High-Risk FLT3+ AML With Liver and Gastrointestinal GVHD

High-Risk FLT3+ AML and Allogeneic HCT

A 39-year-old female with a history of high-risk AML with FLT3 mutation underwent treatment with 7+3 (cytarabine and idarubicin) plus midostaurin. Following induction, the patient was found to be in remission on day 28 marrow. She was given high-dose cytarabine consolidation with midostaurin consolidation while planning for potential allogeneic hematopoietic cell transplantation (alloHCT). The patient’s brother was found to be a haploidentical HLA match, so she underwent alloHCT using matched sibling donor and a busulfan/cyclophosphamide conditioning regimen. She was given post-transplantation cyclophosphamide (PTCy) on days +3 and +4, tacrolimus day +5 and beyond, and mycophenolate mofetil days +5 to 35 for GVHD prophylaxis.  

The post-transplant course was relatively uncomplicated aside from a maculopapular rash, which was biopsied (biopsy consistent with drug rash and less likely to be acute GVHD) and thought to be related to medications. This resolved with discontinuation of the offending agent (allopurinol, which was given for elevated uric acid). The patient’s counts recovered, and she was monitored closely. Peripheral blood was negative for FLT3, and FISH XY was 200/200 XY at day +30 and day +60.  

Unfortunately, upon day +100 workup, bone marrow biopsy came back low-level positive with​ FLT3 mutation, and FISH XY (chimerism in sex mismatched donor) was slightly mixed at 96 cells XY and 4 cells XX. Rapid tacrolimus taper was initiated over 2 weeks. Due to the patient’s high-risk AML, mixed chimerism, and positive FLT3 on bone marrow biopsy, donor lymphocyte infusion (DLI) was arranged for approximately day +133.  

GVHD Development

At approximately day +152 (19 days after DLI), the patient developed an erythematous maculopapular rash on the chest, back, palms, soles, and bilateral arms at 35% body surface area using the rule of nines, as well as jaundice, bloated abdomen, elevated liver function tests (LFTs), and elevated total bilirubin. These symptoms were accompanied by watery diarrhea approximately six times per day. The patient said she had pain and abdominal cramping following eating and watery diarrhea followed with some relief in pain.  

Workup during hospital admission as follows:  

Infectious workup was negative.  

Diarrhea was >1000 mL/day in volume measured by the nursing staff. Based on MAGIC criteria for grading and staging, the patient was diagnosed with stage 2 GVHD of the skin, stage 2 GVHD of the liver, and stage 2 GVHD of the lower GI tract based on stool volumes. Overall GVHD grade was III.¹

Esophagogastroduodenoscopy and colonoscopy were performed and revealed grade 2-3 GI GVHD. High-dose IV steroids were started: solumedrol at 1 mg/kg/day and budesonide at 3 mg three times per day. The patient was also given loperamide and diphenoxylate/atropine as needed for diarrhea. Ursodiol was also continued at 300 mg three times per day. The patient required morphine via a patient-controlled analgesia pump for abdominal pain. The skin rash and liver enzymes/total bilirubin improved. 

  At 1 week into high-dose steroid therapy, LFTs were improved: 

The patient continued experiencing diarrhea at approximately 1000 mL per day for over 7 days and was diagnosed with steroid-refractory GVHD. Second-line therapy with infliximab was started while a prescription for ruxolitinib was sent for insurance approval. The patient required octreotide for continued watery diarrhea. Due to poor oral intake, total parenteral nutrition support was initiated.  

One week later, the patient had continued 1000 mL stool output despite starting octreotide and dosing with infliximab. Ruxolitinib was initially denied by insurance but did get approval and was started at 5 mg twice per day at day +167.  

The patient developed cytomegalovirus (CMV) viremia at 886 copies at approximately day +165. She was started on ganciclovir due to being very immunocompromised.  

Repeat CMV PCR was 3430, and CMV PCR checking was increased to twice weekly. While continuing on  ruxolitinib, solumedrol was carefully tapered successfully, and diet was advanced as tolerated. 

During hospitalization, IV immunoglobulin was given for IgG of < 400. Ganciclovir was switched to valganciclovir at 900 mg twice daily and CMV viremia resolved. Valganciclovir was stopped after two negative values 1 week apart.  

The patient was discharged from the hospital and instructed to take oral prednisone 30 mg daily as well as ruxolitinib 5 mg twice daily and budesonide 3 mg three times per day. 

Eventually, she was successfully tapered off prednisone, and ruxolitinib without recurrence of liver or GI GVHD. She has since experienced occasional skin erythematous maculopapular changes that have required triamcinolone cream as needed. The patient remains in remission from AML and without significant chronic GVHD. 

Discussion

Liver involvement of GVHD is rarely without another organ system involvement. The gold standard to identify liver involvement of GVHD is liver biopsy, although this is not often practical or necessary in the setting of biopsy-proven GVHD in other organ systems. Elevated total bilirubin levels determine the staging of liver GVHD. AST and ALT are often elevated with liver GVHD, but due to a wide differential, these are not used as diagnostic or grading criteria. Patients with haploidentical donors have similar outcomes as patients with 10/10 HLA matches in the setting of PTCy.²DLI increases the risk of GVHD significantly but does so at the benefit of donor vs leukemia effect³

When starting high-dose steroids, it is important to confirm infectious disease workup is negative or being actively treated because infection risk increases significantly while on high-dose steroids. A delay in starting ruxolitinib can lengthen the duration of high-dose steroids for patients in this situation. In this case, the delay was due to insurance approval, which may not be avoidable. However, having ruxolitinib available on hospital formulary or in stock in the pharmacy may decrease the time frame to administration and decrease duration of maximum dose steroids. Sex mismatched transplants and mismatched/haploidentical donor status both have an increased risk of GVHD.^4,5

Another consideration with FLT3-positive low-level disease includes post-transplant maintenance with midostaurin prior to deciding to move to DLI. More recently, another option for prevention of acute GVHD—abatacept—has been used in mismatched unrelated donors and some transplant centers have used this option in haploidentical donors.⁶

References

1. Harris AC, Young R, Devine S, et al. International, multicenter standardization of acute graft-versus-host disease clinical data collection: A report from the Mount Sinai Acute GVHD International Consortium. Biol Blood Marrow Transplant. 2016;22:4-10. 
2.  Ambinder A, Jain T, Tsai HL, et al. HLA-matching with PTCy: A reanalysis of a CIBMTR dataset with propensity score matching and donor age. Blood Adv. 2022;6:4335-4346. 
3. Castagna L, Sarina B, Bramanti S, et al. Donor lymphocyte infusion after allogeneic stem cell transplantation. Transfus Apher Sci. 2016;54:345-355. 
4. Gahrton G. Risk assessment in haematopoietic stem cell transplantation: Impact of donor-recipient sex combination in allogeneic transplantation. Best Pract Res Clin Haematol. 2007;20:219-229. 
5. Baumeister SHC, Rambaldi B, Shapiro RM, et al. Key aspects of the immunobiology of haploidentical hematopoietic cell transplantation. Front Immunol. 2020;11:191.
6. Rimando J, McCurdy SR, Luznik How I prevent GVHD in high-risk patients: Posttransplant cyclophosphamide and beyond. Blood. 2023;141:49-59.