Can Allo-HSCT Improve the Poor Clinical Outcome of the “Internal Tandem Duplication” of the FLT3 Gene?
Authors: Bernasconi Paolo , Klersy Catherine , Colombo Anna Amelia , Caldera Daniela , Ripamonti Francesco , Zappasodi Patrizia , Rocca Barbara , Calvello Celeste , Della Porta Matteo Giovanni , Rossi Marianna , Santantonio Manuela , Dambruoso Irene , Zappatore Rita , Farina Mirko , Troletti Daniela , Boni Marina , Castagnola Carlo , Alessandrino Emilio Paolo 
Published: October 2019

Abstract
AML patients (pts) with a normal chromosome pattern and the “Internal Tandem Duplication” (ITD) of the FLT3 gene have an overall and event-free survival (OS, EFS) inferior than those of pts with a FLT3 “wild-type” gene because of a higher relapse risk, are placed in the intermediate-1 prognostic category, and when in complete remission (CR) are candidates to allogeneic hematopoietic stem cell transplantation (allo-HSCT). However, the role of allo-HSCT in ITD+ pts is still debated and a recent retrospective analysis has stated that FLT3/ITD adversely affected allo-HSCT outcome in the same direction as it does after chemotherapy.
Thus, the present study was aimed to compare the OS, EFS and relapse risk of pts submitted to allo-HSCT in first CR or in initial relapse, defined by a 5-10% bone marrow blast cell percentage, with those of pts submitted to chemotherapy alone.
The study cohort consisted of 54 chromosomally normal, ITD+ consecutive non-M3 AML pts who were included in 168 AML pts aged 18-66 years who came to our observation in the period January 2007-December 2013. At diagnosis median age was 48.6 years (range 18-66), 25 pts were males and 29 females. Median follow-up was 16.2 months (0.4-68.8): median follow-up for responsive pts was 7.15 months (range 0.26-27.6), for relapsed pts was 18.1 (range 1.9-68.8) and for transplanted pts was 9.1 months (range 2.9-26.8). All pts received the same induction treatment that consisted of standard Idarubicine+Ara-c “3+7” followed by two consolidation courses with high-dose Ara-c. Those who failed induction received other treatment schedules among which Fludarabine+Ara-c+Idarubicine was the most common. At the end of consolidation 38 pts were in first CR, achieved after 3+7 in 27 pts and after a second different course in 11. Sixteen pts had a resistant disease. After a median time of five months (range 1-21) 21/38 pts (55.2%) relapsed. All received a re-induction and 8/21 (38.1%) attained a second CR. Allo-HSCT was performed in a total of 23 pts: 12 first CRs, 6 second CRs and 5 initial relapses. The donor was a sibling in 7 pts, an unrelated donor in 13 and an haplo-identical donor in 3; the HSC source was the marrow in 6 pts, the peripheral blood in 16 and the cord blood (CB) in one. The Conditioning regimen was myeloblative (mainly Busulfan+Fludarabine) in 21 and non-myeloblative in 2; GvHD prophylaxis consisted of Cyclosporine A, steroids and methotrexate “short course”. The median number of CD34+ cells infused was 5.14x106/kg (1.3-12.7). All pts except that who received CB engrafted after a median time of 15 days (12-28); 21 were complete chimeras, two partial chimeras. Thirteen pts developed acute GvHD (grade I in 3 pts, grade II in 5, grade III in 2 and grade IV in 3) which totally/partially recovered after high dose steroids along with different immunosuppressive drugs in 4 and 9 pts respectively. Eleven pts developed a chronic GvHD which was the evolution of an aGvHD in 9, targeted different organs, was stable in 3 pts and completely/partially recovered in 4 and 2 pts respectively. Post-transplant relapse occurred in 3/12 first CRs, in none second CRs and in 3/5 initial relapse. The estimated response rate for CR pts submitted to allo-HSCT was 422.1 (95% CI: 262.4-679.1) versus 64.6 (95% CI: 40.7-102.6) for those submitted to chemotherapy alone with a median survival time of 7.2 months (range 5.3-8.8) versus not reached (1.9-not available); on univariable Cox model the HR of allo-HSCT pts was 37.9 (95% CI: 9.4-152.0) with p=0.0000. The estimated relapse rate for CR pts submitted to allo-HSCT was 8.6 (95% CI: 2.1-34.4) versus 44.3 (95% CI: 25.7-76.3) for those submitted to chemotherapy alone with a median survival time not reached (range not available) versus 13.2 (7.2-not available); on univariable Cox model the HR of allo-HSCT pts was 0.5 (95% CI: 0.2-1.1) with p=0.06. The estimated death rate for CR pts submitted to allo-HSCT was 28.7 (95% CI: 13.7-60.4) versus 49.7 (95% CI: 32.1-77.1) for those submitted to chemotherapy alone with a median survival time of 18.3 months (range 14.2-not available) versus 12.2 (8.8-18.9); on univariable Cox model the HR for allo-HSCT pts was 0.48 (95% CI: 0.2-1.1) with p=0.09.
In conclusion, our series suggests that in ITD+ pts allo-HSCT significantly strengthens CR in pts who had already responded to conventional chemotherapy, but it presents only a trend towards significance when its superiority to prevent relapse was considered.

Disclosures
Castagnola: Gilead Sciences: Research Funding.