Risk of Thrombosis in Adult Philadelphia-Positive ALL Treated with an Asparaginase-Free Pediatric-Inspired ALL Regimen with Imatinib
Bibliographic record
Abstract
Background: Venous thromboembolism (VTE) is a well-known complication in adults with acute lymphoblastic leukemia (ALL) receiving asparaginase (ASNase) based therapy. The MD Anderson Cancer Centre reported an overall VTE incidence of 29% (14/49) in patients with Philadelphia positive ALL (Ph+ ALL) treated with Hyper-CVAD and in the absence of ASNase (Vu et al. Cancer Medicine. 2015;4(1):27-35. doi:10.1002/cam4.332). The VTE incidence in adult Ph+ ALL patients treated with tyrosine kinase inhibitor plus the pediatric-inspired regimen modified from the Dana Farber Cancer Institute (DFCI) ALL protocol remains unclear. We have previously compared the incidence of VTE in adults with Ph+ ALL treated with or without ASNase during the intensification phase of the modified DFCI treatment. This study suggested that patients with Ph+ve ALL experience high incidence of VTE, even in the absence of ASNase, and that this risk is not restricted to the intensification phase. As ASNase was omitted from the protocol due to toxicity since 2008, in this report, we provide further insight into the risk of VTE in adults with Ph+ ALL during the entire ASNase-free DFCI treatment course. Methods: A single-institution retrospective review of sequential Ph+ ALL patients treated at Princess Margaret Cancer Center (PMCC) from 2008-2018 with an imatinib-containing DFCI protocol-based regimen that omitted ASNase. VTE events were recorded from the time of diagnosis to the end of modified DFCI treatment, including at the time of allogenic bone marrow transplantation. Co-variants of age, sex, weight, BMI, Padua score, white blood cell count, and platelet count were also collected. Statistical analyses were performed using the 2-tailed t test. Results: Overall, 130 patients were included for analysis; none received prophylactic anticoagulation. Among the 130 Ph+ ALL patients treated with the modified DFCI protocol, 28 (21.5%) patients had at least 1 VTE events from diagnosis to the end of treatment. The mean age of patients with and without VTE were 56.8 and 49.0 years, respectively (p=0.014) (Table 1). The majority of the VTE events occurred during active treatment, with 9 (7.0%), 11 (8.5%), and 4 (3.1%) occurring during induction, intensification, and maintenance, respectively (Figure 1). Only four patients (3.1%) presented with VTE at the time of diagnosis. Of all VTE events, 14 (50%) were DVT and/or PE, 12 (43%) were line-related, and 2 (7%) involved a cardiac thrombus (Table 2). The average Padua score for these patients was 5.4 with a range of 3-10. All VTE events were treated with low weight molecular heparin (LMWH), with 2 patients experiencing a recurrent episode within a year while on LMWH treatment. Bleeding following anticoagulation was rare. One patient experienced a major bleeding into the psoas muscle while on LMWH plus platelet transfusion for a right atrial clot during the induction phase in ICU. No other significant bleeding event was observed. Conclusion: VTE was observed in more than 20% of adults with Ph+ ALL patients treated with imatinib plus a modified DFCI pediatric ALL protocol. The majority of VTE events occurred during active treatment (induction and intensification), and DVT/PE incidence was similar to that of line-related thrombosis. The high observed VTE incidence suggests that prophylactic anticoagulation should be considered for adult patients with Ph+ ALL even in ASNase-free regimens, especially if additional thromboembolic risk factors are present. Disclosures Maze: Pfizer Inc: Consultancy; Novartis: Honoraria, Membership on an entity's Board of Directors or advisory committees. Chan:Celgene: Honoraria, Research Funding; Agios: Honoraria; AbbVie Pharmaceuticals: Research Funding. Gupta:Sierra Oncology: Honoraria, Membership on an entity's Board of Directors or advisory committees; Novartis: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees; Incyte: Honoraria, Research Funding. Yee:Novartis, Pfizer: Honoraria, Membership on an entity's Board of Directors or advisory committees; Astellas, Celgene, Otsuka, Shire, Takeda: Membership on an entity's Board of Directors or advisory committees; Agensys, Astex, Hoffman La Roche, MedImmune, Merck, Millenium, Roche/Genentech: Research Funding. Minden:Trillium Therapetuics: Other: licensing agreement. Schimmer:Novartis Pharmaceuticals: Consultancy; Otsuka Pharmaceuticals: Consultancy; Medivir Pharmaceuticals: Research Funding; Jazz Pharmaceuticals: Consultancy. Schuh:Jazz: Honoraria, Membership on an entity's Board of Directors or advisory committees; Pfizer: Honoraria, Membership on an entity's Board of Directors or advisory committees; Amgen: Honoraria, Membership on an entity's Board of Directors or advisory committees; AbbVie: Honoraria, Membership on an entity's Board of Directors or advisory committees; Agios: Honoraria; Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees; Astellas: Honoraria, Membership on an entity's Board of Directors or advisory committees; Teva Canada Innovation: Honoraria, Membership on an entity's Board of Directors or advisory committees. McNamara:Novartis Pharmaceutical Canada Inc.: Consultancy.
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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 | 0.000 | 0.002 |
| Meta-epidemiology (narrow) | 0.000 | 0.000 |
| Meta-epidemiology (broad) | 0.000 | 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) | 0.001 | 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 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".