Hi,
this is a question about a 17 year old boy now day +239 post allo BMT for TKI resistant CML .

Here are post BMT results for BCR-ABL t(9;22) RT-PCR:

+ 1 month: PB negative, BM 0.0072
+2 months: PB N/A, BM 0.0044
+3 months: PB negative, BM 0.0025
+5 months: PB N/A, BM <0.002
+8 months: PB N/A, BM 0.0042

When would you repeat another BM exam for confirmation of the slightly higher BCR-ABL level ?
How worrisome is the positive signal in bone marrow at this timepoint after BMT and at what BCR-ABL level would you consider TKI treatment meant or DLI ?
Our patients most recent STR chimerism from BM was 99.77 %.

Many thanks,
Uli

This case comprises a 17 year old boy who underwent allo-SCT (no info on conditioning, no info on donor matching) because of treatment-resistant CML 7 months ago (no info on duration of treatment since diagnosis of CML, no info of treatment applied prior to SCT). There is no info on the course of disease or any treatment post SCT (acute or chronic GvHD? still on immunosuppression? any TKI treatment post SCT?).
MRD has been assessed regularly and is positive and fluctuating at a level of lower than MR4 in the bone marrow. No data on MRD derived from analysis of the peripheral blood is availiable (does the abbreviation N/A stand for: not available? not applicable? not assessed). There is no info on the quality of the PCR applied (type of reference gene, number of copies of reference gene, number of copies of BCR-ABL1) and there is no info whether the methodology applied followed the IS criteria. That is why it is hard to interpret the measurments of a transcript ratio <0.002 at month 5 and another measurement of 0.0042 at months 8.
On this background my advice would be not to perform another BM analysis right now (to confirm a doubling of the ratio from 0.002 to 0.004) but to continue bone marrow assessment in 3 month intervals and consider intervention by a TKI only once MR4.0 should be lost.

Thank you very much Professor Suttorp for sharing your thoughts. Regarding the questions you stated in your answer I would like to add the following additional information.

This boy was initially treated with dasatinib he achieved hematologic and cytogenetic remission but never molecular. After 15 months BCR-ABL was 1.9 % and it was decided to move to allo BMT. At that timepoint dasatinib was switched to nilotinib and after more 2 more months before start of conditioning BCR-ABL was at 1.4 %.

Because of an underlying Gilbert syndrome a non busulfan based conditioning consisting of 12 Gy fractionated TBI, 100 mg/kg cyclophosphamide and ATG (6 mg/kg Thymoglobulin) was given. A bone marrow graft from a 9/10 MUD (bidirectional B mismatch) was used. MMF was stopped at day +30 and tacrolimus stopped after a 7 week taper on day +120. No evidence of GvHD. No TKI treatment post BMT.

This BCR-ABL assay uses FDA approved Quantidex qPCR BCR-ABL IS Kit to quantify BCR-ABL1 major breakpoints fusion transcripts (type e13a2 and/or e14a2) on the Applied Biosystems 7500 Fast Dx Real-Time PCR Instrument. The ratio of BCR-ABL1 major to ABL1 is calibrated and reported to the baseline of 100% on the International Scale (%IS). The analytical sensitivity of this assay has been determined at 0.002%IS (MR4.7).

"N/A" in my posting above means BCR-ABL was not done from peripheral blood at these timepoints. At +1 month and +3 months BCR-ABL was negative in peripheral blood.
I hope this information clarifies the questions you had. Please let me know if additional information is needed. Many thanks again for sharing your experience.

I would suggest that there is no need for any further bone marrows, monitoring from peripheral blood is fine. In the great majority of cases there is no difference in MRD levels between blood and marrow, providing you are testing total leukocytes as recommended and not MNCs. The change from 0.002 to 0.004 is an insignificant change within the range of experimental error.