Table 7.
Adverse events in 1149 courses of rituximab
| Adverse Events | No. (%) or Median (IQR) | P Value | |||||||
|---|---|---|---|---|---|---|---|---|---|
| All Courses (n=1149) | Course 1 (n=346) | Course 2 (n=346) | Course 3 (n=201) | Course 4 (n=118) | Course 5 (n=68) | Course 6 (n=40) | Course ≥7 (n=30) | ||
| Hypogammaglobulinemia | |||||||||
| Courses of rituximab with IgG monitoring | 693 | 177 | 207 | 138 | 76 | 46 | 26 | 23 | |
| Hypogammaglobulinemia (all) | 353 (50.9) | 85 (48.0) | 103 (49.8) | 64 (46.4) | 38 (50) | 26 (56.5) | 19 (73.1) | 18 (78.3) | 0.46 |
| Onset time after each course (mo)a,b | 1.6 (0.3–6.7) | 1.3 (0.3–5.9) | 1.8 (0.3–8.4) | 1.1 (0.3–6.6) | 2.1 (0.3–10.8) | 2.8 (0.7–4.9) | 0.8 (0.3–11.0) | 2.7 (1.4–5.5) | |
| Lowest IgG value (mg/dl) | 348 (238–462) | 341 (205–467) | 351 (264–495) | 334 (196–452) | 355 (256–510) | 376 (282–451) | 295 (246–410) | 316 (224–373) | 0.40 |
| Prolonged episodes (>6 months) | 67 (9.7) | 19 (10.7) | 15 (7.2) | 14 (10.1) | 7 (9.2) | 6 (13.0) | 2 (7.7) | 4 (17.4) | 0.17 |
| Recovery time (mo)c | 11.5 (8.1–21.8) | 17.6 (9.1–44.5) | 11.3 (7.8–15.9) | 8.7 (6.9–11.4) | 10.2 (8.6–27.1) | 10.8 (9.9–11.7) | 24.6 (19.5–29.7) | 14.8 (11.9–19.4) | 0.73 |
| Significant hypogammaglobulinemiad | 78 (11.3) | 21 (11.9) | 19 (9.2) | 19 (13.8) | 9 (11.8) | 5 (10.9) | 3 (11.5) | 2 (8.7) | 0.75 |
| Onset time after each course (mo) | 5.8 (0.6–10.6) | 2.6 (0.6–9.5) | 10.9 (6.3–15.5) | 2.2 (0.5–7.0) | 9 (0.3–11.3) | 4.3 (3.2–5.5) | 4.7 (2.6–7.6) | 8.0 (7.0–8.9) | |
| Very low IgG levels (<200 mg/dl) | 66 (9.5) | 19 (10.7) | 15 (7.2) | 16 (11.6) | 8 (10.5) | 3 (6.5) | 3 (11.5) | 2 (8.7) | 0.48 |
| Concomitant infection | 8 (1.2) | 1 (0.6) | 4 (1.9) | 2 (1.4) | 1 (1.3) | 0 | 0 | 0 | — |
| Need of IVIG replacement | 25 (3.6) | 6 (3.4) | 9 (4.3) | 6 (4.3) | 0 | 3 (6.5) | 1 (3.8) | 0 | — |
| Isolated hypogammaglobulinemia | 17 | 5 | 5 | 3 | 0 | 3 | 1 | 0 | |
| Severe infection | 3 | 0 | 2 | 1 | 0 | 0 | 0 | 0 | |
| Recurrent infections | 2 | 0 | 1 | 1 | 0 | 0 | 0 | 0 | |
| Additional immunomodulation | 2 | 0 | 1 | 1 | 0 | 0 | 0 | 0 | |
| Unknown | 1 | 1 | 0 | 0 | 0 | 0 | 0 | 0 | |
| Neutropeniae | |||||||||
| Courses of rituximab with count monitoring | 1120 | 337 | 339 | 197 | 116 | 66 | 38 | 27 | |
