Joseph Maly

Incidence and risk of central nervous system metastases as site of first recurrence in patients with HER2-positive breast cancer treated with adjuvant trastuzumab

BACKGROUND Central nervous system (CNS) disease as the site of first relapse after exposure to adjuvant trastuzumab has been reported. We carried out comprehensive meta-analysis to determine the risk of CNS metastases as the first site of recurrence in patients with HER2-positive breast cancer who received adjuvant trastuzumab. METHODS Eligible studies include randomized trials of adjuvant trastuzumab administered for 1 year to patients with HER2-positive breast cancer who reported CNS metastases as first site of disease recurrence. Statistical analyses were conducted to calculate the incidence, relative risk (RR), and 95% confidence intervals (CIs) using fixed-effects inverse variance and random-effects models. RESULTS A total of 9020 patients were included. The incidence of CNS metastases as first site of disease recurrence in HER2-positive patients receiving adjuvant trastuzumab was 2.56% (95% CI 2.07% to 3.01%) compared with 1.94% (95% CI 1.54% to 2.38%) in HER2-positive patients who did not receive adjuvant trastuzumab. The RR of the CNS as first site of relapse in trastuzumab-treated patients was 1.35 (95% CI 1.02-1.78, P = 0.038) compared with control arms without trastuzumab therapy. The ratio of CNS metastases to total number of recurrence events was 16.94% (95% CI 10.85% to 24.07%) and 8.33% (95% CI 6.49% to 10.86%) for the trastuzumab-treated and control groups, respectively. No statistically significant differences were found based on trastuzumab schedule or median follow-up time. No evidence of publication bias was observed. CONCLUSIONS Adjuvant trastuzumab is associated with a significant increased risk of CNS metastases as the site of first recurrence in HER2-positive breast cancer patients.

Outcomes of Patients With Double-Hit Lymphoma Who Achieve First Complete Remission

Purpose Patients with double-hit lymphoma (DHL) rarely achieve long-term survival following disease relapse. Some patients with DHL undergo consolidative autologous stem-cell transplantation (autoSCT) to reduce the risk of relapse, although the benefit of this treatment strategy is unclear. Methods Patients with DHL who achieved first complete remission following completion of front-line therapy with either rituximab plus cyclophosphamide, doxorubicin, vincristine, and prednisone (R-CHOP) or intensive front-line therapy, and deemed fit for autoSCT, were included. A landmark analysis was performed, with time zero defined as 3 months after completion of front-line therapy. Patients who experienced relapse before or who were not followed until that time were excluded. Results Relapse-free survival (RFS) and overall survival (OS) rates at 3 years were 80% and 87%, respectively, for all patients (n = 159). Three-year RFS and OS rates did not differ significantly for autoSCT (n = 62) versus non-autoSCT patients (n = 97), but 3-year RFS was inferior in patients who received R-CHOP compared with intensive therapy (56% v 88%; P = .002). Three-year RFS and OS did not differ significantly for patients in the R-CHOP or intensive therapy cohorts when analyzed by receipt of autoSCT. The median OS following relapse was 8.6 months. Conclusion In the largest reported series, to our knowledge, of patients with DHL to achieve first complete remission, consolidative autoSCT was not associated with improved 3-year RFS or OS. In addition, patients treated with R-CHOP experienced inferior 3-year RFS compared with those who received intensive front-line therapy. When considered in conjunction with reports of patients with newly diagnosed DHL, which demonstrate lower rates of disease response to R-CHOP compared with intensive front-line therapy, our findings further support the use of intensive front-line therapy for this patient population.

