Considering the first treatment, I suggest to repeat a bone marrow analysis with, if possible, mutation screening. HMA+ven+pona required more than one cycle to achieve CR. If patient did not obtain a clear response, then procede with chemo (Flag-Ida) and HSCT soon after.

So long as this person gets a second chronic phase with chemo plus PON, then go to allograft and consider post-allo maintenance with PON once GVHD prophylaxis is off, which should be as early as possible, my preference by 60-70 days. If GVH occurs delay PON until therapy is completed, again as soon as possible. Length of PON maintenance is controversial - anywhere from 2-3 years to indefinite. If CP2 is not obtained, then SCT has limited if any value - see ELN recommendations.

Clearly this is a challenging situation. It isn't clear how many cycles of ven-aza the patient has had so far and if there has been any reduction in the percentage of blasts. It may take more than one cycle of pon-ven-aza to achieve a response.

I would therefore repeat a bone marrow assessment to evaluate blast percentage and improvement from baseline. I would also assess a BCR::ABL1 kinase domain mutation screen. If there is no response to the pon-ven-aza, then I would consider a switch to FLAG-Ida, probably with ponatinib if the patient is sufficiently fit for this. I would also plan for alloSCT if the patient has a suitable donor as soon as second chronic phase is achieved.

Considering the age of the patient and the absence of relevant comorbidities, I suggest intensive chemotherapy (FLAG Ida + ponatinib; see doi.org/10.1016/S2352-3026(21)00370-7) followed by Allo-HSCT.

If possible, I would consider cytogenetic and molecular analysis (including NGS) on bone marrow samples, a PET and biopsy to confirm the leukemic infiltration of the skin.

Case from Pakistan

52 years old male, sales manager by profession, having no known co-morbid, presented in April 2024 with complaints of night sweats, easy fatigability and weight loss. Blood CP showed leukocytosis (WBC 55 x109/L). On examination, the spleen was palpable 05 cm BCM. A bone marrow exam from (15/04/24) was consistent with CML AP (10% blast cells). The PCR for BCR ABL 1 was (26.86 %) IS. Cytogenetics showed 46 XY t (9:22). He was started on Tab Nilotinib 800 mg daily. On subsequent follow up he was having Leucopenia and the TKI dose was lowered to 600 mg daily. TKI was later escalated to 600 mg alternating with 800 mg daily and then to 800 mg daily on count recovery. PCR for BCR ABL1 at 3 months was (9.87% IS). He was admitted to a tertiary care hospital on 12/11/2024 with fever and shortness of breath. On examination, there was decreased air entry on right chest base. He also had nodular violaceous lesions on forearms and torso, suggestive of leukemia cutis. HRCT Chest (13/11/24) showed moderate right-sided pleural effusion. ECHO (13/11/24) showed mild pericardial effusion. Repeat PCR for BCR ABL at 06 months (08/11/24) was 21.90% IS which showed treatment failure. His peripheral blood film showed 45% Myeloid Blasts. Immunophenotyping by Flow cytometry showed 50% of Myeloid blasts, positive for weak CD45 (-to+), CD34+, CD33++, CD 13++, CD117++, CD 38++, cMPO++. BME was consisted with CML transformed into AML.

Considering ongoing active infection and CML transformed into AML, he was started on Azacitadine and Venetoclax + Ponatinib. During the course of treatment, the patient developed prolonged neutropenia and neutropenic sepsis, which required management with broad spectrum antibiotics and supportive care as per the institutional protocols. Aza+Ven+ponatinib was withheld due to cytopenias. He was given 3 x doses of Buffy Coat along with GCSF support to manage sepsis and cytopenia, but the counts did not improve and the patient continued to spike fever. He was then administered HLA Matched Granulocytes and Pegfilgrastim, after which his counts recovered. His fever has subsided. The patient has been started on Ponatinib 15 mg OD, with plan to escalate the dose with monitoring for cytopemias. The peripheral blood film exam shows circulating blasts. BME has been done and the report is pending.

Clinically the patient is stable. Fever has spaced out and he is being given supportive care. He has an ECOG of 0. Chest examination has crepts at right base. CBC shows WBC 9.72, ANC 2.99, HB 10.9, PLT 27, CRP 69.8, Creatinine 65 and alt 29. 

What should be the further course of management? Should the patient be treated with intensive chemo + ponatinib VS AZA/VEN + ponatinib followed by MSD HSCT? Patient has an HLA Matched Donor.