENTS AND METHODS: Three-hundred and seventy-seven patients with refractory/relapsed, pathologically confirmed, CTCL, with advanced stages and at least treated with two previous effective regimens in CTCL, were randomized to receive IFN and low doses of MTX compared with IFN and all trans-retinoid acid during 6 months; if a complete response (CR) was not achieved, treatment was continued until 12 months in both arms. At this time, if patient achieves CR, MTX or retinoid was stopped, and the patient continues to receive IFN until progression disease or toxicity. One-hundred and eight patients received IFN for more than 5 years. RESULTS: Toxicity was minimal and well tolerated, no patients needed to modify the administration of IFN secondary to toxicity. The overall complete response was achieved 80% in both arms. Actuarial curves at 5 years showed that progression-free survival was 60% in the IFN/MTX group and 62% in the IFN/retinoids group (P = 0.8) that were not statistically different and overall survival (OS) rates were 70 and 67%, respectively (P = 0.03). DISCUSSION: Both present schedules showed good tolerance and an excellent OS at 5 years, which is better than the other, more expensive and toxic, regimens. Considering the indolent course of CTCL, we suggested that those regimens, mentioned in this paper, will be regarded as the standard therapy, for patients of this setting. CONCLUSION: The use of IFN and retinoids or low dose of cytotoxic drugs will be preferred in patients with refractory/relapse CTCL, because OS is good and toxicity is minimal.

Combined therapy in untreated patients improves outcome in nasal NK/T lymphoma: results of a clinical trial.

Nasal NK/T-cell lymphoma is a rare presentation of T-cell lymphoma in USA and in Europe, but is the most common presentation in Latin America. The lymphoma is associated with a worse prognosis even in the early stage. Until now, a better treatment has not been determined. We performed a prospective, open-label, controlled clinical trial to assess the efficacy and toxicity of the most common treatment options. We treated 427 patients, of whom 109 patients received radiotherapy (RT), 116 patients received chemotherapy (C), and 202 patients received combined therapy (CT), which were balanced according to stage and prognostic factors. Complete response was achieved in 91 % (95 % confidence interval CI 88-102 %) in CT arm 69 % (95 % CI 61-75 %) in RT arm; and 59 % (95 % CI 48-64 %) in C arm (p < 0.01). A progression-free disease was 91 % (95 % CI 83-96 %); 78 % (95 % CI 69-86 %); and 40 % (95 % CI 32-46 %), respectively (p < 0.01). Actuarial curves of overall survival at 5 years were as follows: 86 % (95 % CI 81-90 %), for CT; 64 % (95 % CI 59-70 %) for RT; and 45 % (95 % CI 39-51 %) for C (p < 0.001). Toxicity was mild and well tolerated. To our knowledge, this is the first controlled clinical trial, with a large number of patients and longer follow-up. Thus, we conclude that CT is the best therapeutic option in this setting of patients.

Hematological malignancies and pregnancy: treat or no treat during first trimester.

Treatment of hematological malignancies (HM) during pregnancy remain unsolved, although the use of chemotherapy during second and third trimester has been accepted because of the low rate of toxicities, the use of cytotoxic drugs during first trimester is generally forbidden. Most of the concerns are related to congenital abnormalities and development, but long-term follow-up of these children are not available. From 1975 to 2008, we diagnosed and treated 15,750 cases of HM, and 143 female patients were pregnant during this time that were treated with combined chemotherapy. In our study, we present the long-term follow-up (the median follow-up was 22.4 years with a range of 3.8-32.0 years) of 54 newborns, whose mothers received chemotherapy during the first trimester of pregnancy with an intent-to-cure HM. Physical and neurological development were carefully assessed, and cardiac and chromosomal studies were performed until the age of 20 years to evaluate late toxicities. The obstetrical development of pregnancy was normal, chemotherapy was used at doses and schedules used in normal patients. Low-weight birth was the most frequent finding. No congenital abnormalities were detected. Physical, psychological and neurological developments were normal. Education and academic degree were according to the economical and social factors. Cardiac function and chromosomal examination were normal. No neoplasm or acute leukemia has been observed in these children. Forty-three mothers are alive and disease-free and can be considered cured. The use of cytotoxic drugs during the first trimester to treat HM seems to be beneficial to both the mother and fetus, and chemotherapy during the first trimester can be considered if the cure of the patient is the goal.

Rituximab and chemotherapy in primary gastric lymphoma.

