Note: This review is based upon two presentations at the 2012 American Society of Hematology (ASH) Annual Meeting, December 7-10 in Atlanta, Georgia. The full abstracts may be viewed on the ASH Annual Meeting Web site. Search by entering the title in the search box. The abstract number is referenced to access the full report.
Mutations in genes that are key to the telomerase complex can lead to a variety of disorders, including bone marrow failure and liver and lung fibrosis. The lab led by Neal Young at the NHLBI presented two studies at the 2012 American Society of Hematology Meeting in Atlanta delineating the heterogeneity of bone marrow failure syndromes associated with telomere abnormalities and the role of telomere abnormalities in aplastic anemia.
Hyoung Jin Kang, Ji Won Lee, Hyery Kim, Kyung Duk Park, Hee Young Shin, Hyun Joo Jung, Jun Eun Park, Jae Wook Lee, Nak Gyun Chung, Bin Cho, Hack Ki Kim, Jae Hee Lee, Yeon Jung Lim, Sun Young Kim, Eun Sun Yoo, Kyung Ha Ryu, Young Ho Lee, Jeong A Park, Young Tak Lim, Soo Hyun Lee, Keon Hee Yoo, Ki Woong Sung, Hong Hoe Koo, Kyung Nam Koh, Ho Joon Im, Jong Jin Seo, Sang Kyu Park and Hyo Seop Ahn
In this ASH oral abstract presentation, the investigators sought to shed light on the unanswered question of what is the best conditioning regimen for patients with severe aplastic anemia who are being prepared for bone marrow transplantation with an unrelated donor. The treatment-related mortalities were compared between two different studies from this group of investigators. The hope was that by reducing the dose of cyclophosphamide, increasing the dose of fludarabine, and maintaining the same dose of thymoglobulin used in their first study; the benefits of good engraftment would be maintained with this three drug conditioning regimen and that the toxicities from this treatment would be reduced to an acceptable level.
The first study enrolled 28 patients who received cyclophosphamide (50mg/kg x 4 days), fludarabine (30mg/m2 for 4 days), and thymoglobulin (2.5mg/kg for 3 days). The second study enrolled 31 patients who received cyclophosphamide (60mg/kg x 2 days), fludarabine (40 mg/m2 for 5 days) and thymoglobulin (2.5mg/kg for 3 days).
For both studies, all patients had good engraftment and one patient in each study had delayed graft failure. The dose modifications in study 2 resulted in significantly less treatment related mortality (TRM). There were 9 patients with TRM in study 1 compared to 1 patient with TRM in study 2 (pneumonia). In addition to the toxicity improvement, study 2 also showed a higher overall survival and event free survival rates compared to study 1.
These results support the consideration of the dosing in study 2 with cyclophosphamide (60mg/kg once daily on days -8 and -7), fludarabine (40mg/m2 on days -6,-5,-4,-3,and -2), and thymoglobulin (2.5mg/kg daily on days -4,-3,and -2) as the optimal conditioning regimen for patients with severe aplastic anemia receiving a bone marrow transplant from an unrelated donor.