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Letters to the Editor
Quantitative polymerase chain reaction-based chimerism in bone marrow or peripheral blood to predict acute myeloid leukemia relapse in high-risk patients: results from the KIM-PB prospective study
Allogeneic hematopoietic stem cell transplantation (HSCT) represents the best curative option for many patients with acute myeloid leukemia (AML). Nevertheless, relapses are extremely frequent, especially in patients with a high or very high disease risk index.1,2 Although salvage treatments are expectedly more effec- tive when given before overt recurrence, it is difficult to identify this clinically relevant time-window in such patients, because of the rapid growth kinetics of the dis- ease leading to early relapse. Moreover, the genetic het- erogeneity and clonal plasticity of AML hamper the iden- tification of reliable and stable genetic markers to moni- tor minimal residual disease.3
After myeloablative allogeneic HSCT, reappearance of host-specific hematopoietic chimerism has been strongly associated with relapse,4 and thus represents a practical surrogate marker of minimal residual disease. The devel- opment of quantitative polymerase chain reaction (PCR)- based assays has increased the sensitivity of chimerism monitoring dramatically5 and a number of studies have shown its clinical utility in relapse prediction.6-9 However, most of these studies were performed retrospectively and in highly heterogeneous cohorts of patients, and it has not yet been addressed whether the increased sensitivity of this approach might allow disease reappearance to be monitored using peripheral blood (PB) samples and in very high-risk AML patients.
To answer these questions we designed an exploratory, prospective, non-interventional, single-center study to compare chimerism monitoring in PB or bone marrow (BM) in patients undergoing myeloablative allogeneic HSCT for high-risk AML (the "KIM-PB" study, approved by the San Raffaele Ethics Committee on September 1st, 2014). The primary endpoint of the study was prediction of relapse. To monitor post-transplant fluctuations in chimerism not related to the disease, we included a con- trol group of patients with Hodgkin or non-Hodgkin lym- phomas without BM disease involvement. In the initial design, the study group comprised 30 AML patients with a high or very high disease risk index, and the control group was formed of 15 patients. Conditioning regimens and graft-versus-host disease prophylaxis were similar in both groups, and mainly based on treosulfan plus flu- darabine and sirolimus plus mycophenolate. Between September 2014 and March 2016, 29 patients were enrolled into the study group (one patient was left out of the study because his donor refused to participate in the study), but only 20 were evaluable for the study end- point, since four were excluded because of early non- relapse-related deaths, two because of disease persist- ence at first hematologic evaluation, two because of ran- domization to a non-myeloablative conditioning regi- men, and one because of graft rejection. We enrolled eight patients into the control group, excluding one because of early non-relapse-related death and, upon a planned ad interim analysis, considered the seven evalu- able patients sufficient to perform the relevant compar- isons. Patient and transplant characteristics are summa- rized in Table 1. Chimerism was monitored using com- mercially available quantitative PCR-based assays (KMRtype and KMRtrack, GenDx, Utrecht, the Netherlands) (see Online Supplementary Methods). BM evaluations were performed on days 30, 60, 90, 180, 270
Table 1. Patient and transplant characteristics. Study Group
Control Group (n=7) Number (%)
30 (19-36)
2 (28.6)
5 (71.4)
-
3 (42.9) 4 (57.1)
4 (57.1)
3 (42.8)
1 (14.2) 3 (42.9) 3 (42.9) 0
1 (14.3)
3 (42.9)
3 (42.9) 372 (26-385)
18 (3-25)
0
2 (28.6)
70 (26-114)
5 (71.4)
Median age, years (range)
Sex
Male
Female Disease
Acute myeloid leukemia Hodgkin lymphoma Non-Hodgkin lymphoma
Disease status at HSCT
Complete remission
Active disease Disease Risk Index
Low Intermediate High
Very high
Donor type
Matched related Matched unrelated Haploidentical
Median follow-up after HSCT, days (range)
Median time to engraftment, days (range)
Relapse
Median time to relapse, days (range)
Transplant-related mortality
Median time to TRM, days
(range)
End-of-study survivors
(n=20) Number (%)
54 (29-72)
13 (65.0)
7 (35.0) 20 (100)
- -
9 (45.0)
11 (55.0)
0
0
17 (85.0) 3 (15.0)
1 (5.0)
5 (25.0) 14 (70.0) 351 (56-375)
20 (13-31)
7 (35.0) 72 (60-91)
2 (10.0)
84 (56-112)
11 (55.0)
1480
AML: acute myeloid leukemia; HL: Hodgkin leukemia; NHL: non-Hodgkin leukemia; HSCT: hematopoietic stem cell transplantation; TRM: transplant-related mortality.
and 360 after allogeneic HSCT, according to the practice of our center. PB evaluations were performed on days 3, 7 and 15, then twice a month for the first 4 months and monthly from month 5 to 12. The 1-year timespan for study follow-up was selected because approximately 80% of relapses in patients with AML a high or very high disease risk index occur during the first 12 months after allogeneic HSCT.2 The sampling schedule is summarized in Figure 1A.
Of the 20 patients in the study group, seven relapsed (median time to relapse: 73 days; range, 61-93), 11 were alive and in complete remission at the end of follow-up and two died in remission before the end of the follow- up (at day 58 and 112 after HSCT) (Figure 1B). In the con- trol group, five of the seven evaluable patients were alive at the end of follow-up and two died before that (at days 25 and 116), with no patient developing BM involve- ment. Altogether, we collected and analyzed 409 samples (PB, n=310; BM, n=99). When we compared the values of host-specific chimerism obtained from paired PB and BM samples (n=97) we detected a significantly higher host
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