Maria-Jesus Nambo

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.

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

Abstract 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.

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

Micro‐Abstract To assess whether prolonged use of zoledronic acid (ZA; 4 years) improves outcome in multiple myeloma patients, we performed a clinical trial to compare the effect of 48 and 24 months of treatment. A total of 170 patients were randomly assigned to the 2 groups in the trial. Overall survival was not improved, however, the ZA group showed a reduced number of skeletal events. Thus, we suggest that ZA should be considered to be used for longer duration, in an attempt to improve patient quality of life. 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.

Overexpression of hypoxia-inducible factor 1 alpha impacts FoxP3 levels in mycosis fungoides--cutaneous T-cell lymphoma: clinical implications.

Mycosis fungoides (MF) is the most common variant of primary cutaneous T‐cell lymphoma, and decreased forkhead box P3 (FoxP3) expression has been reported in MF late stages. Hypoxia‐inducible factor 1 alpha (HIF‐1α) may regulate FoxP3 expression; however, it is unknown whether HIF‐1α is expressed in the CD4+ T cells of MF patients and how it could affect the expression of FoxP3. Therefore, we evaluated the expression of HIF‐1α and FoxP3 in CD4+ T cells obtained from the skin lesions of MF patients. We found increased cell proliferation and an increase in CD4+ T cells with an aberrant phenotype among early stage MF patients. HIF‐1α was overexpressed in these CD4+ T cells. In addition, we found a decrease in the percentage of FoxP3+ cells both in the skin of MF patients, when compared with control skin samples, and with disease progression. In addition, a negative correlation was established between HIF‐1α and FoxP3 expression. Skin HIF‐1α expression in MF patients correlated with the extent of the affected area and increased with the disease progression. Finally, we showed that ex vivo inhibition of HIF‐1α degradation increases the percentage of FoxP3+ T cells in skin lesions. Our results suggest that overexpression of HIF‐1α affects the levels of FoxP3 in MF patients, which could have relevant implications in terms of disease outcome.

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”.

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.

Risk of a second neoplasm on long-term survivors of Hodgkin's lymphoma

Although advances in Hodgkins lymphoma treatment have led to improvements in overall survival (OS), this has been accompanied by an increased risk of second neoplasm (SN) development. We analyzed the incidence and outcome of SN development in patients treated at a single cancer center.

Lymphoma and pregnancy

To the Editor: We read with interest the paper of Miyamoto et al. (1) about the use of anticancer drugs during pregnancy. We would like to comment a different point of view. The authors cited two papers of our group [Refs. (38,39)] and mentioned that we report that with the use of chemotherapy, an increase rate of congenital skeletal malformations was observed when cyclophosphamide was administered during the first trimester. However, in these reports [and in subsequent reports (2–4)], we reported the current status of 84 children that were treated with different schedules, which included cyclophosphamide in combination with another drugs, and we did not observe any congenital malformation. Moreover, we performed an analysis of 58 mothers (14 acute leukemia, 25 non-Hodgkin’s lymphoma and 19 Hodgkin’s lymphoma) treated with different combinations, which include alkylant, antibiotic and antimetabolite agents, during the first trimester of pregnancy, and no congenital abnormalities were observed (5). Actually, we treated 126 cases of hematological malignancies during pregnancy, and, until now, no congenital abnormalities have been observed, with a median follow-up of 19.8 years (range 2.0–38.0). The authors mentioned that some cardiac toxicities have been reported when anthracyclines were employed during pregnancy, but the mentioned abnormalities were observed only in echocardiogram studies, without clinical manifestation. We performed the first cardiac evaluation in children who received anthracyclines during pregnancy: 81 children (29 acute leukemia, 19 Hodgkin’s lymphoma and 33 malignant lymphoma), and echocardiograms were performed every 3 or 5 years from a range of 9.3 to 29.5 years, and all echocardiograms were normal, and no clinical evidence of cardiac toxicity was observed (6). Taking into consideration that modern echocardiogram techniques have improved the possibility to detect early cardiac damage, we performed a study in 90 children and young adult with the speckled tracking echocardiogram technique, and again, all studies were normal. Thus, until now, no radiologic studies or clinical evidence of cardiac damage secondary to the use of anthracyclines has been observed (7). Finally, the authors mentioned that rituximab appears to be safe when administered during pregnancy, including the first trimester, but we differ in this observation. Between 2001 and 2012, we diagnosed nine cases of diffuse large B-cell lymphoma who were treated with the R-CHOP (cyclophosphamide, doxorubicin, vincristine, prednisone and rituximab) at a standard dose, and observed that six children (66%) developed, between 6 and 9 months after birth, severe infections that required unit care unit to resolve these clinical situations. It is evident that more studies are necessary to define whether long follow-up will be performed in children that received rituximab during pregnancy (8). We agree that the treatment of mother with cancer and pregnancy is a dilemma, because ethical, familial, legal and religious facts will be considered. But, the recent literature confirms that treatment during second and third trimesters is useful to mother and is minimally toxic to the fetus. Also, treatment during first trimester remains to be a dilemma, but, in hematological malignancies of which some are very aggressive such as acute leukemia and diffuse large B-cell lymphoma, the prognosis is very poor, with an 80% of possibilities to be lethal, if early treatment is not employed. Taking into consideration of our experience, we have 124 children and younger adults alive and 96 mothers alive with free disease. In the setting of patients, delay of treatment or diminish the doses of cytotoxic drugs, the possibility of death could be very higher. However, it is the experience of a single center, thus we considered that it is necessary to perform a multicenter collaborative study to clarify the better moment to began chemotherapy, and also, what is the best chemotherapy regimen in each patient. Sincerely yours Agustin Avilès, Marìa Jesus Nambo, Natividad Neri