Addition of low dose total body irradiation to fludarabine melphalan reduced intensity conditioning is feasible, tolerable, and may improve outcomes in patients with high-risk acute myeloid leukaemia and other high risk myeloid malignancies
Authors: Grace Gifford, Kelly Wong, Ian Kerridge, William Stevenson, Chris Arthur, Keith Fay, Matthew Greenwood
Journal: American Journal of Hematology (2015)

Allogeneic haemopoietic stem cell transplantation (allo-HSCT) following induction and consolidation chemotherapy reduces relapse for all AML risk groups. Age over 60 years is an independent poor prognosticator on multivariate analyses. Reduced intensity conditioning (RIC) has permitted older and poorer performance status patients to receive allo-HSCT as a potentially curative treatment. RIC for AML in CR1 reduces treatment related mortality (TRM) by almost half compared to myeloablative conditioning. Furthermore, RIC results in similar disease free survival (DFS) and overall survival (OS) and significantly reduces nonrelapse mortality (NRM) for patients over the age of 40 years 1. While RIC produces durable engraftment and demonstrable graft versus malignancy effect 2, less intense regimens carry an increased risk of graft failure, and relapse 3. These data suggest further development of RIC conditioning protocols should focus on reduction of disease relapse without increasing TRM. In Australia, the most commonly used RIC regimen is fludarabine-melphalan (Flu-Mel) 4, 5. This is usually administered intravenously over 6 days: fludarabine 25 mg/m2 D-7 to D-3 and melphalan 140 mg/m2 D-2 6. This regimen has acceptable treatment related toxicities and yields stable engraftment 7. When oral fludarabine is used, it results in similar donor engraftment and chimerism to intravenous formulations 8, 9. Oral fludarabine has been used for over 10 years in our centre with the benefits of reduced hospitalization. As high-risk AML and myeloid malignancies have an increased risk of relapse, intensification of conditioning may offer a survival advantage 10. Our aim was to intensify conditioning to improve clinical outcomes in high-risk disease without additional toxicities or NRM. We considered addition of low dose total body irradiation (TBI) to be a feasible manipulation of Flu-Mel conditioning. First, engraftment is possible with low doses of TBI at 2 or 4 Gy with minimal toxicities 11-13. Second, low dose TBI is safe, tolerable, easy to administer, low in cost, and does not lengthen hospitalization. From January 2010 until time of writing, our institution adopted a risk-adapted approach that conditioned all MAC ineligible patients with high-risk AML or other myeloid malignancies with Flu-Mel-TBI. This consisted of oral fludarabine (40 mg/m2) days -6 to -2 inclusively, intravenous melphalan (140 mg/m2) day -2, and low dose TBI (200cGy day -1, or 400cGY fractionated on days -1 and 0). TBI dose was determined by physician preference. Patients self-administered oral fludarabine at home, and were admitted from D-2 for intravenous melphalan until discharge following engraftment and stabilization of medical issues. Supportive care was uniform for all patients. This included barrier nursing in single rooms with high efficiency particular air filters and protective isolation in a purpose-built ward. All patients received a low bacterial load diet. Antimicrobial prophylaxis included azole fungal prophylaxis, valaciclovir for herpes virus prophylaxis, and a pre-emptive approach to cytomegalovirus. Total parenteral nutrition (TPN) and conversion to intravenous medications was used for patients intolerant of oral intake. Graft versus host disease (GVHD) prophylaxis was uniform for all patients, consisting of cyclosporine (3 mg/kg intravenously daily, targeted to 100–200 µg/L with therapeutic drug monitoring), methotrexate (15 mg/m2 intravenously days +1, 3, 6, 11), and prednisolone, dosed as per Ruutu et al. 14. Twenty-four patients with AML or high-risk myeloid malignancies were referred for allo-HSCT in this period. Fourteen consecutive patients with high-risk disease ineligible for conventional-intensity allo-HSCT but suitable for RIC were conditioned with Flu-Mel-TBI; 13 had AML and 1 had myelofibrosis. All patients received 400cGy TBI apart from 1 patient transplanted for myelofibrosis who received 200cGy. Patients were judged to have high-risk AML if they had primary induction failure, unfavorable cytogenetics or molecular features, secondary AML, and relapsed disease. Of 13 AML patients, 7 patients had 1, and 6 patients had 2 risk factors. The patient with myelofibrosis had an IPSS (international prognostic scoring system) of 4. Median age was 60.5 years (range 27–69). If age > 60 was included as an independent risk factor, then 3 patients had 1, 8 patients had 2, and 3 patients had 3 risk factors. Patients and transplant characteristics