Hematologic Profiles in the Phase 3 APEX Trial.
Bibliographic record
Abstract
Abstract Introduction: Bortezomib (Bz, VELCADE®) is a novel proteasome inhibitor that has demonstrated safety and efficacy for patients (pts) with relapsed and/or refractory multiple myeloma (MM) in phase 2 and 3 trials. Bz was associated with transient, cyclical thrombocytopenia in SUMMIT (NEJM.2003;348:2609) and CREST (BJH.2004;127:165). This analysis evaluated the hematologic profiles in pts treated with Bz or high-dose dexamethasone (Dex) in APEX, the largest phase 3 MM trial in relapsed pts. (NEJM.2005;352:2487). Methods:669 pts with relapsed MM were randomized to Bz 1.3 mg/m2 d 1, 4, 8, 11 q3wk for 8 cycles, then 3 cycles on d 1, 8, 15, 22 q5wk, or Dex 40 mg d 1–4, 9–12, 17–20 q5wk for 4 cycles, then 5 cycles on d 1–4 q28d. Data were collected at baseline and regularly through therapy for adverse events, laboratory values, and transfusion (tf) experience. Results:Thrombocytopenia, anemia, and neutropenia reported as adverse events, all grades (G) and those ≥ G3 in pts are shown (Table). Bz-associated thrombocytopenia was cyclical, with recovery toward baseline during the rest period of each cycle. Overall, 15% of pts on Bz and 1% of those on Dex received platelet (plt) tfs and 33% of pts on Bz and 20% of those on Dex received blood tfs. The majority of plt and blood tfs were completed in the first 2 cycles in both treatment arms. Although the number of plt tfs was higher with Bz, the number of clinically significant bleeding events was similar in the 2 arms. Pts on Bz with complete or partial response experienced an increase in mean hemoglobin over time and the requirement for blood tfs decreased from 21% in cycle 1 to 0% after cycle 4. Median duration of therapy for plt transfused pts was 3.8 and 3.4 mo in the Bz and Dex arms, respectively. Bz-associated neutropenia was also transient and cyclical, and febrile neutropenia was rare. Bz was otherwise not associated with severe myelosuppression. Conclusions:Bz is associated with transient, reversible thrombocytopenia and neutropenia—both with a periodicity related to drug administration—but with rapid recovery and few complications compared with Dex. When clinically indicated, plt tf support, rather than dose reduction, particularly in the first 2 cycles, may be warranted to maximize the benefit of Bz therapy. Impact on plts does not appear to be cumulative, and the mechanism of the cyclic variation in neutrophil counts needs further study. Event Bz (n = 331) Dex (n = 332) *Tfs between baseline and last dose of treatment. Thrombocytopenia, n (%) 116 (35) 36 (11) G3/4 98 (30) 22 (7) Neutropenia, n (%) 63 (19) 6 (2) G3/4 49 (15) 5 (2) Anemia, n (%) 92 (28) 77 (23) G3/4 33 (10) 39 (12) Median plt count, x 109/L (range) Baseline count in blood transfused pts 132 146 Baseline count in plt transfused pts 99 74.5 Responders Baseline 205 162.5 First response 195 175 Last assessment 199 198
Fetched live from OpenAlex and de-inverted. Abstracts are not stored in this database: the inverted indexes are 8.6 GB of the frame’s 9.3 GB of text, and the host has 13 GB free.
How this classification was reachedexpand
Full frame machine prediction
Teacher imitationNot calibrated prevalence, not ground truth. Human validation pending. The Gemma side is a direct model label for every work in the frame, read from the title-only record. The Codex side is a classifier learned from the 10,348 direct Codex labels and calibrated to design-weighted sample rates; fields without enough sample support carry no Codex call. Candidate is the union of the two sides; consensus is their intersection. These outputs are machine_predicted_unvalidated and are not human labels.
Distilled classifier scores by category (both heads)
| Category | Codex | Gemma |
|---|---|---|
| Metaresearch | 0.003 | 0.002 |
| Meta-epidemiology (narrow) | 0.001 | 0.000 |
| Meta-epidemiology (broad) | 0.001 | 0.001 |
| Bibliometrics | 0.000 | 0.000 |
| Science and technology studies | 0.000 | 0.000 |
| Scholarly communication | 0.001 | 0.001 |
| Open science | 0.000 | 0.001 |
| Research integrity | 0.001 | 0.003 |
| Insufficient payload (model declined to judge) | 0.008 | 0.001 |
Machine scores (provisional)
The two teacher heads of the student model, read on this work. A score orders the frame for review; it never asserts a category, and the validation status ships verbatim with every row.
Baseline scores from an immature model (maturity gate not passed, 7 training rounds). Scores rank; they never assert a category.
score_only:v0-immature-baseline · verbatim from the scoring run: score_only means the number may rank works, and no category label ships from itClassification
machine, unvalidatedMachine predicted; a candidate call from one source (direct Gemma or distilled Codex), not a consensus.
How this classification was reached, model by model and score by score, is at the end of the page under "How this classification was reached".