Aplasia in Chronic Phase CML Post-TKI Therapy: A Management Dilemma

Table 1

Description of reported cases of TKI-related Bone Marrow Hypoplasia/Aplasia.

	Demographics	Phase of CML	TKI therapy	Timeline for cytopenias	Bone marrow biopsy	Clinical course
Lokeshwar et al. [4]	46 yo, male	Chronic phase CML	Imatinib 400 mg/d.; Prior treatments: busulfan, IFNα + low-dose Ara-C, hydroxyurea.	Pancytopenia at week 6.	D56: severely hypoplastic (5%) and fatty; no significant fibrosis. Blast cells not appreciable.	Admitted for febrile neutropenia secondary to gastroenteritis and Escherichia coli bacteremia. She clinically declined with the development of bilateral pulmonary infiltrates. The patient passed, with postmortem confirming pulmonary mucormycosis.
Sumi et al. [5]	73 yo, female	Chronic phase CML	Imaitinib 400 mg/d.; Prior treatments: IFNα, hydroxyurea, busulfan.	Pancytopenia at week 17; GIV neutropenia at day 35; GIII thrombocytopenia at day 122.	D87: severe hypocellularity.	Supportive care: transfusion PRBC, platelet; filgrastim.
Khan et al. [6]	51 yo, male	Chronic phase CML	Imatinib 400 mg daily initially, then dose reduced to 300 mg daily, then 200 mg daily for thrombocytopenia.	Anemia and thrombocytopenia at week 13, progressing to pancytopenia by week 19.	D126: slightly depressed cellularity.	Deceased: pulmonary tuberculosis, liver failure, worsening pancytopenia.; Passed away despite supportive care.
Song et al. [7]	77 yo, male	Chronic phase CML	Imatinib 400 mg PO daily, dose reduced to 300 mg secondary to patient intolerance, then eventually discontinued.; Nilotinib 400 mg po BID.	CCR after 9 months of imatinib therapy. No evidence of pancytopenia.; Pancytopenia at week 8 of nilotinib therapy.	D252 (imatinib): CCR; D56 (nilotinib): <5% normal cellularity. Fatty tissue without myelofibrosis or adipocyte deposition. No chromosomal abnormalities.	Four months after discontinuation of nilotinib, the patient remained in CCR, in the absence of further CML-specific therapy.; Hematologic parameters did not recover by this time.
Poudyal et al. [3]	35 yo, male	Chronic phase CML	Imatinib 400 mg po daily. Rechallenged with 300 mg po daily after recovery of PRCA.; Eventually switched to Nilotinib 400 mg po BID, then dose-reduced to 200 mg po BID secondary to recurrence of PRCA.	Anemia with reticulopenia at week 16.; Anemia recurred with rechallenge of imatinib 300 mg, at week 8.; Anemia recurred with nilotinib 400 mg BID, at day 40.	Three BMBx performed, each prompted by anemia while on TKI. Each BMBx demonstrated PRCA.	PRCA developed with initial dose of imatinib 400 mg daily. Discontinuation of TKI and initiation of prednisone 1 mg/kg resulted in recovery of marrow by D21.; Rechallenge with imatinib 300 mg daily also resulted in recurrence of PRCA but was steroid refractory. Oral cyclosporine facilitated marrow recovery.; Nilotinib 400 mg po BID was initiated, but PRCA recurred. Nilotinib was held and cyclosporine continued, with recovery of counts.; Nilotinib was resumed at 200 mg BID, with continuous cyclosporine. There were no further declines in hemoglobin.
Estephan et al. [8]	53 yo, female	Chronic phase CML	Nilotinib 300 mg po BID. Discontinued secondary to pancytopenia.; Switched to Dasatinib 50 mg daily once, cytopenias recovered.	Pancytopenia at week 10.	D70: hypocellular (<5%) with decreased trilineage hematopoiesis (panhypoplasia) and no residual CML.; D140: mormocellular; marrow (40%) and trilineage hematopoiesis. No left shift in maturation or increased blasts. Cyteogenetics 46XX.	Romiplostim initiated with development of pancytopenia. By 3 months, intervals between transfusions lengthened. By 5 months, repeat BMBx demonstrated recovery.; Dasatinib started with good cytogenetic response.
Prodduturi et al. [9]	49 yo, male	Chronic phase CML	Imatinib 400 mg po daily. Therapy switched as milestones not achieved at 7 months.; Dasatinib 100 mg po daily. Discontinued due to anaphylactic reaction.; Nilotinib 400 mg po BID, then daily, then 200 mg daily. Dose reduced and eventually discontinued secondary to cytopenias.	Pancytopenia with nilotinib 400 mg BID at month 6, but with CCR.; Pancytopenia recurred after 1 month of dose-reduced nilotinib 200 mg daily.	D168 (nilotinib 400 mg BID): 5–10% cellularity; CCR; D364 (nilotinib 400 mg BID): 5% cellularity; CCR; D56 (discontinuation of nilotinib): 40% cellularity, Ph^+ in 13/20 metaphases; D30 (Nilotinib 200 mg daily): <5% cellularity; Ph^+ in 12/20 metaphases.	Milestones not achieved after 7 months of Imatinib 400 mg daily.; Anaphylaxis to Dasatinib 100 mg precluded further use.; Initially started on nilotinib 400 mg po BID which was decreased to daily secondary to cytopenias. BMBx showed progression, and dose was escalated to twice daily. BMBx at 6 months, then after further 7 months, it showed 5% cellularity but CCR. Marrow recovered following discontinuation of nilotinib but also with disease progression. Thereafter, resumption of nilotinib at 200 mg daily resulted in pancytopenia after 1 month, with persistent disease.; All CML-directed therapy discontinued with recovery of peripheral counts.

TKI, tyrosine kinase inhibitor; IFNα, interferon alfa; GIII, grade III; GIV, grade IV; CCR, complete cytogenetic remission; CHR, complete hematologic response; PRCA, pure red cell aplasia; BMBx, bone marrow biopsy.