On December 18, 2020, US Food and Drug Administration (FDA) approved a supplemental application for ponatinib extending the indication in patients with chronic-phase chronic myeloid leukemia (CP-CML) to patients with resistance or intolerance of at least 2 prior kinase inhibitors. Ponatinib was initially approved in December 2012 but was briefly voluntarily withdrawn due to serious safety concerns including the risk of arterial occlusive events (AOE). It returned to the market in December 2013 with an indication limited to patients with T315I mutation or for whom no other tyrosine kinase inhibitor (TKI) therapy was indicated with revised warnings and precautions. A post-marketing requirement was issued to identify the optimal safe and effective dose for CP-CML. Thus, the OPTIC trial was performed, which randomized patients to 1 of 3 doses, 45 mg, 30 mg, or 15 mg, with a dose reduction to 15 mg on achievement of MR2 (BCR-ABLIS ≤1%). Patients enrolled were treated with at least 2 prior TKIs or had a T315I mutation. Patients with a history of clinically significant, uncontrolled, or active cardiovascular disease were excluded. Efficacy was established on an interim analysis based on the rate of MR2 at 12 months in the modified intent-to-treat population of 261 patients, with 88, 86, and 87 patients in the 45, 30, and 15 mg cohorts, respectively. With a median follow-up of 28 months, the rate of achievement of MR2 at 12 months was 42%, 28%, and 24% in the respective cohorts. The safety profile was consistent with that observed in prior evaluations of ponatinib with notable adverse reactions including pancreatitis, hypertension, hyperlipidemia, liver dysfunction, and AOE. Of patients treated at the 45/15 mg dose, AOEs were seen in 13%, with a higher rate being observed in patients age 65 or older compared to younger patients. A readjudication of AOEs seen on the prior pivotal phase 2 study resulted in a rate of 26%. Overall, the results supported a modification of the recommended dose for patients with CP-CML to 45 mg until the achievement of MR2 followed by a reduction to 15 mg. The expansion of the indication to patients with exposure to 2 prior TKIs was approved given data showing that ponatinib could be successfully used for the treatment of this population with appropriate monitoring and screening for risk factors.
Abstract Background Chronic lymphocytic leukemia (CLL) is characterized by accumulation of mature appearing lymphocytes and is rarely complicated by thrombosis. One possible explanation for the paucity of thrombotic events in these patients may be the presence of the ecto-nucleotidase CD39/NTDPase-1 on the surface of the malignant cells in CLL. CD39 is the major promoter of platelet inhibition in vivo via its metabolism of ADP to AMP. We hypothesize that if CD39 is observed on CLL cells, then patients with CLL may be relatively protected against platelet aggregation and recruitment and that CD39 may have other effects on CLL, including modulation of the disease, via its metabolism of ATP. Methods Normal and malignant lymphocytes were isolated from whole blood from patients with CLL and healthy volunteers. Enzyme activity was measured via radio-TLC assay and expression via FACS. Semi-quantititative RT-PCR for CD39 splice variants and platelet function tests were performed on several samples. Results Functional assays demonstrated that ADPase and ATPase activities were much higher in CLL cells than in total lymphocytes from the normal population on a per cell basis (p-value < 0.00001). CD39 activity was elevated in stage 0–2 CLL compared to stage 3–4 (p < 0.01). FACS of lymphocytes demonstrated CD39 expression on > 90% of normal and malignant B-lymphocytes and ~8% of normal T-lymphocytes. RT-PCR showed increased full length CD39 and splice variant 1.5, but decreased variant 1.3 in CLL cells. Platelet function tests showed inhibition of platelet activation and recruitment to ADP by CLL cells. Conclusion CD39 is expressed and active on CLL cells. Enzyme activity is higher in earlier stages of CLL and decreased enzyme activity may be associated with worsening disease. These results suggest that CD39 may play a role in the pathogenesis of malignancy and protect CLL patients from thrombotic events.
