E. Van Den Neste

Remission of severe cold agglutinin disease after Rituximab therapy

Figure 1 Monitoring of platelet count during 96 h after the onset of the first rituximab infusion. At baseline, the patient’s platelet count was 86 × 109/l. Rituximab infusion was started at time 0, lasted approximately 3 h and was followed by a drastic fall in platelet count by the 6 h. The patient received a platelet transfusion and prednisolone 100 mg i.v. (indicated by an arrow in the figure), after which the platelet count was 28 × 106/l. Subsequently, the platelet count rose spontaneously and returned to baseline levels by 96 h.

Myelodysplastic syndrome with monosomy 5 and/or 7 following therapy with 2-chloro-2'-deoxyadenosine.

A few cases of secondary neoplasms occurring after treatment with 2‐chloro‐2′‐deoxyadenosine (2CdA) have been reported, mostly in patients previously exposed to other anti‐cancer drugs including alkylating agents (AA). Here we report on the occurrence of a myelodysplastic syndrome (MDS) with monosomy 5 and/or 7 in two patients after 2CdA treatment, without or prior to other toxic exposure. In light of a literature review and given the involvement of chromosomes frequently abnormal in secondary leukaemias, we suggest that 2CdA may induce therapy‐related MDS (t‐MDS).

High incidence of complications after 2-chloro-2’-deoxyadenosine combined with cyclophosphamide in patients with advanced lymphoproliferative malignancies

The combination of purine analogs with alkylating agents is able to produce a synergistic antitumoral effect. However, the addition of immunosuppressive and DNA-targeting agents might increase purine analog-related complications. The risk for serious complications was evaluated in 38 patients treated with 2-chloro-2’-deoxyadenosine (CDA) and cyclophosphamide (CP). The diagnoses were chronic lymphocytic leukemia (CLL) in 15, Waldenström’s macroglobulinemia in 4, mantle cell lymphoma in 6, follicular non-Hodgkin’s lymphoma (NHL) in 10, and other low-grade NHL in 3 patients. All patients were pretreated (median: 2 lines, range: 1–5) and 23 (61%) were refractory. The patients received a median of two courses (range: 1–5) of 5.6xa0mg/m2 CDA, followed by a median of 200xa0mg/m2 CP, for 3xa0days. The response rate was 51% [complete remission (CR): 14%, partial remission (PR): 38%]. Grade 3/4 infections occurred in 16 (42%) patients. Dose-limiting cytopenias were seen in 22 (58%) patients. In 12 (32%) patients, autoimmune manifestations developed requiring treatment in most of them. Second cancers arose in five (13%) patients (myelodysplastic syndrome/acute myelocytic leukemia in three, lung cancer in two). Multivariate analysis showed that cytopenias, gender (F), prior radiotherapy, and age (>65xa0years) predicted for the complications seen after CDA-CP. To conclude, because of the high incidence of complications, caution is warranted in selecting patients with advanced lymphoid malignancies for the CDA-CP protocol.

Nucleoside analogs induce proteasomal down-regulation of p21 in chronic lymphocytic leukemia cell lines

Nucleoside analogs (NAs) represent an important class of anticancer agents that induce cell death after conversion to triphosphate derivatives. One of their most important mechanisms of action is the activation of p53, leading to apoptosis through the intrinsic pathway. Classically, the activation of p53 also induces p21 accumulation, which leads to cell cycle arrest at the G1/S transition. In previous work, we observed that 2-chloro-2-deoxyadenosine (CdA), a NA with high activity in lymphoid disorders, including chronic lymphocytic leukemia (CLL), promotes the G1/S transition in the CLL cell line EHEB at cytotoxic concentrations. This finding led us to investigate the p21 response to NAs in these cells. We show here that CdA, but also fludarabine, gemcitabine, and cytarabine, strongly reduced the p21 protein level in EHEB cells as well as in JVM-2 cells, another CLL cell line. This p21 depletion occurred despite induction of p53 and increase of p21 mRNA and was prevented by proteasome inhibitors. Increase of proteasomal degradation caused by NAs appeared to be ubiquitin-independent. Also, NAs induced in these cells an increase of cyclin-dependent kinase (Cdk2) activity and a monoubiquitination of cell proliferating nuclear antigen (PCNA), two processes that are negatively regulated by p21. These changes were not observed with other p53 activators, like etoposide and nutlin-3a that increased the p21 protein level. In conclusion, our study reveals that NAs can induce an alternative pattern of cellular response in some cell models.

A PHASE 2B RANDOMIZED STUDY OF SINGLE AGENT SELINEXOR IN PATIENTS WITH RELAPSED/REFRACTORY DIFFUSE LARGE B-CELL LYMPHOMA (DLBCL)

high‐dose steroids. All patients have efficacy reassessment after RLI window with an ORR of 82% and CR rate of 42%. The 6 patients who have completed all therapy have all achieved a CR. Conclusions: The combination of RLI has shown impressive efficacy both alone and with chemotherapy in this ongoing study in newly diagnosed non‐GCB DLBCL. One patient had an invasive fungal infection, prompting a protocol amendment to prohibit steroid use during the window portion, and no further events have occurred. Additional results will be presented at the meeting.