Patient Background
A 61-year-old man with significant comorbidities including hypertension, type 2 diabetes mellitus, dyslipidemia, and a prior cerebrovascular accident was referred with newly diagnosed chronic phase chronic myeloid leukemia (CML) and prostate adenocarcinoma. He presented emergently prior to scheduled hematology review due to severe musculoskeletal pain and swelling.

Initial Presentation
The patient initially presented with acute swelling, pain, warmth, and erythema involving the left wrist and elbow, unresponsive to oral antibiotics. There was no preceding trauma, intravenous access, or prior exposure to tyrosine kinase inhibitors (TKIs). He was hemodynamically stable, with no organomegaly on examination.

Initial laboratory findings:

• - WBC: 74.6 × 10⁹/L
• - Peripheral blood smear: Consistent with chronic phase CML (blasts 1%)
• - Renal function: Urea 10.6 mmol/L, creatinine 145 µmol/L

Initial Management and Diagnostic Workup
The patient was admitted for cytoreduction and supportive care, including hydroxyurea, intravenous hydration, antibiotics, analgesia, allopurinol, and antimicrobial prophylaxis. A multidisciplinary approach involving hematology, medical oncology, rheumatology, nephrology, and cardiology was adopted.
Diagnostic evaluation confirmed:

• - Bone marrow biopsy: Hypercellular marrow, M:E ratio 20:1, MF-1 fibrosis
• - BCR::ABL1 (p210): Strongly positive (IS 94%)
• - Cytogenetics: t(9;22)
• - PSA: 25.9 ng/mL
• - Elevated inflammatory markers (ESR 120 mm/hr, CRP 116 mg/L)
• - Autoimmune and vasculitis screen: Negative
• - Doppler ultrasound of limbs: No evidence of arterial or venous thrombosis
• - PSMA PET-CT and MRI: Localized prostate malignancy with an indeterminate right femoral head marrow lesion; no definitive metastatic disease

Course During First Admission
Dasatinib was initiated for CML management. Two days later, the patient developed new-onset atrial fibrillation with rapid ventricular response, necessitating ICU admission. Cardiac evaluation was unremarkable, and the arrhythmia was considered TKI-related. Dasatinib was discontinued, and rate control and anticoagulation were instituted.During the same admission, the patient developed acute inflammatory arthritis involving the right knee and foot. Synovial fluid analysis was inflammatory but sterile. Rheumatology assessment concluded severe seronegative inflammatory arthritis, and high-dose intravenous methylprednisolone (500 mg daily for three days) resulted in significant clinical improvement, supporting an immune-mediated mechanism.Following hematology MDT discussion, asciminib was initiated. For prostate cancer, goserelin was administered, with plans for radiotherapy assessment after clinical stabilization. The patient was discharged in stable condition.

Second Admission
Six days following discharge, the patient re-presented with generalized limb swelling and pain.
Laboratory findings on readmission:

• - Hemoglobin: 7.9 g/dL
• - WBC: 7.6 × 10⁹/L
• - Platelets: 160 × 10⁹/L
• - Creatinine: 151 µmol/L
• - CRP: 123 mg/L

He developed rapidly progressive acute kidney injury with oliguria progressing to anuria, with creatinine peaking at 329 µmol/L. Asciminib was withheld due to concern for drug-induced or immune-mediated nephritis. High-dose intravenous methylprednisolone was reintroduced, and the patient required one session of hemodialysis.Renal function improved progressively with normalization of urine output. Complement levels (C3, C4) were normal. A renal biopsy was considered but deferred as renal function recovered.During this admission, the patient also developed bilateral pleural effusions, requiring drainage with pigtail catheters.

Subsequent Course and Further Investigations
Given recurrent inflammatory and edema-related manifestations, an extended complement panel was requested. This revealed C1 esterase inhibitor deficiency, a potentially life-threatening condition characterized by recurrent episodes of severe angioedema affecting face, limbs, abdomen and genitals, due to dysregulated activation of the complement and kallikrein–kinin pathways.This condition may be hereditary (HAE), inherited in an autosomal dominant manner, or acquired (AAE), which is often associated with lymphoproliferative or autoimmune disorders.Following MDT discussion and international expert input, asciminib was permanently discontinued, and bosutinib was selected as an alternative TKI. After clinical stabilization, bosutinib was initiated at 100 mg daily. Renal function remained stable initially; however, following dose escalation to 200 mg daily and the introduction of hydroxychloroquine, serum creatinine again increased. Both agents were discontinued, although a mild upward trend in creatinine persisted.Throughout the clinical course, hematologic parameters remained controlled, with no evidence of CML progression.

