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LETTERS TO THE EDITOR
Mixed myeloid chimerism and relapse of myelofi-
brosis after allogeneic stem cell transplantation
Allogeneic stem cell transplantation (allo-SCT) remains the only potentially curative treatment for myelofibrosis (MF).1,2 The 5-year overall survival (OS) rates in MF patients after allo-SCT have improved over the past several years, ranging from 47% to 62%.3-7 However, relapse after transplantation remains a frequent cause of death, with relapse rates ranging from 10-43% after allo- SCT.1,8 Strategies for detecting early relapse and improv- ing outcomes in these high-risk patients represent an unmet need.
Assessing response and confirming early relapse after transplant for MF is often challenging based on the clini- cal criteria,9 and it usually takes a few months for fibrosis to resolve and the bone marrow morphologic remission to be achieved.10 Detecting the JAK2 V617F mutation after SCT in MF is a strong predictor of relapse and a potential marker for guiding adoptive immunotherapy.7,11- 13 Few studies have focused on the potential role of mixed chimerism in predicting early relapse, particularly in those with mixed myeloid chimerism (MMC).14-18 The influence of MMC on posttransplantation relapse of MF has not been well studied. Therefore, we aimed to deter- mine the role of MMC in predicting relapse in MF patients after allo-SCT. We further explored the correla- tion between myeloid chimerism and molecular relapse of MF.
Eighty-two consecutive patients with primary or secondary MF who underwent their first allo-SCT at The University of Texas MD Anderson Cancer Center from January 2005 to July 2015 were identified. Patients with double cord or haploidentical donors or with primary graft failure were excluded. MF relapse was defined as any evidence of persistent or recurrent morphologic disease. Molecular relapse was defined as any patient with persistent and/or reappearance of pretransplant molecular genetic abnormalities (JAK2 V617F, CALR and MPL). In this cohort, all patients with molecular relapse had evidence of morphologic persistent and/or relapsed bone marrow disease, except for one patient. Patients were determined to have MMC if they had less than 95% of donor myeloid cells at any time after day 30 after transplantation. This study was approved by the institu- tional review board.
Chimerism testing was performed using eight highly polymorphic microsatellite markers. It included lineage- specific analysis via separation of myeloid cell and T-lym- phocyte populations as described previously.19 For the majority of patients, peripheral blood chimerism testing and molecular testing for MF were performed routinely per institutional policies at months 1, 3, 6, 9, 12, 18, 24, and 36 after transplant, and more frequently as indicated at the discretion of the treating physician.
The primary end point was the frequency of MMC among patients with evidence of morphologic and/or molecular relapse. Secondary end points were the pro- gression-free survival (PFS) and OS rates. Treatment responses were defined as described previously.20 Additionally, molecular remission was defined as JAK2 V617F or CALR/MPL negativity in patients previously positive for them. Survival estimates were calculated for all patients and according to myeloid chimerism status using the Kaplan-Meier method
Forty-four of the 82 patients were male, and the medi- an age at allo-SCT was 57.5 years. Fourty-seven patients (57%) were positive for a molecular marker before trans-
Table 1. Patient, disease, and transplant characteristics of study cohort.
Number of patients
Sex Male
Female
Median age in years at transplant (range)
Diagnosis Primary MF Secondary MF Other MPN
Molecular mutation status Jak2 V617F positive CALR positive
MPL positive
Not available
Donor type Sibling
Unrelated
Source of stem cells Marrow
Peripheral blood
Conditioning regimen Myeloablative Reduced intensity
Mixed myeloid chimerism Yes
No
MF: myelofibrosis; MPN: myeloproliferative neoplasm.
82
44 38
57.5 (27-74)
53 25 4
41 5 1 5
38 44
10
72
66 16
35
47
plantation. Thirty-five patients (43%) developed MMC, of which 24 patients received a myeloablative conditio- ning regimen. Twenty-nine of these 35 patients had ini- tial full donor myeloid chimerisn after transplant before they developed MMC. Table 1 summarizes the patient, disease, and transplant characteristics of study popula- tion.
During the study period, a total of 34 patients (41%) had persistent or relapsed disease after SCT. The flow charts in Figure 1 and the Online Supplementary Figure S1 show the study patients and their disease outcomes according to the MMC status and by molecular status. Only one patient with full donor myeloid chimerism (n=47) experienced disease progression during the study period (Figure 1). In contrast, all but two patients with MMC had morphologic and/or molecular relapse either at the time when MMC was detected or soon afterwards. When we analyzed the study patients with relapsed disease (n=34), all but one patient had MMC.
Among the 47 patients with pretransplant positive molecular marker, 21 patients developed MMC of whom 95% (n=20) had concomitant molecular relapses. The exception was a patient with complete conversion to full chimerism after immunosuppression reduction. Similarly, for the 30 patients with negative molecular testing before transplantation, 13 of 14 patients (93%) with MMC eventually experienced morphologic relapse. The excep- tion was a patient with the successful conversion to full donor chimerism after immunosuppression reduction.
The Online Supplementary Table S1 and Online Supplementary Figure S2 summarize the patient character- istics, disease outcomes, and interventions done of the 35 patients with MMC. The most common cause of death for these patients was persistent/recurrent disease. Thirteen of the 18 deaths were attributed to progressive disease, of which seven had transformed acute myeloid
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haematologica | 2021; 106(7)