Therapy-related myeloid neoplasms following chimeric antigen receptor T-cell therapy for Non-Hodgkin Lymphoma

Dear Editor, Chimeric antigen receptor T-cell therapy (CAR-T) is a novel class of therapeutics with expanding indications. Currently, CAR-T is FDA approved for relapsed, refractory B-cell acute lymphoblastic leukemia, various subtypes of non-Hodgkin lymphoma (NHL)

We next compared t-MN that developed following the two cellular therapy platforms: patients who developed t-MN following SCT (SCT t-MN cohort, n = 28) and CAR T-cell therapy (CAR-T t-MN cohort, n = 10). As noted above, 5 of the 10 CAR-T t-MN patients had received a prior autologous SCT. The clinical and laboratory characteristics of the two cohorts are shown (Supplementary Table  3). CAR-T t-MN cohort patients received more lines of therapy (5 vs. 4, P = 0.02), though the cumulative doses of doxorubicin (262.5 vs. 300 mg/m 2 , P = 0.025) and melphalan (70 vs. 140 mg/m 2 , P = 0.01) were lower. The cumulative doses of the other alkylators as well as the proportion of the patients who received platinumbased or nucleoside analog-based chemotherapies were not different. At t-MN diagnosis, CAR-T t-MN patients had lower hemoglobin (6.8 vs. 8.7 g/dL, P = 0.008), ANC (2 vs. 4.6 × 10 9 /L, P = 0.016, and platelet count (21 vs. 65 × 10 9 /L, P = 0.009). Cytogenetic and genetic profiles including the proportions of patients with CK, MK, and PV in TP53 were not different between the two cohorts.
The median myeloid-neoplasm-free survival (MNFS) from the first intervention was shorter for CAR-T t-MN patients compared to SCT t-MN patients (43 vs. 100 months, P = 0.01, Fig. 2A). This observation remained valid when patients who received both SCT and CAR-T (n = 5) were excluded (29 vs. 100 months, P = 0.01, Fig.  2B). Similarly, the median MNFS from day 0 for CAR-T t-MN cohort was shorter compared to the SCT t-MN cohort-both when patients who received both SCT and CAR-T were included (22 vs. 44 months, P = 0.01, Fig. 2C), or excluded (11 vs. 44 months, P < 0.001, Fig. 2D). The median MNFS for CAR-T t-MN was not different when stratified by having received prior SCT (n = 5) or not (n = 5, 27 vs. 11 months, P = 0.11), though this analysis was limited by small sample size. Finally, overall survival following t-MN development was not different between the cohorts (Fig. 2E, F).
Our two most notable observations include a relatively high incidence of t-MN and the short interval from CAR-T to t-MN. No prior studies have reported the CI of t-MN following CAR-T. On the other hand, short latency appears to be a common theme in post-CAR-T t-MN. For example, Shouse et al. identified four patients who developed t-MN at a median interval of 3 months (range 2-3)

Fig. 1 Cumulative incidence and cytopenia associated with therapy-related myeloid neoplasm (t-MN) development in non-Hodgkin
Lymphoma patients undergoing chimeric antigen receptor (CAR)-T therapy. A Cumulative incidence of t-MN in NHL patients undergoing CAR T cell therapy at 2 years. B Complete blood count at day +30 post CAR T-cell therapy, day +100 post-CAR T-cell therapy, and at t-MN diagnosis. Hemoglobin in g/dL, platelets ×10 9 /L, white blood cell count (WBC)-×10 9 /L, and absolute neutrophil count (ANC)-×10 9 /L. Correspondence Fig. 2 The latency to develop therapy-related myeloid neoplasm is significantly shorter following chimeric antigen receptor (CAR)-T therapy compared to autologous stem cell transplant (SCT) in NHL. A Myeloid neoplasm-free survival (MNFS) from the first intervention comparing patients who underwent SCT (n = 28) with those who underwent CAR T cell therapy with or without prior SCT (CAR-T, n = 10). B MNFS from the first intervention comparing patients who underwent SCT only (n = 28) or CAR-T only (n = 5). C MNFS from day 0 comparing patients who underwent SCT (n = 28) with those who underwent CAR-T with or without prior SCT (n = 10). D MNFS from day 0 comparing patients who underwent SCT only (n = 28) or CAR-T only (n = 5). E Comparing OS from t-MN diagnosis in patients who underwent SCT (n = 28) with those who underwent CAR-T with or without prior SCT (n = 10), and F comparing OS from t-MN diagnosis in patients who underwent SCT only (n = 28) or CAR-T only (n = 5).
[10], and Cordeiro et al. observed 4 of 86 patients developed t-MN at a median of 6 months (range 4-17) [11]. In both cases, a subset of patients was noted to have evidence of dysplasia [10] or clonal abnormalities prior to CAR-T therapy [11].
Potential explanations for the shorter latency and a substantially higher CI of t-MN following CAR-T compared to historical observations therapies [3,12,13], include the additional DNAdamaging therapy received, improved survival due to better lymphoma control, or that CAR-T, by yet an unknown mechanism, increased the risk of t-MN. While patients who received CAR-T indeed received a median of one additional line of therapy, cumulative exposures to the known DNA-damaging agent were not different. Second, the interval from day 0 to t-MN was not different between CAR T-cell patients whether they received prior SCT or not. Finally, we consistently observed shorter MNFS in the CAR-T t-MN cohort-both when calculated from the first intervention or day 0. However, proving the causality of t-MN is challenging [12], especially as NHL patients receive multiple lines of DNA-damaging therapies over a variable interval. Moreover, there is a debate that SCT acts as an additional risk factor for t-MN [6,12]. Given that half of the CAR T-cell t-MN cohort also received prior SCT, this small retrospective analysis does not allow for establishing CAR-T as a contributory factor for t-MN and the mechanism underlying our observations remains undetermined. Other limitations of our study include those of single-institution retrospective studies. Second, it has not been our practice to obtain cytogenetics and NGS on all NHL patients undergoing CAR-T, limiting our ability to track the clonal evolution before and after CAR-T.
Our observations have notable implications. First, given the strikingly short interval between CAR-T and the development of t-MN, all patients undergoing CAR-T for NHL should have a careful discussion regarding this potentially fatal complication. Second, we and others noted that a subset of patients had dysplasia [10] or clonal abnormalities [11,14] before CAR-T. Therefore, a careful bone marrow evaluation including cytogenetics and NGS may be beneficial [14]. Finally, as the utilization of CAR-T increases;