| Neutropenia (all) | 42 (3.8) | 18 (5.3) | 11 (3.2) | 4 (2.0) | 4 (3.4) | 2 (3.0) | 1 (2.6) | 2 (7.4) | 0.06 |
| Onset time after each course (mo)b | 2.9 (1.7–4.6) | 3.5 (1.4–4.5) | 2.4 (1.7–4.6) | 2.0 (1.5–2.8) | 2.5 (1.4–4.2) | 2.8 (2.7–2.8) | 15.7 | 4.9 (4.0–5.7) | |
| Lowest value (mg/dl) | 0.7 (0.2–1.2) | 0.4 (0.2–1.2) | 1.0 (0.6–1.2) | 1.1 (0.7–1.2) | 0.7 (0.4–0.9) | 0.5 (0.2–0.7) | 0.5 | 0.4 (0.2–0.5) | 0.51 |
| Concomitant infection | 9 (0.8) | 5 (1.5) | 1 (0.3) | 1 (0.5) | 0 | 1 (1.5) | 0 | 1 (3.7) | — |
| Agranulocytosisf | 18 (1.6) | 10 (3.0) | 3 (0.9) | 1 (0.5) | 1 (0.9) | 1 (1.5) | 1 (2.6) | 1 (3.7) | 0.001 |
| Onset time after each course (mo)b | 2.9 (1.7–4.5) | 3.7 (2–4.7) | 1.8 (1.7–2.3) | 1.7 | 0.5 | 2.7 | 15.7 | 3.2 | |
| Other adverse events | |||||||||
| Any other adverse events | 74 (6.4) | 20 (5.8) | 27 (7.8) | 12 (6.0) | 7 (5.9) | 3 (4.4) | 3 (7.5) | 2 (6.7) | 0.90 |
| Infection | 53 (4.6) | 15 (4.3) | 19 (5.5) | 9 (4.5) | 4 (3.4) | 3 (4.4) | 1 (2.5) | 2 (6.7) | 0.92 |
| Severe infusion reactiong | 9 (0.8) | 4 (1.2) | 2 (0.6) | 1 (0.5) | 2 (1.7) | 0 | 0 | 0 | — |
| Neurologic | 3 (0.3) | 0 | 2 (0.6) | 0 | 0 | 0 | 1 (2.5) | 0 | — |
| Cutaneous | 2 (0.2) | 0 | 1 (0.3) | 0 | 0 | 0 | 1 (2.5) | 0 | — |
| Benign tumor | 1 (0.1) | 0 | 1 (0.3) | 0 | 0 | 0 | 0 | 0 | — |
| Cardiovascular | 1 (0.1) | 0 | 0 | 0 | 0 | 0 | 1 (2.5) | 0 | — |
| Malignancy | 1 (0.1) | 0 | 0 | 1 (0.5) | 0 | 0 | 0 | 0 | — |
| Others | 5 (0.4) | 1 (0.3) | 2 (0.6) | 1 (0.5) | 1 (0.8) | 0 | 0 | 0 | — |
Data are expressed as n (%) or median (IQR), as appropriate. P values were derived from the likelihood ratio test.
Thirty episodes of hypogammaglobulinemia lasted for more than one course of rituximab.
Missing onset time for hypogammaglobulinemia, neutropenia, and agranulocytosis in a total of eight rituximab episodes.
Seven episodes of hypogammaglobulinemia had not resolved at last follow-up.
Clinically significant hypogammaglobulinemia was defined as episodes with very low IgG levels (<200 mg/dl), associated with concomitant infections and/or requiring IVIG replacement.
Neutropenia was defined as an absolute neutrophil count <1.5 × 109 per liter.
Agranulocytosis was defined as an absolute neutrophil count <0.5 × 109 per liter.
Severe infusion reactions that required termination of the rituximab treatment.