Keywords
acute kidney injury - blast phase - chronic myeloid leukemia - chronic phase - extramedullary
blast crisis - tyrosine kinase inhibitors
Introduction
Chronic myeloid leukemia (CML) is a hematologic malignancy driven by the BCR-ABL1 fusion gene, which results in the abnormal proliferation of myeloid cells. The disease
typically has two phases: chronic (CP) and blast crisis (BC), with most patients initially
presenting in the CP, characterized by a relatively stable clinical course. However,
progression to BC can occur, characterized by ≥20% blasts in peripheral blood or bone
marrow.[1]
Extramedullary blast crisis (EBC) in CML refers to the presence of blast cells in
extramedullary sites, irrespective of the blast proliferation occurring in the bone
marrow. Extramedullary involvement, particularly in the kidneys, is a rare and under-recognized
phenomenon.[2]
[3] This case report highlights a unique presentation of CML in BC, with renal involvement,
despite the bone marrow remaining in the CP. Such a clinical scenario is uncommon
and challenges our understanding of the systemic effects of CML. This case emphasizes
the importance of considering renal dysfunction in patients with CML due to leukemic
infiltration, even in the CP or during BC, and the complexities involved in managing
such atypical presentations.
Case Report
-
A 51-year-old man, with no prior comorbid conditions, presented with a 1-month history
of decreased urine output, abdominal discomfort, and bilateral lower limb swelling
up to the knee. His medical and family history were unremarkable. On examination,
he exhibited pallor, pedal edema, and splenomegaly.
A complete hemogram revealed significant abnormalities: hemoglobin of 8.2 g/dL, total
leukocyte count of 243,000/µL with a left shift, and a platelet count of 800,000/µL.
Severe renal impairment was noted, with urea of 175 mg/dL and serum creatinine of
11.5 mg/dL. Lactate dehydrogenase was elevated at 350 U/L, but other parameters (uric
acid, potassium, phosphate, and calcium) were normal. Due to fluid overload, the patient
required hemodialysis after a nephrology consultation. Bone marrow aspiration and
biopsy showed overwhelming leukocytosis with a myeloid left shift and 4% blasts, consistent
with CML in CP ([Fig. 1]). Reverse transcription polymerase chain reaction for BCR-ABL1 confirmed the presence of the p210 transcript, and no tyrosine kinase domain mutations
were detected. An ultrasound of the abdomen revealed enlarged kidneys with grade 2
renal parenchymal changes. Given the rarity of renal failure in CP CML, a renal biopsy
has been performed under the nephrology team to exclude other coexisting etiologies
contributing to the renal dysfunction. The kidney biopsy showed interstitial infiltration
composed of myeloid precursors, eosinophils, and large atypical cells, staining positive
for myeloperoxidase and Cluster of Differentiation 34 on immunohistochemistry. This
was suggestive of direct infiltration of renal parenchyma by the blast cells. Patient
is diagnosed with myeloid BC ([Figs. 2]
[3]
[4]).
Fig. 1 Bone marrow aspirate showing overwhelming leucocytosis with myeloid left shift.
Fig. 2 Renal interstitium showing dense infiltrate composed of myeloid precursors, eosinophils,
and large atypical cells.
Fig. 3 Immunohistochemistry with MPO highlights myeloid precursors. MPO, myeloperoxidase.
Fig. 4 CD34 staining highlights the large atypical cells. CD34, Cluster of Differentiation
34.
The patient was started on tablet dasatinib 140 mg daily, with no chemotherapy. Within
3 weeks, the white blood cell count significantly declined, and renal function improved,
allowing discontinuation of dialysis. Serum creatinine reduced to 0.3 mg/dL, and the
renal parenchyma showed a normal echotexture on the repeat ultrasonogram, suggesting
renal recovery. At 3 weeks, the patient achieved complete hematological remission.
At 3 months, the BCR-ABL1 transcript percentage (International Scale) was 15.8%, and he continues on dasatinib
therapy with regular monitoring.
