PF189 APPROPRIATE INTERVAL OF MONITORING FOR DETECTION OF MOLECULAR RELAPSE AFTER STOP OF TKI IN PH+ALL IN PH+ ALL CALCULATING BY MRD KINETICS
Authors: Miyamura K. , Morishita T. , Goto T. , Nishiwaki S. , Ozawa Y. 
Published: June 2019

Please indicate where the abstract has been published before: Blood 2018 132:5291; doi: https://doi.org/10.1182/blood‐2018–99–112293

Background:

Usually TKI is stopped in patients with Ph+ leukemia (CML/ALL) who have sustained a deep molecular response. The MRD monitoring interval and threshold of restarting TKI is mostly established in CML. In Ph+ALL patients, prophylactic/maintenance administrations of TKI are used during post hematopoietic stem cell transplantation (HSCT) as well as post chemotherapy. Unlike CML, no established selection of patients who can stop TKI. In addition, after TKI stopped, there is no consensus about how often to monitor MRD and threshold of restart for TKI.

Aims:

In the current study, we tried to determine the optimal frequency of MRD monitor after the cessation of TKI in Ph+ALL using a mathematical model.

Methods:

Mimicking CML, we defined BCR‐ABL/ABL ratio of 0.1% as“MR3” and undetectable levels of BCR‐ABL transcript as “MR5”. We estimate that patients with MR3 and MR5 have 109 and 107 Ph+ cells in the body, respectively. In this perspective, we defined “MR3” and “MR5” as “optimal intervention threshold” and “detection threshold”. From the literatures, we determined that growth rate of leukemia is distributed between 1%/day and 100%/day (doubling time of leukemic cells is 1 day). Also, we assumed that single cell have a relapse potency and the growth rate is constant during observation in each patient.

Results:

Table shows the interval from single leukemia cell to MR5 leukemia burden (1 x 107 cells) and the interval from MR5 to MR3 (X100) according to growth rate. Figure is a graph of Table. We calculated using most extreme cases. In the highest growing speed (100%/day), if the number of Ph+ cells is just below detection level (MR5), it will take 6.6 days to reach MR3 (optimal intervention threshold). Also, if the number of Ph+ cells is only 1 cell, it will take 23.3 days to reach MR5. The other ultimate condition is that the number of leukemia cells is only one in the body and has the slowest growth rate (1%/day). In this case it will take 1620 days (4.4 years) to reach MR5. It was reported that the growth rate of Ph+ cells in the blastic phase of CML is approximately 8% (doubling time 9 days) (Branford. Blood. 2012;119:4264). Applying this value to our model, it will take 209 days to reach MR5 (detection threshold) from single Ph+ cell. If the number of leukemia cells is just below the detection level (MR5), it will take 60 days to reach MR3 (optimal intervention threshold). In this patient a 2 months interval can detect MRD before it reaches to MR3 (Success). If 1 Ph+ cell remains when TKI is stopped, it will reach the MRD detection level (MR5) in 269 days. If Ph+ cells does not appear until this time, this patient is supposed to be cured in this model. In the clinical setting, growth rate is unknown. Thus in the beginning, a highest growth rate of 100% is applied. (Figure) As mentioned above, monitoring should be performed every 6.6 days until 23.3 days, At this point, interval MRD monitoring can be prolonged to 23.3 days until 81.7 days. (Likewise interval of 81.7 days until 285.8 days and interval of 290.1 days until 1015 days)

Summary/Conclusion:

Taken together, soon after stop of TKI, frequent monitoring of MRD is needed. The interval can be prolonged with the passage of time. After allogeneic HSCT, the growth rate of leukemia may be down regulated to some extent according to the GVL effect. The current strategy may be applied to other leukemia in which MRD monitoring by PCR is established.

image