are summarized in Table 1. Median follow-up was 12.7 months (range 0.8–106.2 months). PBSC graft contained a median of 5 (range 3.38–8.42) × 106 CD34+ cells per kg. Median duration of hospitalization was 23.5 days (range 17–32 days), similar to AML patients conditioned with Flu-Mel during the same period in our institution (23.5 days, range 15–72). Median time to neutrophil and platelet engraftment for the remaining patients was 17 and 20 days, respectively. Mucositis grade II–IV occurred in 3 (21%), 2 (14%), and 2 (14%) patients, respectively. Severe sepsis requiring admission to the intensive care unit occurred in 3/14 (21%) patients; of these, 2/3 requiredaggressive fluid management and 1/3 required inotropic support. One patient died of Pseudomonas aeruginosa infection, while 1 with Staphylococcus haemolyticus and and 1 with Escheria coli infection were both successfully treated. Hepatic sinusoidal obstructive syndrome occurred in 2/14 (14%) patients and both recovered following treatment with defibrotide (10 mg/kg twice daily for 14 days or until resolution). Posterior reversible encephalopathy syndrome occurred in 1/14 (7%) patients secondary to cyclosporine. Acute kidney injury requiring short-term dialysis occurred in 1/14 (7%) patients. Graft failure occurred in 1(7%) patients who died of sepsis in aplasia. Three (21%) patients received TPN following admission to the intensive care unit for severe sepsis. Donor chimerism was 100% for all patients who had chimerism studies performed (n = 12). Cytogenetic or molecular remission was achieved in all but one patient who died in aplasia. aGVHD occurred in 6 patients (43%), severity Glucksberg Stages I–IV in 2 (14%), 1 (7%), 1 (7%) and 2 (14%) patients, respectively. Chronic GVHD occurred in 6 patients (43%), 4 (29%) had mild and limited, 1 (7%) had moderate and limited, and 1 (7%) had severe and extensive disease. Engraftment, nonhaematopoietic toxicities, GVHD, and clinical outcomes are summarized in Table 4. NRM at D100 was 7%. One patient died at D25 due to infection prior to engraftment. One year NRM was 28%; two patients died of infection (D25, D244) and two died of acute GVHD (D111 and D178). Relapse occurred in 14% (2/14) at a median of 4.5 months (range 3 to 6 months) from allo-HSCT, both died of relapsed disease. Estimated 1 year DFS and OS was 57, and 50% at 3 years. In this series of older, high-risk patients with uniformly poor prognosis myeloid malignancies, the combination of Flu-Mel and low dose TBI appears to be tolerable with an acceptably low early relapse rate. Our results compare favourably with similar intensified RIC regimens including FLAMSA-RIC 15 and TBI added to Flu-ivBu-ATG12. The FLAMSA-RIC protocol described by Schmid et al. used fludarabine-Ara-C-amsacrin followed by 400cGy TBI-cyclophosphamide-antithymocyte globulin (ATG) RIC and prophylactic donor lymphocyte infusions. For a group of high-risk AML patients (n = 75, median age 52 years), OS and DFS was 42% and 40% at 2 years, 23% died of refractory or relapsed leukaemia, and NRM was 20% at D100 and 33% at 1 year. Reported toxicities in this study included 28% grade I/II mucositis, and 26 episodes grade III/IV regimen related toxicity including 5 deaths in aplasia. 37/75 patients experienced a septic episode which included 31 patients with radiologically documented pneumonia. . Russell et al reported that the addition of 400cGy TBI to Fludarabine and IV Busulfan (n = 22), together with ATG reduced relapse rates from 79% to 33% when compared to Flu-ivBU alone (n = 34) in a retrospective analysis. In that study, the exact DFS, OS and NRM cannot be determined due to inclusion of low-risk patients in survival analyses. However, the authors reported no difference in NRM across risk groups when TBI was included in the conditioning. In comparison to the two studies summarized above, our combination of low dose TBI with oral Fludarabine and IV Melphalan resulted in a low early relapse rate, enables reliable engraftment, and was straightforward to administer. Despite small numbers and short median follow-up, Flu-Mel-TBI appears to be a tolerable RIC regimen with intensive antileukemia effect and acceptable NRM in MAC ineligible patients with high risk AML/myeloid neoplasms. Further prospective studies are warranted. Grace Gifford wrote the article, with all authors critically revised the drafts, and Matthew Greenwood approved the final version. Chris Arthur and Matthew Greenwood designed the conditioning protocol. Kelly Wong analysed the data with all authors critically reviewing the results. Grace Gifford1, Kelly Wong1, Ian Kerridge1, William Stevenson1, Chris Arthur1, Keith Fay1,2, and Matthew Greenwood1 1Haematology Department, Royal North Shore Hospital, Sydney, New South Wales, Australia 2Haematology Department, St Vincent's Hospital, Sydney, New South Wales, Australia