Sole rearrangement but not amplification of MYC is associated with a poor prognosis in patients with diffuse large B cell lymphoma and B cell lymphoma unclassifiable

Rearrangement of MYC is associated with a poor prognosis in patients with diffuse large B cell lymphoma (DLBCL) and B cell lymphoma unclassifiable (BCLU), particularly in the setting of double hit lymphoma (DHL). However, little is known about outcomes of patients who demonstrate MYC rearrangement without evidence of BCL2 or BCL6 rearrangement (single hit) or amplification (>4 copies) of MYC. We identified 87 patients with single hit lymphoma (SHL), 22 patients with MYC‐amplified lymphoma (MYC amp) as well as 127 DLBCL patients without MYC rearrangement or amplification (MYC normal) and 45 patients with DHL, all treated with either R‐CHOP (rituximab, cyclophosphamide, doxorubicin, vincristine, prednisone) or intensive induction therapy. For SHL and MYC amp patients, the 2‐year progression‐free survival rate (PFS) was 49% and 48% and 2‐year overall survival rate (OS) was 59% and 71%, respectively. SHL patients receiving intensive induction experienced higher 2‐year PFS (59% vs. 23%, P = 0·006) but similar 2‐year OS as compared with SHL patients receiving R‐CHOP. SHL DLBCL patients treated with R‐CHOP, but not intensive induction, experienced significantly lower 2‐year PFS and OS (P < 0·001 for both) when compared with MYC normal patients. SHL patients appear to have a poor prognosis, which may be improved with receipt of intensive induction.

Incidence and risk of central nervous system (CNS) metastases as a site of first recurrence in patients (pts) with HER2-positive (HER2+) breast cancer treated with adjuvant trastuzumab (T).

609 Background: Resistance to conventional chemotherapy remains a major challenge in Stage IV colon cancer. CRM1 inhibition leads to nuclear sequestration of proteins such as tumor suppressor p53, growth regulatory proteins, and chemotherapy targets such as topoisomerase I/II. We examined the effects of combination use of KPT185 (a novel CRM1 inhibitor) with SN38 (active metabolite of irinotecan) and the effect of drug administration sequence in human colon cancer cell lines to determine if CRM1 inhibition enhances the cytotoxic effect of chemotherapy. METHODS We evaluated the combination effect of KPT185 with SN-38 on both Lovo (KPT-sensitive, IC50 = ∼ 500nM) and HT29 cells (KPT-resistant, IC50 = 1000 ∼ 3000nM) by the Chou-Talalay method, an MTT-based assay that interrogates response across a spectrum of drug dosages: KPT185 (0, 1, 10, 100, 1000, 10000 nM) and SN38 (0, 100, 500, 1000 nM). Cell cycle analysis by FACS with propidium iodide (PI) staining was performed. Effects on apoptosis were determined by FACS (Annexin V/PI staining) and Cell Death Detection ELISA assay. RESULTS The Chou-Talalay method determined that there is a synergistic effect when KPT185 is combined with SN38 in both Lovo and HT29 cells (combination index > 1). FACS analysis demonstrated combination use of KPT185 and SN38 induced an increase in the apoptotic sub-G1 fraction and a shift toward G2/M arrest. Combination treatment also significantly increased the Annexin V/PI-positive fraction compared with SN38 alone case (P < 0.05). Treatment sequence studies demonstrated that pretreatment of SN38 followed by KPT185 (KPT-post) produced the maximum synergistic effect compared with pretreatment of KPT185 followed by SN38 (KPT-pre) or concurrent use (KPT-con); Cell Death Detection ELISA assay showed KPT-post increased apoptosis most (4.3-fold) compared with KPT-pre (4.2-fold), KPT-con (3.8-fold) and SN38 alone (1-fold). CONCLUSIONS Our results show KPT185, a novel CRM1 inhibitor, sensitizes the response to SN38 in KPT-sensitive as well as KPT-resistant colon cancer cells. This method of sensitizing colon cancer cells warrants further evaluation in preclinical models of colon cancer.

