Severe aplastic anemia is a life-threatening disease. Since 1976, stem cell transplants (SCTs) have been established as the best curative option in patients who are younger than 40 years old, 1 particularly in children and adolescents for whom this is a firstline treatment. The overall survival rate, as described by authors from different countries, is about 90-95%. 2,3 The delay of a SCT, however, could result in higher morbimortality because of the continuous risk of infectious diseases, and transfusion-related
Background: fludarabine (F) is licensed for the management of indolent non Hodgkin’s lymphoma in countries such as Canada and Switzerland. Clinical evidence suggests that fludarabine monotherapy is as least as effective, than conventional therapies such as cyclophosphamide, vincristine, prednisone (CVP) for the first and second line treatment of B-cell low grade NHL achieving objective response rates. Better response rates can be achieved combining F with Mitoxantrone (M) in low grade NHL even in refractory relapsed (RR) patients (pts). The Latin American Cooperative Oncology Hematology Group (LACOHG) proposed a multicenter study in Latin American countries in 2002 to use FM in RR B-cell low grade NHL.
Aims: to assess the response rate, safety, disease free survival (DFS) and overall survival (OS) of FM in RR B-cell low grade NHL during (2003–2006).
Methods: Forty-eight patients in the period of January 2003 to February 2006 were evaluated. Forty-four pts. had follicular lymphoma and 4 small lymphocytic lymphoma. Median age 63.5 years old (range: 24–83). Gender: female 56% and male 44%. Inclusion criteria for low grade NHL-LG was: any previous treatment excluding autologous transplantation, Ann Arbor stage II to IV, age > 18 years old, ECOG performance status 0–2 and written informed consent. ECOG performance status 0: 2%, 1: 71% and 2: 27%. Ann Arbor staging: II: 2%, III: 29% and IV: 69%. International Prognostic Index (IPI): 0–1: 19%, 2–3: 71% and 4–5: 10%. Median previous treatment was 1 (range: 1–3). FM treatment consisted of F 25 mg/m2 i.v. (day 1–3) and M 10 mg/m m2 i.v. (day 1) each 28 days for 6–8 cycles.
Results: on this low grade NHL cohort the overall response rate (ORR was 81%; progressive disease and non-response 19%. With a median follow up of 17 months, OS at 24 months was 86% (DE 5.2%) and DFS at 24 months 57.1% (DE 11.3%). LDH in serum was not an adverse prognostic factor for DFS and OS.
Safety: on the 286 cycles in 48 pts, the toxicity was: 18 episodes of grade 3-4 neutropenias, 15 episodes of grade 3-4 thrombocytopenia, 7 episodes of grade 1–2 nausea/vomiting, grade 1–2 diarrhea in 4 pts, 8 pts were admitted to the clinic, 11 fever episodes, 2 allopecia, 4 pts developed grade 1–2 peripheral neuropathy and infections 7%: one case herpes zoster.
Mortality rate: 12,5% (6/48 patients), 5 of them because progressive disease. No cardiac toxicity was reported.
Conclusions: FM is an effective and safe treatment for RR low grade NHL. A longer follow up and a larger trial, might be needed to confirm these results in a multicenter, randomized study.
DFS with FM in RR low grade NHL : LACOHG DFS with FM in RR low grade NHL : LACOHG
INTRODUCTION: Acute Graft-versus-host disease (aGVHD) is a major complication of allogeneic stem cell transplantation (alloSCT). Risk factors include patient age, sex matching, CMV status and degree of match. Regulatory T cells are critical for immune tolerance processes such as aGVHD, and express the transcription factor FOXP3, a member of the forkhead/winged-helix family, identified as a key regulatory gene required for the development and activity of these cells. It has been suggested that genetic expression of FOXP3 is inversely correlated with the severity of the GVHD. We studied donor’s DNA looking for 5 polymorphisms on the promoter region of the FOXP3 gene, and we tried to correlate them with presence and degree of aGVHD.
PATIENTS AND METHODS: We studied donors of stem cells for allogeneic stem cell transplants. We looked for the presence of the following polymorphisms by PCR: POL01 −5906 T/A rs2869211; POL03 −3279 A/C rs3761548 ; POL04 −2383 C/T rs3761549 ; POL05 −1383 C/T rs2232364 ; POL06 −924 A/G rs2232365.
RESULTS: Our sample consisted of 31 donors, all siblings. In them we found only 2 of the 5 FOXP3 polymorphisms, either as homozygous or heterozygous. These polymorphisms were found in 15/31 donors, with 12 being homozygous (38.7%), and 3 heterozygous (9.7%). These genes polymorphisms were POL03 y POL06. The most observed polymorphism was POL-06 with 9 cases, while POL-03 was found in 6 donors. Only sex difference and CMV status had an elevated hazard ratio for developing GVHD (HR=1.18, CI95%: 0.18 to 7.64; p=0.85) and (HR=3.0, CI95%: 0.07 to 126; p=0.46) respectively. We found no statistically significant difference in the incidence of GVHD between patients who had received cells from donor with or without a FOXP3 polymorphism (p=0.87). When we analyzed the risk of presenting GVHD, results suggest that having one of the 2 positive polymorphisms of the FOXP3 gene could have a protective effect for the patient. For POL03 HR=0.87, CI95%:0.18 to 4.14; p=0.86, and for POL06, HR=1, CI95%: 0.37 to 2.64, p=0.67.
CONCLUSIONS: Even though our sample is still small to make conclusive remarks, we believe that our results point toward some level of “protection” from acute GVHD in patients receiving cells from donors expressing POL03 and POL06. It is also worthwhile mentioning the relatively high frequency of these polymorphisms, as well as the absence of the other 3.
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