PURPOSE: We performed a phase II clinical trial to assess the efficacy and toxicity of the addition of rituximab and conventional chemotherapy in primary gastric lymphoma (PGL). METHODS: Forty-two (42) patients with PGL, stage IE and IIE, and with low- or low-intermediate clinical risk were treated in a prospective longitudinal study with standard CHOP (cyclophosphamide, doxorubicin, vincristine, and prednisone) chemotherapy and rituximab (375 mg/m2, intravenously) on day 1 of each cycle administered every 21 days, for 6 cycles. The endpoint was to assess improvement in outcome measured by prolongation in event-free survival (EFS) and overall survival (OS). Complete response was achieved in 40 cases (95%) (95% confidence interval [CI]: 88%-102%). Relapse was observed in 2 cases. Two (2) patients died secondary to tumor progression. Thus, actuarial 5-year EFS was 95% (95 % CI: 87%-104%) and OS was 95% (95% CI: 88%-101%), which was not statistically different to historic controls. Acute toxicity was minimal and well tolerated, 4 cases developed late toxicity, 2 cases of herpes zoster infection, and 2 cases with granulocytopenia; in 1 case, the patient continued with mild granulocytopenia 3 years after treatment. CONCLUSIONS: The addition of rituximab to CHOP chemotherapy did not improve outcome in early-stage PGL.

Rituximab and escalated chemotherapy in elderly patients with aggressive diffuse large-cell lymphoma: a controlled clinical trial.

The treatment of elderly patients with aggressive malignant lymphoma has not been defined. The addition of rituximab to conventional chemotherapy has been reported to improve the outcome, but most patients have good prognostic factors (performance status < 2, no severe associated diseases, low or low-intermediate clinical risk). Thus, we developed a combined regimen, including escalated doses of anthracycline and rituximab. The endpoint was to improve event-free survival (EFS) and overall survival. Two hundred and four (204) patients were randomly assigned to receive an escalated chemotherapy regimen (CEOP) with escalated dose of epirubicin, compared to the same regimen and addition of rituximab. All patients had poor prognostic factors: high- or high-intermediate clinical risk, poor performance status, bulky disease, and more than 2 with extranodal involvement. In an intent-to-treat analysis, all patients were evaluable for efficacy and toxicity. The complete response rates were similar in both arms: 74% in chemotherapy and 78% in the rituximab + chemotherapy program. EFS and overall survival were similar: 77% and 84%, respectively, in combined chemotherapy and 75% and 81% in the rituximab-chemotherapy regimen. Toxicity was mild and well tolerated. In elderly patients with diffuse large-cell lymphoma and poor prognostic factors, rituximab did not improve their outcome.

CMED in the treatment of nasal natural killer cell lymphoma with distant metastases.

INTRODUCTION: Nasal natural killer (NK) cell lymphoma that showed distant metastases generally showed an poor prognosis. We described a group of patients with these atypical presentation and that were treated with an intensive, short chemotherapy/radiotherapy regimen. METHODS: Sixty-one patients fulfilled the criteria for NK cell lymphoma with distant metastases and all have very poor prognostic factors: high clinical risk, multiple extranodal presentation and bulky disease (tumor mass >10 cm). They were treated with CMED (cyclophosphamide 2000 mg/m(2), iv, day 1, methotrexate 400 mg/m(2), iv, day 1(with leucovorin rescue), etoposide 400 mg/m(2) twice and dexametasone 40 mg daily for 4 days). If complete response (CR) was observed, they were received adjuvant radiotherapy (50 Gy) to nasal region. Patients with failure were treated with different salvage treatments. RESULTS: Forty nine patients achieved CR and 12 were considered failure, all patients that were failure and nine that relapse die secondary to tumor progression. Median follow-up were 46 months (range 34-68 months). Median has not been observed in relapse-free survival (RFS) and overall survival (OS). Actuarial curves at 5 years showed that RFS was 81% and OS was 65%. Treatment was well tolerated. CONCLUSIONS: Nasal NK cell lymphoma with distant metastases is considered an rare clinical entity, probably is under diagnosis because it has been included as stage III and IV in previous reports, that showed an very poor RFS and OS. The treatment herein report could achieve good response and outcome, but it is evident that more specific and aggressive therapy is necessary in these setting of patients.

Mucosa-associated lymphoid tissue (MALT) lymphoma of the stomach: results of a controlled clinical trial.

Treatment of patients with early stage gastric mucosa-associated lymphoid tissue (MALT) remains undefined. We began a controlled clinical trial to evaluate efficacy and toxicity of the most common therapies. Two hundred and forty-one patients with gastric low-grade MALT lymphoma in early stage (IE and IIE) were randomized to surgery (80 cases), radiotherapy (78 cases), and chemotherapy (83 cases). With a median follow-up of 7.5 yr, actuarial curves at 10 yr showed that event-free survival was 52% in patients treated with surgery, 52% in radiotherapy arm, and 87% in the chemotherapy group (p < 0.01). However, overall survival did not showed any statistical differences: 80%, 75% and 87%, respectively (p = 0.4). Acute and late toxicities were mild. No death-related treatments were observed. No clear differences were observed between the most common therapies in patients with primary gastric MALT lymphoma in early stages, probably because this type of lymphoma has an high response rate to salvage treatment after failure to local treatment (surgery and radiotherapy). Thus considered, chemotherapy alone is an effective and safe therapeutic approach in this setting of patients. Surgery or radiotherapy will be reserved to patients that are not candidates for chemotherapy.