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Letters to the Editor
Figure 1. Flow chart of myelofibrosis patient cohorts and outcomes according to myeloid chimerism and molecular disease status. *These two patients under- went immunosuppression reduction before any evidence of relapse. One was converted to full donor chimerism, and the other had progressive loss of donor myeloid chimerism and graft failure. **This patient with mixed T-cell chimerism had a molecular relapse (recurrent JAK2 mutation) that responded to a tacrolimus dose reduction (converted to full donor chimerism and had molecular remission).
leukemia and one patient had accelerated MF with 19% blasts. One patient died from complications of graft-versus-host disease (GvHD) (after immunosuppres- sion reduction) and persistent disease. The other four patients died while in complete remission (CR); two patients achieved CR with immunosuppression reduc- tion alone (died from GvHD complications), and one patient each achieved CR after donor leukocyte infusion and second allogeneic SCT (both died of second malig- nancy). For the 17 surviving patients, nine responded to immunosuppression reduction alone and converted to full donor myeloid chimerism and complete remission, seven patients were salvaged with second allogeneic SCT, and one patient was not evaluable at time of last follow-up.
The majority of the patients underwent molecular test- ing for both chimera and clonal molecular markers on the same date. MMC and molecular relapse were concurrent- ly detected in all but five patients. Among these five patients, molecular relapse was preceded by MMC in three patients, and one patient had an initially positive JAK2 V617F molecular relapse followed shortly by MMC. The fifth patient did not undergo concomitant clonal molecular testing at the initial presentation when found to have MMC but had a molecular relapse 6 months later.
We assessed survival in the whole patient group and according to MMC status. With a median follow-up of 49 months (range: 3-105), the 4-year PFS and OS rates in all study patients were 32% and 51%, respectively. When stratified according to chimerism status, the 4-year PFS rate was 4% in those with MMC versus 60% in those with full donor myeloid chimerism (P<0.0001) (Online Supplementary Figure S3). Similarly, patients with MMC had a 4-year OS of 47% compared to 59% in those with full chimerism. However, this difference was not statisti- cally significant, likely because of the small sample size and salvage treatment interventions.
Highly sensitive molecular testing is increasingly being used for early detection of relapse and guidance of thera- pies. Approximately 60% of patients with MF harbor the JAK2 mutation.21 Other molecular markers (MPL and CALR) are increasingly being used, but not yet validated as strong predictors of relapse after allo-SCT. Hence, the need for a better universal marker to predict relapse because morphologic findings are not helpful in many
cases. Loss of donor chimerism has long been correlated with increased relapse incidence after allo-SCT in various hematologic neoplasms. Furthermore, Thiede et al.17 proved that MMC not only predicts clinical relapse of chronic myeloid leukemia but is also associated with reappearance of BCR-ABL1 translocation transcripts.
The present study is one of the largest to demonstrate a strong association between MMC and morphologic and molecular relapse in patients with MF. The finding in a few patients that loss of myeloid chimerism may precede early molecular relapse is worth further investigation. Patients who never developed MMC rarely relapse. We propose that myeloid chimerism testing alone or in com- bination with other clonal molecular markers can be one of the earliest and most accurate methods of predicting relapse, particularly early after transplant where clinical and morphologic bone marrow findings are frequently not useful in confirming relapse. Our findings suggest the unmet need for a revised definition of MF relapse after allogeneic SCT to account for the role of MMF and molecular data in the posttransplant setting. Early inter- vention with immunosuppression reduction alone in this high-risk population with MMC is feasible and worth further investigation.
Samer A. Srour,1 Amanda Olsonr,1 Stefan O. Ciurear,1
Parth Desair,2 Qaiser Bashirr,1 Betul Oranr,1 Prithviraj Boser,3 Rohtesh Mehtar,1 Keyur P. Patelr,4 Naveen Pemmarajur,3 Naval Daverr,3 Srdan Verstovsekr,3 Richard E. Champlinr1 and Uday R. Popatr1
1Department of Stem Cell Transplantation and Cellular Therapy, The University of Texas MD Anderson Cancer Center, Houston; 2Department of Medicine, The University of Texas Health Science Center at San Antonio, San Antonio; 3Department of Leukemia, The University of Texas MD Anderson Cancer Center, Houston and 4Department of Hematopathology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA
Correspondence: UDAY R. POPAT upopat@mdanderson.org doi:10.3324/haematol.2019.223503 Received: April 1, 2019.
Accepted: July 10, 2019.
Pre-published: July 11, 2019.
Disclosures: no conflicts of interest to disclose.
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