A Phase I/II Trial of Panobinostat in Combination With Lenalidomide in Patients With Relapsed or Refractory Hodgkin Lymphoma

Micro‐Abstract On the basis of previous studies showing single‐agent efficacy with lenalidomide and panobinostat in patients with relapsed or refractory Hodgkin lymphoma (HL), we conducted a phase I/II study to evaluate the safety and efficacy of the combination in this patient population. The recommended phase II dose was 25 mg lenalidomide on days 1 to 21 with 15 mg panobinostat 3 times per week, and an overall response rate of 16.7% in patients was observed, with a durable response in 1 patient with lymphocyte‐predominant HL. Background: Lenalidomide and panobinostat have shown single‐agent efficacy of 14% to 50% and 27% to 58%, respectively, in Hodgkin lymphoma (HL). This phase I/II study was conducted to determine the maximum tolerated dose (MTD), safety, and efficacy of lenalidomide combined with panobinostat in relapsed/refractory HL. Patients and Methods: In the phase I trial, previously treated patients with classical or lymphocyte‐predominant HL received escalating doses of lenalidomide on days 1 to 21 and panobinostat 3 times a week (TIW) every 28 days. Dose‐limiting toxicity (DLT) was defined during cycle 1. When the MTD was determined, a phase II study was conducted to determine overall response (OR). Results: Twenty‐four patients enrolled; 11 in the phase I and 13 in phase II portions. No DLTs were observed but 2 patients who received 25 mg lenalidomide and 20 mg panobinostat experienced neutropenia and thrombocytopenia > 14 days in cycle 2, leading to selection of 25 mg lenalidomide on days 1 to 21 and 15 mg panobinostat TIW for the phase II dose. In all 24 patients, Grade 3 to 4 toxicities consisted of neutropenia (58%), thrombocytopenia (42%), lymphopenia (25%), and febrile neutropenia (25%). OR was 16.7% (2 complete response [CR] and 2 partial response). One patient with CR had lymphocyte‐predominant HL and received 22 cycles. Median progression‐free survival and overall survival were 3.8 and 16.4 months, respectively. Conclusion: Although the combination of panobinostat and lenalidomide appears safe in patients with relapsed/refractory HL, the limited efficacy and significant rates of neutropenia and febrile neutropenia observed do not support further evaluation of this combination in HL.

Surveillance imaging in mantle cell lymphoma in first remission lacks clinical utility

Abstract Mantle cell lymphoma (MCL) is a heterogeneous disease with high relapse rates. Limited data guide the use of surveillance imaging following treatment. We constructed a retrospective cohort from two academic institutions of patients with MCL who completed first-line therapy and underwent follow-up for relapse, analyzing the effect of surveillance imaging on survival. Of 217 patients, 102 had documented relapse, with 38 (37%) diagnosed by surveillance imaging and 64 (63%) by other methods. Relapse diagnosis by surveillance imaging had no significant advantage in overall survival from diagnosis date (hazard ratio [HR] = 0.80, p = .39) or relapse date (HR = 0.72, p = .22). Of 801 surveillance images, PET/CT had a positive predictive value (PPV) of 24% and number needed-to-scan/treat (NNT) of 51 to detect one relapse, and CT had a PPV of 49% and NNT of 24. For MCL after first-line therapy, relapse detection by surveillance imaging was not associated with improved survival and lacks clinical benefit.

Complex karyotype in patients with mantle cell lymphoma predicts inferior survival and poor response to intensive induction therapy

Risk stratification of newly diagnosed patients with mantle cell lymphoma (MCL) primarily is based on the MCL International Prognostic Index (MIPI) and Ki‐67 proliferative index. Single‐center studies have reported inferior outcomes in patients with a complex karyotype (CK), but this remains an area of controversy.

Deferred treatment is a safe and viable option for selected patients with mantle cell lymphoma.

Abstract Prospective identification of candidates for deferred therapy is not standardized and many patients receive immediate therapy regardless of risk. We conducted a retrospective, multi-center cohort analysis of MCL patients with comprehensive clinical data to examine the use and safety of deferred therapy for newly diagnosed patients. Previously untreated patients ≥18 years-old with MCL diagnosed in 1993–2015 at five academic sites were included. Of 395 patients, 72 (18%) received deferred therapy (defined as receipt of first treatment >90 days following initial diagnosis). Patients receiving deferred therapy were more likely to have an ECOG performance status of 0 (67 versus 44% p = .001), have no B symptoms (83 versus 65% p = .003) and have normal LDH levels at diagnosis (87 versus 55% p < .001). In multivariable analysis, deferred therapy was not associated with a significant difference in OS (HR 0.64: 95% CI 0.22–1.84, p = .407).