This study provides up-to-date and detailed cancer survival estimates of German patients with non-Hodgkin lymphoma (NHL, International Statistical Classification of Diseases 10th Revision [ICD-10] codes C82-C85) based on data from 11 cancer registries. Period analysis was used to calculate 5-year relative survival in 2002-2006, overall and by gender, age and histology. Comparison was made with patients with NHL in the United States (US) Surveillance, Epidemiology and End Results database in the same time period. Overall 5-year relative survival for patients with NHL in Germany in 2002-2006 was 62.8% and in the US was 65.1%. Survival decreased with age from 81.7% at age 15-49 to 46.5% at age 75+. Survival in the US was 75.3% at age 15-49 and 52% at age 75+. Survival was higher for women than for men, at 65.2% for women and 60.7% for men. Survivals for diffuse B-cell lymphoma and follicular lymphoma, the two most common subtypes of NHL, were 57.3% and 77.5%, respectively. Between 2002 and 2006, overall 5-year relative survival increased by 5.3 percentage points. We conclude that survival for NHL is increasing in Germany in recent years. Survival was higher in Germany than in the US for patients aged 15-49 but lower for older patients.
The human leukemic T-cell line Jurkat was used to define the role of the cellular stress pathway with its key player kinase JNK in cancer therapy-induced apoptosis. JNK activity was inhibited by stable transfection with a dominant negative mutant of the upstream kinase JNKK/MKK4 or with the novel, potent and selective JNK1, -2 and -3 inhibitor SP600125. Inhibition of JNK activity delayed the onset of apoptosis induced by cisplatin, doxorubicin, gamma-irradiation and CD95-L but did not prevent apoptosis per se. Early events during apoptosis such as induction of CD95-L, activation of caspase-8 and exposure of phosphatidylserine on the cell surface were strongly inhibited. Also, at early time points of apoptosis, loss of the mitochondrial membrane potential and release of cytochrome c were markedly impaired. However, late signaling events during apoptosis such as cleavage of PARP and DNA fragmentation apoptosis were only marginally affected. These findings are in accordance with the activity of initiator and effector caspases. Whereas activity of the initiator caspase-8 was strongly inhibited early and late after induction, an inhibition of caspase-3 activity was only observed early after induction of apoptosis. We therefore suggest that cellular stress signaling contributes to the initiation of apoptosis, whereas it might be dispensable for the progression of apoptosis. Dysfunction of this pathway under pathological conditions might contribute to therapy resistance of cancer cells.
7191 Background: Lymph node (LN) involvement predicts relapse in patients after resection of apparently localized nonsmall cell lung cancer (NSCLC). Molecular staging (MS) techniques can be used to detect micrometastatic disease, while sentinel lymph node (SLN) mapping can indicate which LNs are most likely to contain micrometastases. Methods: We used SLN mapping and MS to more sensitively detect LN micrometastases. RT-PCR for cytokeratin7 (CK7), a gene expressed in normal and malignant lung, but not in LNs, was used to identify tumor-derived material in LNs. Results: SLN mapping was performed in 13 patients during resection, 1–3 SLNs were identified in each, and sufficient RNA for molecular studies was obtained in 12/13 patients. No major adverse reactions occurred. 11/12 of the primary tumors expressed CK7. 65 LNs were examined, including 21 SLNs from the 11 evaluable patients. Overall, 32/65 LNs were CK7+, including 13/21 SLNs. 10/11 patients with evaluable SLNs had at least one CK7+ SLN. Routine histology showed T1N0-T2N0 disease in 8 patients, T3N0 in 1 patient, and N1 in 2 patients. Of the 9 patients with N0 disease by routine histology, 8 were upstaged by RT-PCR. All LN that were positive by routine histology were RT-PCR-positive. Conclusions: SLN mapping with MS is feasible in NSCLC. SLN mapping identifies LNs likely to contain micrometastases. In this study, SLN status by RT-PCR predicted total LN status in all patients; there were no “skip metastases.” This suggests that molecular study of SLNs alone may be sufficient for MS, which would make MS feasible in the routine clinical setting. This technique may be of use in stratifying patients with N0 disease by routine histology into high (molecular N1) and low (molecular N0) risk groups. Our results suggest that LN micrometastasis is pervasive in resected NSCLC; true molecular N0 disease appears to be rare. No significant financial relationships to disclose.