Current Status and Follow-up
The patient has been off TKI therapy for approximately 1.5 months. Renal function has returned to the normal range. However, he continues to experience intermittent localized swelling, predominantly affecting the right foot. According to rheumatology review, the overall clinical presentation did not align with features of C1 esterase inhibitor deficiency.”For Ca prostate management, patient has been on Goserelin x 3 monthly and has received local RT x 6 sessions (ongoing)He was recently admitted under the surgical team with progressive right foot pain and swelling. Ultrasound of the foot demonstrated subcutaneous edema and inflammatory changes, with no evidence of deep vein thrombosis.

Questions

1.     Is the acute kidney injury more likely attributable to tyrosine kinase inhibitor therapy, or could it be secondary to an underlying immune-mediated process?
2.     Would re-challenge with a tyrosine kinase inhibitor be advisable in this patient, and if so, which agent would be considered the most appropriate?
3.     Should allogeneic hematopoietic stem cell transplantation be considered in this patient, and at what stage of disease or clinical course? 

Thanks for sharing this complex case for further input by CML clinicians. I am a little reluctant to offer specific advice without seeing all of the clinical data and investigations. You have provided an incredibly detailed summary all the same so I will have a go - not to be taken as any more than speculation and an invitation for further discussion.

Despite all of the alarming clinical events including:

1. Atrial fibrillation
2. Acute seronegative Inflammatory Arthritis
3. Acute renal failure ?nephritis
4. Bilateral pleural effusions
5. C1 Esterase inhibitor deficiency

His underlying CP-CML is looking pretty stable and low risk. At diagnosis he had no splenogemaly and only 1% blasts so I suspect he has a low ELTS score. There were no additional cytogenetic abnormalities as well. Not sure if NGS was done. He has also maintained a normal WCC despite minimal therapy recently. So fortunately there is probably no rush to restart TKI. There is also no need to consider an early allograft unless he exhausts every possible TKI due to toxicity (possible but unlikely) or he progresses. I found that lesion in his femoral head a little concerning - may be worth re-imaging in a few weeks or even getting a biopsy. Extramedullay plastic disease can sometimes present like this. Leaving this one concern aside, things look pretty stable. In addition he would be a really bad risk patient for an allograft, so hopefully that stays off the table.

Since all of his other problems are likely to be unrelated to his CML but in some cases possibly related to his TKI therapy, I think there is a reasonable argument for staying off active CML therapy for a bit longer in the hope that his acute inflammatory problems (arthritis, nephritis) will settle with therapy and/or time. Once the situation is more stable (or you have waited 1-2 months without resolution) you could cautiously restart therapy. Given his (possible) toxicity related to dasatinib, asciminib and bosutinib I think my next step would be imatinib, perhaps starting at 200 mg/day given his previous very rapid events on the other TKIs.

I guess there is the possibility that his CML is contributing to all of these clinical problems which would be an argument for getting on with TKI therapy straight away, but I think that is unlikely.

Interested to hear other opinions on this case and to hear a follow up.

This is a very complex case made difficult by co-existing medical conditions. Three TKIs have caused renal dysfunction and in some cases pleural effusions and edema.

I would start by going over what probably is not an option. Stem allografting should not be on the table because of co-morbidities and especially the prostate cancer, the current status uncertain. Although not an immune dependent malignancy, these do sometimes explode given the meds used for an allograft. The fact that immune modulate events also seem to have occurred is another risk. Also the issues with edema(s) make transplant risky.

What about another TKI? Three have been tried and are no longer options. Historically, imatinib is felt to be safe but edema and renal dysfunction are common known side effects and I would not be comfortable using it. That leaves two drugs - nilotinib and ponatinib. Both potentially have cardiac risks and edema can be associated with all drugs. Atrial fibrillation has been associated with both. We do know that risks of side effects are better at lower doses. It is a bit of a toss of a coin here. Personally, for maximum efficacy at a low dose, I would try ponatinib at 15mg. If autoimmune side effects, edema, or cardiac dysfunction occur, then all TKIs are off the table. Interferon is not an option because of the autoimmune side effects as it is an immune stimulant.

If all else fails, then count control with hydroxyurea may be the best option, although the response time is limited. As well, if the prostate cancer is not well controlled, then I would go directly to hydroxyurea as the drug of choice. When long term control or cure is not possible, quality of life is most important.

Jeff