A Rare Case of AML with ZBTB16-RARA (PLZF-RARA) Fusion: Diagnostic Challenges and Morphologic Remission with CLIA + Venetoclax

Gamaliel Monge-Ruiz, MD, MPH¹, Gabriela Torres-Torres, MD², Patricia Dávila-Cardona, MD², Pedro Rivas-Vega, MD², Carolina Machado-De La Torre, MD¹, 

Brian Virella-Berio, MD¹, Alexis M. Cruz Chacón, MD²

¹Department of Internal Medicine, San Juan City Hospital, San Juan, PR ²Department of Hematology/Oncology, San Juan City Hospital, San Juan, PR

 

BACKGROUND 

Classic APL (PML::RARA) is highly curable with ATRA + ATO. ZBTB16-RARA (t(11;17)) is a rare variant (~1% of RARA-rearranged AML) with APL-like morphology but ATRA/ATO resistance due to PLZF repressive domains. Intensive chemotherapy yields CR rates of 55–88% with high relapse risk. Round non-lobulated nuclei, hypergranulation, scarce Auer rods, and crystalline inclusions can suggest the variant early (Dowse & Ireland, Blood 2017).

 

CASE PRESENTATION

31-year-old Hispanic man; no significant past medical history. Transferred November 20, 2025 from Hospital Auxilio Mutuo Bayamón after 3 weeks of fatigue and 1 week of generalized body heaviness. Denied fever, night sweats, weight loss, and bleeding.

Admission laboratories: WBC 34.2–36.4 × 10³/µL with ~76% immature-like cells. Hemoglobin 7.5–7.7 g/dL after 2 PRBC. Platelets 10–16 × 10³/µL. Mild coagulopathy (INR 1.3).

Peripheral-blood flow (November 24, 2025 — BM25-2084): 90.1% myeloblasts: CD13+, CD33+, CD117+, CD34 partial (~42%); aberrant CD56, CD2, CD15; CD38− and HLA-DR−.

Diagnostic marrow (December 1, 2025 — BM25-2114): 99% cellular, 75% blasts, reticulin fibrosis grade 1–2/3. Blasts with granular cytoplasm, some indented or bilobed nuclei, rare Auer rods. FISH: RARA rearrangement + (79%), trisomy 8 +, PML::RARA −. Karyotype: 45,X,−Y,t(11;17)(q23;q21)[13]/47,idem,+8[7]. NGS: ZBTB16-RARA fusion; WT1 LOF (VAF 45.4%); SMARCB1 LOF (VAF 44.4%). FLT3, NPM1, IDH1/2, and CEBPA not detected.

 

TREATMENT COURSE 

ZBTB16-RARA is ATRA/ATO-resistant. Plan: intensive CLIA (cladribine, idarubicin, cytarabine) plus venetoclax.

Supportive measures: hydroxyurea 1 g PO every 8 hours; allopurinol and 0.9% NS for TLS prophylaxis; transfuse for hemoglobin >7 g/dL and platelets >20K (raised to >60K before access); cryoprecipitate if fibrinogen <150 mg/dL. Venetoclax crushed after swallowing difficulty (written waiver). Central line December 10, 2025. Mediport December 18, 2025.

Induction — December 12, 2025: CLIA + venetoclax. Complicated by ANC <50 and a maculopapular rash (TMP-SMX switched to atovaquone). Multiple PRBC, platelet apheresis, and cryoprecipitate transfusions.

Re-induction — February 17–23, 2026: second CLIA + venetoclax cycle completed. Discharged stable: WBC 6.0, hemoglobin 11.7 g/dL, platelets 132K.

 

SERIAL MARROW RESPONSE 

Dec 1, 2025: cellularity 99%, blasts 75%. ZBTB16-RARA+, trisomy 8, fibrosis grade 1–2/3. 

Jan 14, 2026: cellularity 95%, blasts 6%. Partial response. Karyotype 46,XY[20]. Flow negative for high-grade disease. 

Mar 16, 2026: cellularity 40%, blasts 3% by IHC. Morphologic remission. NGS negative.

 

FIGURES 

Diagnostic karyotype showed 45,X,−Y,t(11;17)(q23;q21)[13]/47,idem,+8[7], with arrows marking the t(11;17) at 11q23 and 17q21 and the +8 clone. After CLIA plus venetoclax, the karyotype normalized to 46,XY[20], and the prior t(11;17) and trisomy 8 were no longer detected. Interphase FISH confirmed an extra D8Z1 signal consistent with trisomy 8, a RARA rearrangement in 79% of nuclei, and no PML::RARA fusion, excluding classic t(15;17) APL.

 

DISCUSSION

Molecular testing is required. APL-like cases need urgent FISH and NGS for the RARA partner. ZBTB16-RARA is intrinsically ATRA/ATO-resistant; misclassification delays effective intensive therapy.

Morphology can raise early suspicion. Round non-lobulated nuclei, dense granules, few or no Auer rods, and crystalline inclusions differ from classic APL and should trigger testing beyond PML::RARA (Dowse & Ireland, Blood 2017).

Venetoclax plus intensive chemotherapy is a rational option. Blasts fell 75% → 6% → 3%, with karyotype normalization and NGS clearance after CLIA + venetoclax induction and re-induction.

Supportive care enabled delivery of therapy. Transfusions, TLS and infection prophylaxis, delayed but successful access placement, and crushed venetoclax allowed full-intensity treatment.

 

CONCLUSIONS 

Confirm the RARA partner before choosing ATRA/ATO. CLIA + venetoclax achieved morphologic remission. Serial marrows showed 75% → 6% → 3% blasts. Venetoclax-based intensive therapy is a practical option while targeted agents are studied. Continue molecular follow-up; consider consolidation or transplant.

 

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Grimwade D, et al. Blood. 2000;96:1297-1308.

Dowse RT, Ireland RM. Blood. 2017;129(14):2038. Yin CC, et al. B

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