In July 2019, a 46-years-old woman was admitted to our Haematological Unit for an hyperleucocytic AML (WBC 35,000/microL). The immunophenotype analysis on bone marrow aspirate showed > 80% blasts cells positive for CD117, CD13, CD33, CD34, CD38 and aberrant CD7. At the diagnosis, a normal 46 XX karyotype and FLT3-ITD and NPM1B mutations were present. The disease was completely resistant to the induction chemotherapy with the 3 + 7 (daunorubicin 60 mg/m2 days 1,2,3, cytosine arabinoside 100 mg/m2 days 1-7) plus midostaurin (50 mg every 12 hours at days 8-21) regimen. For this reason, at the end of August 2019 a reinduction therapy with the FLA-IDA regimen (fludarabine 50 mg/m2 at days 1-5 + cytosine arabinoside 2000 mg/m2 at days 1-5 + idarubicin 10 mg/m2 at days 3,4,5) was started, with a partial remission due to persistence of 7% blasts on bone marrow.
On September 2019, the patient received a FLA3 chemotherapy (fludarabine 50 mg/m2 at days 1-3 plus cytosine arabinoside 2000 mg/m2 at days 1-3) as a bridge for bone marrow transplantation during the iatrogenic aplastic phase. After the TBF (thiotepa, busulfan, fludarabine) conditioning and a graft versus host disease (GVHD) prophylaxis with post-transplant cyclophosphamide, an haploidentical bone marrow transplantation was performed on October 28th, 2019 (donor: brother).
The re-evaluation of disease at 30, 60, 90 days after the transplant showed the achievement and the maintenance of a haematological complete remission, a FLT3-ITD and NPM1B negativity, and a complete chimerism with 100% donor cells. In February 2020, during the cyclosporine reduction phase, a chronic mild gastric GVHD was successfully treated with beclomethasone dipropionate. Unfortunately, 6 months after transplantation the patient developed a disease relapse: for this reason, a third induction line therapy with MEC (mitoxantrone 6 mg/m2 at days 1-6 plus etoposide 80 mg/m2 at days 1-6 and cytosine arabinoside 1000 mg/m2 at days 1-6) regimen was administered starting from May 2020, showing a complete resistance. Moreover, a very severe septic shock caused by resistant to carbapenems (KPC positive) E. coli and K. Pneumoniae strains complicated the chemotherapy.
From June 18th 2020, the patient started gilteritinib 40 mg three times daily, which was stopped on July 30th 2020 due to a CVC-related infection with second septic shock caused by extended spectrum beta lactamase (ESBL) positive K. Pneumoniae. After the resolution of the severe infection, the treatment with gilteritinib was re-started at the dose of 40 mg two times daily due to the persistent grade III neutropenia. During the gilteritinib therapy with a reduced dose, the patient experienced a progressive clinical improvement and was transfusion-free; the neutrophils count progressive recovered according to the progressive reduction blasts count, as well as quantitative PCR for FLT3-ITD and NPM1B mutation on bone marrow with consensual near complete chimerism recovery (Figure 1). After 3.5 months of gilteritinib therapy (October 2020), the patient was in good clinical condition, neutropenia was solved (neutrophils 3700/microL) and noteworthy she achieved the second haematological complete remission with minimal molecular disease positivity for FLT3-ITD e NPM1B mutation and a near complete chimerism (Figure 2). At that time, the patient was considered eligible by another centre for the enrolment in a Phase 1/2 clinical trial on allogeneic CIK (Cytokine induced Killer) cells from haploidentical donor with a reduced risk of induction of GVHD and increased antileukemia activity following the in vitro expansion process. This experimental therapy was administered from December 2nd 2020 to January 13th 2021: the patient is actually GVHD free and waiting for a re-evaluation of the leukemic disease.