Clinical Case Discussion Forum
To share and enhance best practice management of CML, experts and interested clinicians can discuss difficult or interesting CML cases here. Physicians submit a brief history of the patient and the case for discussion using this forum.
CML and severe aplastic marrow failure
Dear Colleagues,
I would appreciate your opinion regarding the following challenging case.
Male patient, a 36-year-old male, with a remote history of childhood bleeding episodes (no available documentation), was initially followed by an internist colleague and diagnosed 8 months ago with chronic-phase CML based on: - Splenomegaly., WBC count: 300 × 10⁹/L., Bone marrow aspirate: marked granulocytic hyperplasia without excess blasts. Cytogenetics: t(9;22). BCR::ABL1 transcript: 139% IS.
He was started on imatinib 400 mg/day. The initial response was favorable, with disappearance of splenomegaly and normalization of the white blood cell count. However, after approximately 5 months of treatment, he developed thrombocytopenia (52 × 10⁹/L), leading to temporary interruption of imatinib. At that time, the BCR::ABL1 transcript was still 48% IS, indicating failure to achieve an optimal molecular response. Platelets recovered to 132 × 10⁹/L after a 15-day interruption, and imatinib was resumed.
Subsequently, he developed severe thrombocytopenia (6 × 10⁹/L) and severe neutropenia (ANC 0.3 × 10⁹/L), persisting despite discontinuation of imatinib for one month and G-CSF support. At this stage, the patient was referred to my hematology office. Bone marrow aspirate showed a markedly hypocellular ("empty") marrow with only occasional erythroid precursors and lymphocytes. Bone marrow biopsy was consistent with severe aplastic marrow failure. Reassessment demonstrated: BCR::ABL1 transcript: 11% IS. Persistent Philadelphia chromosome t(9;22) on bone marrow cytogenetics. Therefore, the patient currently presents with persistent Ph-positive CML associated with severe aplastic marrow failure, possibly TKI-induced.
Current management: Eltrombopag 50 mg/day. G-CSF support. TKI discontinued.
Questions: How would you interpret this situation: TKI-induced aplastic anemia versus immune-mediated aplastic anemia in a patient with persistent CML clone?
Is there a role for ATG + cyclosporine, as reported in a few case reports?
In the absence of hematologic recovery, would you proceed directly to allogeneic stem cell transplantation? No matched sibling donor is available (only a half-brother and a half-sister). Would you favor a haploidentical or matched unrelated donor transplant in this setting?
If marrow recovery occurs, would you reintroduce a TKI, and if so, which agent would you prefer?
Thank you for your insights and experience with similar cases.
There are two problems. The first is that there is an inadequate response to IM, so that is an out. The second is there is either no recovery of normal hemopoiesis with therapy or there is TKI-induced aplasia. Not clear from the history which is the case here.
I would give a short try to a 2G drug with support as necessary. If aplasia persists, then regardless of the cause, then I think TKI therapy is off the table. Response with the 2G but aplasia suggests dormant normal hemopoiesis. No response suggests resistance and I do not think a hunt for mutation given that this is primary resistance will be productive. TKI toxicity might be drug specific, so a switch might correct this but not the disease response.
Immunosuppressive therapy may work. If it does, it leaves a patient on immunosuppression and TKI therapy, which can be complicated. Although CML does have some immunoresponsive properties (Graft-vs-tumor effect of an allograft, immunosuppression may not be optimal. CML would remain at best with TFR although I might hesitate to try it in this case or long term/lifelong therapy.
I would give a 2G attempt no more than 3-4 months to show benefit, ie CML response and blood count recovery. If none, then bail.
Allografting will possibly kill two birds with one stone. In a young man, a MUD for both the CML and AA could be curative. There is now even haplo data for both - more for the AA than CML. Rather than wait for him to get into trouble from disease progression or cytopenias, I would move to allograft if 2G fails and not wait around. Wearing both my CML and Allograft hats, I do not have discomfort in moving on.