Antitumor Activity of Bortezomib (PS-341; Velcade) in a Phase II Study of Patients with Previously Untreated or Treated Waldenstrom’s Macroglobulinemia (WM).
Bibliographic record
Abstract
Abstract Background: WM is a clonal disorder of lymphoplasmacytoid cells that shares features with lymphoma and myeloma. It is generally considered an indolent lymphoma hence traditional first-line treatments include single-agent alkylators (RR 50–80%) or purine analogues (RR 70–80%). For relapsed/refractory disease, purine analogues lead to responses in only 30% of pts. Newer agents such as rituximab or thalidomide have moderate activity. Regardless of regimen, responses tend to be partial and transient. Bortezomib is a proteasome inhibitor that has shown activity in myeloma. Objective responses were reported in phase I studies of lymphoma, including WM, making this agent of interest to evaluate. Methods: Eligible pts for this ongoing multicentre study must have symptomatic WM (Hb <110g/L; symptomatic lymphadenopathy; hepatomegaly and/or splenomegaly; or hyperviscosity) and received <3 prior chemotherapy regimens (rituximab allowed as a 3rd regimen). Pts receive bortezomib 1.3 mg/m2 IV bolus twice weekly x 2 wks on a 3 wk cycle until PD or 2 cycles beyond CR/stable PR. Planned accrual = 25 pts. Results: Sixteen pts are enrolled thus far. Demographics: median age 63 (range 46–87), M:F ratio = 9:7, ECOG 0:1:2 ratio = 5:10:1. Eight of 16 pts were chemonaive; 8 previously treated (prior regimens: chlorambucil, cladribine, fludarabine, CHOP). At study entry, most pts (12/16) had IgM levels >30g/L (range 11.2–79.8), measurable nodal disease (10/16 pts), and Hb levels <110g/L (10/16 pts). Responses have been observed: 3 confirmed PR (≥50% decrease in both IgM and bidimensional disease), 10 SD, no CR (of 13 evaluable pts). PR in 3 pts was reached after 3, 4, and 8 cycles, respectively. No pts have progressed on treatment. A ≥50% decrease in IgM alone with lagging nodal responses has been observed in another 3 pts. Therefore, a total of 6/13 pts (46%) have achieved PR based on paraprotein response alone. Hematologic improvements (Hb increases ≥ 10g/L) were observed in 9/13 pts (69%). Most common toxicities: fatigue (69%), sensory neuropathy (61.5%), headache (54%), myalgias (61.5%). Neuropathy is described as tingling, numbness, or pain in feet/legs generally within 2–4 cycles. Gr 3 neuropathy developed in 4 pts (none had clinical neuropathy at baseline). Four pts were removed from study due to neuropathy. Reversibility of neuropathy is pending longer followup. Other Gr 3 toxicities: thrombocytopenia (3/13), myalgias (2/13), neutropenia (2/13). Thrombocytopenia and neutropenia were transient, mandating a dose reduction in only 1 pt (neutropenia). Gr 3 myalgias (leg cramps) led to drug discontinuation in 1 pt with rapid resolution. No Gr 4 toxicities have been reported. Conclusions: Bortezomib appears to have activity in WM with objective responses in 3 of 13 pts and SD in 10 additional pts evaluable thus far. Despite prompt IgM reductions and hematologic improvements, objective responses are slow due to lags in nodal reductions. Bortezomib is well-tolerated although sensory neuropathy is common. These interim results are promising and encourage further study of this drug in WM.
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How this classification was reachedexpand
Full frame distilled prediction
Teacher imitationNot calibrated prevalence, not ground truth. Human validation pending. Learned from the 10,348 direct Codex labels and 10,348 direct Gemma labels. Candidate is the union of thresholded teacher heads; consensus is their intersection. These outputs are machine_predicted_unvalidated and are not human labels or direct frontier model labels.
Codex and Gemma teacher scores by category
| Category | Codex | Gemma |
|---|---|---|
| Metaresearch | 0.000 | 0.000 |
| Meta-epidemiology (narrow) | 0.000 | 0.000 |
| Meta-epidemiology (broad) | 0.001 | 0.000 |
| Bibliometrics | 0.000 | 0.001 |
| Science and technology studies | 0.000 | 0.000 |
| Scholarly communication | 0.000 | 0.000 |
| Open science | 0.000 | 0.000 |
| Research integrity | 0.000 | 0.000 |
| Insufficient payload (model declined to judge) | 0.000 | 0.000 |
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 teacher head, 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".