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P. Strati et al.
P=0.22). Four cases of MDS were diagnosed, after a median of 13.5 months (range, 4-26 months) from axi-cel infusion, all attributed to previous chemotherapies: median number of previous systemic therapies in these four patients was five (range, 4-7), including autologous stem cell transplant in one patient. No significant difference in the incidence of MDS was observed between patients with and without grade 3-4 D30 cytopenia (three of 15 [20%] vs. one of 16 [6%], P=0.33).
Infectious complications
All 31 patients received granulocyte colony stimulating factor (GCSF) support for neutropenia; 13 (42%) received prophylactic IVIG and four (13%) therapeutic IVIG; two (6%) patients received antibacterial prophylaxis, 13 (42%) Pneumocystis jiroveci pneumonia (PJP) prophylaxis, and 22 (71%) antiviral prophylaxis, while no patient received anti- fungal prophylaxis. Overall, among patients with ongoing response, 24 (77%) developed infectious complications with grade ≥3 in 13 (42%) (Figure 2). There was a trend for association between grade 3-4 D30 cytopenia and grade ≥3 infectious complications (nine of 15 [60%] vs. four of 16 [25%], P=0.07), which was statistically significant when limiting the analysis to grade 3-4 D30 lymphopenia (nine of 14 [64%] vs. four of 17 [24%], P=0.03). Due to small sample size, the association between D30 CD4 count and infec- tions could not be assessed. Among all 31 patients, 71 infec- tious events of any grade were reported, with no isolated organism in 40 (56%) cases (Table 2). For these 71 infectious events, the most common etiology was viral (17 of 71 [24%]), followed by bacterial (ten of 71 [14%]) and fungal (four of 71 [6%]), whereas in the remaining cases an organ- ism could not be isolated. Among viral infections, herpes zoster skin infection was the most common event, reported in five patients (16%), none of whom were on antiviral pro- phylaxis. Median time from axi-cel infusion to onset of her- pes zoster infection was 79 days (range, 49-723 days), and all cases resolved with valacyclovir therapy. One patient who was not on prophylaxis developed PJP 18 days after axi-cel infusion, and was successfully treated with sul- famethoxazole-trimethoprim.
Toxicity and efficacy
Among all 31 patients, 30 (97%) patients developed CRS of any grade, grade 3-4 in three (10%), and 20 (65%) patients developed neurotoxicity of any grade, grade 3-4 in 15 (48%). No significant difference in incidence of grade 3-
Figure 2. Median time to infection (TTI).
4 CRS (13% vs. 6%, P=0.60) and in incidence of grade 3-4 neurotoxicity (53% vs. 44%, P=0.72) was observed when comparing patients who developed D30 grade 3-4 cytope- nia to those who did not.
In order to manage either CRS or neurotoxicity, 12 (39%) patients required corticosteroids, and 21 (68%) required tocilizumab. No difference in use of corticosteroids (53% vs. 25%, P=0.15) or use of tocilizumab (73% vs. 63%, P=0.70) was observed when comparing patients who developed D30 grade 3-4 cytopenia to those who did not.
Overall, 26 (84%) patients achieved a response, and 19 (61%) a complete response (CR). No statistically significant difference in overall response rate (87% vs. 81%, P=1) or CR rate (60% vs. 63%, P=1) was observed when comparing patients with D30 G3-4 cytopenia to those without. No sta- tistically significant difference in median baseline ALC was observed when comparing patients who achieved a response to those who did not (0.52x109/L vs. 0.34x109/L; P=0.37), or patients who achieved a CR to those who did not (0.55x109/L vs. 0.39x109/L; P=0.34).
Discussion
In summary, our results indicate that grade 3-4 cytopenia beyond D30 occurs after CAR T-cell therapy in a subset of patients. While cytopenias resolve in most patients, it can persist in one third of evaluable patients at 1 year, highlight- ing the importance of long-term monitoring.
The comparable incidence between our study and other reports suggests that the MDS was most likely due to prior therapies.13,14 Unfortunately, myeloid driver mutations were not tested in these patients before lymphodepleting chemotherapy, to further corroborate this hypothesis. While previous chemotherapies (and subsequent marrow reserve) and conditioning therapy may contribute to the prolonged myelosuppression,15,16 the observation of severe cytopenias in patients who have not received it suggests the intriguing hypothesis that they may instead signify intra- bone marrow CAR T-cell activity.17 To this regard, in our study grade 3-4 D30 cytopenia was more common in heav- ily pretreated patients with low baseline ALC, which may indicate a weaker recipient immune system due to prior therapy, and a potentially easier product engraftment.18 A
Table 2. Infection types (all grades included) Total (N= 71)
No isolated organism
(17 respiratory, 13 ENT, 3 skin, 4 GU, 2 GI, 1 sepsis)
Viral, total
Herpetic (5 VZV, 3 HSV, 2 CMV, 1 HHV6) Respiratory
Enteric
Parvovirus
Hepatitis B
Bacterial, total
Gram negative (2 UTI, 2 GI, 1 bacteremia) Gram positive (3 GI, 2 skin)
Fungal, total
Yeast (skin)
Pneumocystis (pneumonia)
Number (%)
40 (56)
17 (24) 11 (15) 3 (4) 1 (1) 1 (1) 1 (1)
10 (14) 5 (7) 5 (7)
4 (6) 3 (4) 1 (1)
ENT: ear nose throat; VZV: varicella zoster virus; CMV: cytomegalovirus; HSV: herpes simplex virus; HHV6: human herpes virus 6; UTI: urinary tract infection; GI: gastro- intestinal.
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haematologica | 2021; 106(10)