Discussion
BC in CML can either be medullary or extramedullary. The lineage of the blasts can
be myeloid, lymphoid, or mixed.[2] Isolated EBC with the bone marrow in CP is uncommon. Extramedullary disease can
occur either as a part of a frank BC or as a predecessor of an impending BC. EBC is,
after a few months, almost always followed by hematological BC, so it is considered
to be an early sign of BC in the bone marrow.[3]
EBC in CML most frequently involves the lymph nodes, bones, skin, and central nervous
system (CNS).[4] Two large series on EBC were reported by Inverardi et al and Specchia et al. Inverardi
et al identified the bone (57%) as the most commonly involved site, followed by lymph
nodes (29%), whereas Specchia et al found lymph node involvement in 86% of cases,
making it the predominant site in their cohort.[3]
[5] These sites often present with palpable masses, neurological symptoms, or localized
pain, which make diagnosis relatively straightforward. Literature on the involvement
of sites other than these is lacking. Renal EBC is exceedingly rare and presents atypically,
often mimicking primary renal disease rather than an extramedullary leukemic manifestation.[6] Consequently, diagnosis may only occur after significant organ damage, as in our
patient who presented with severe renal dysfunction requiring dialysis. Renal biopsy
was critical for diagnosis and should be considered in similar cases where unexplained
renal failure occurs in CML patients.[6]
Unlike lymph nodes and CNS, which serve as common extramedullary niches for leukemic
infiltration, the kidneys have limited lymphoid tissue and a unique microvascular
environment, which may explain their infrequent involvement.[7] When renal EBC occurs, it can lead to acute kidney injury (AKI), requiring urgent
dialysis, as seen in our case, whereas other sites typically do not cause acute organ
failure.[2]
Another key distinction is treatment response. While CNS or lymph node involvement
often necessitates intrathecal chemotherapy or radiation, renal EBC in our patient
responded rapidly to systemic tyrosine kinase inhibitor (TKI) therapy, suggesting
a potential reversibility of leukemic infiltration in the kidneys.[8]
[9]
[10]
[11]
[12]
[13] Given the rarity of renal EBC, clinicians should maintain a high index of suspicion
in CML patients with unexplained renal dysfunction, as timely diagnosis and treatment
can lead to significant renal recovery.
Few reports have described renal involvement in EBC. A case of AKI due to isolated
renal BC while on treatment with imatinib has been reported by Yuzawa et al. Bone
marrow examination revealed a Philadelphia chromosome, but there was no evidence of
blasts.[6] In contrast, our patient presented with biopsy-confirmed renal EBC at initial diagnosis,
responding rapidly to dasatinib monotherapy.
Gao et al have reported lymph nodal involvement with myeloid and T-cell lineage blasts,
with marrow in CP of CML. The patient had been treated with chemotherapy and TKI therapy,
and the patient had a myeloid blast-positive CNS relapse post 5 months of treatment.[14]
Treatment of BC CML typically involves a TKI combined with lineage-specific chemotherapy,
aiming to induce remission and return to CP. Imatinib, dasatinib, nilotinib, and ponatinib
have received approval from both the Food and Drug Administration and EMA for use
in all phases of CML, including BC. Cytopenias may need TKI dose reduction or treatment
interruption, along with the support of blood products and growth factors.[8]
The preferred treatment approach for myeloid BC typically involves the administration
of a TKI, either alone or in combination with chemotherapy, followed by allogeneic
hematopoietic stem cell transplantation. Research suggests that when managing de novo
myeloid BC, initiating treatment with a TKI and subsequently evaluating the patient's
response is advised. In cases where myeloid BC arises during ongoing TKI therapy,
the recommended approach is to administer acute myeloid leukemia (AML)-type induction
chemotherapy alongside a more potent TKI for improved outcomes.[7]
[8]
Patients who present with or progress to the blast phase (BP) of CML generally have
poor long-term outcomes, even with current TKIs.[15] Achieving initial disease control should be followed by prompt consideration of
allogeneic stem cell transplantation (allo-SCT), as this remains the most effective
curative option. Evidence suggests that patients who achieve a second chronic phase
(CP2) prior to transplantation experience significantly better outcomes.[16]
[17]
Combining a TKI with acute leukemia-directed chemotherapy—whether AML-based or acute
lymphoblastic leukemia–based regimens—has been shown to enhance the likelihood of
attaining CP2. The selection of a TKI should take into account prior treatment history
and BCR-ABL1 kinase domain mutation status. Once CP2 is achieved, transplantation should be pursued
without delay, as progression-free survival in BP remains limited, and timely transplant
plays a pivotal role in prognosis.[18] Importantly, proceeding to allo-SCT during the overt BP is generally discouraged
due to inferior outcomes. Consolidation chemotherapy and TKI maintenance are recommended
for patients who are not candidates for allogenic hematopoietic cell transplantation.
TKI + steroids is appropriate for patients with lymphoid BC, and TKI alone is an option
for those with myeloid BC, in these patients.[16]
[19]
To the best of our knowledge, this is the first case of EBC involving the kidneys
with marrow in CP. The diagnosis was confirmed via histopathology, and the patient
showed significant clinical and biochemical recovery with dasatinib alone. However,
the report is limited by the lack of cytogenetics of the blast cells and a short follow-up
period. Given the rarity of renal EBC, this report contributes valuable insight, but
larger studies are needed to determine its pathogenesis, prognostic implications,
and optimal management strategies. Future studies should also explore why certain
tissues serve as EBC sites and whether specific blast lineages influence tissue tropism.
Conclusion
Our case highlights the need for vigilance in CML patients presenting with unexplained
renal dysfunction. Unlike typical EBC in CML, which frequently involves lymph nodes,
bones, and CNS, renal EBC is a rare but clinically significant entity that may not
be accompanied by medullary BC. Given its potential to cause AKI, prompt biopsy and
early TKI initiation can lead to substantial renal recovery. Clinicians should consider
renal EBC in patients with CML and unexplained renal impairment, even when bone marrow
findings suggest a CP.
