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1.  Ibrutinib as initial therapy for elderly patients with chronic lymphocytic leukaemia or small lymphocytic lymphoma: an open-label, multicentre, phase 1b/2 trial 
The Lancet. Oncology  2013;15(1):48-58.
Summary
Background
Chemoimmunotherapy has led to improved numbers of patients achieving disease response, and longer overall survival in young patients with chronic lymphocytic leukaemia; however, its application in elderly patients has been restricted by substantial myelosuppression and infection. We aimed to assess safety and activity of ibrutinib, an orally administered covalent inhibitor of Bruton tyrosine kinase (BTK), in treatment-naive patients aged 65 years and older with chronic lymphocytic leukaemia.
Methods
In our open-label phase 1b/2 trial, we enrolled previously untreated patients at clinical sites in the USA. Eligible patients were aged at least 65 years, and had symptomatic chronic lymphocytic leukaemia or small lymphocytic lymphoma requiring therapy. Patients received 28 day cycles of once-daily ibrutinib 420 mg or ibrutinib 840 mg. The 840 mg dose was discontinued after enrolment had begun because comparable activity of the doses has been shown. The primary endpoint was the safety of the dose-fixed regimen in terms of frequency and severity of adverse events for all patients who received treatment. This study is registered with ClinicalTrials.gov, number NCT01105247.
Findings
Between May 20, 2010, and Dec 18, 2012, we enrolled 29 patients with chronic lymphocytic leukaemia and two patients with small lymphocytic lymphoma. Median age was 71 years (range 65–84), and 23 (74%) patients were at least 70 years old. Toxicity was mainly of mild-to-moderate severity (grade 1–2). 21 (68%) patients had diarrhoea (grade 1 in 14 [45%] patients, grade 2 in three [10%] patients, and grade 3 in four [13%] patients). 15 (48%) patients developed nausea (grade 1 in 12 [39%] patients and grade 2 in three [10%] patients). Ten (32%) patients developed fatigue (grade 1 in five [16%] patients, grade 2 in four [13%] patients, and grade 3 in one [3%] patient). Three (10%) patients developed grade 3 infections, although no grade 4 or 5 infections occurred. One patient developed grade 3 neutropenia, and one developed grade 4 thrombocytopenia. After a median follow-up of 22·1 months (IQR 18·4–23·2), 22 (71%) of 31 patients achieved an objective response (95% CI 52·0–85·8); four patients (13%) had a complete response, one patient (3%) had a nodular partial response, and 17 (55%) patients had a partial response.
Interpretation
The safety and activity of ibrutinib in elderly, previously untreated patients with symptomatic chronic lymphocytic leukaemia, or small lymphocytic lymphoma is encouraging, and merits further investigation in phase 3 trials.
Funding
Pharmacyclics, Leukemia and Lymphoma Society, D Warren Brown Foundation, Mr and Mrs Michael Thomas, Harry Mangurian Foundation, P50 CA140158 to Prof J C Byrd MD.
doi:10.1016/S1470-2045(13)70513-8
PMCID: PMC4134524  PMID: 24332241
2.  Overcoming the response plateau in multiple myeloma: A novel bortezomib-based strategy for secondary induction and high-yield CD34+ stem cell mobilization 
Purpose
This phase 2 study evaluated bortezomib-based secondary induction and stem cell mobilization in 38 transplant-eligible myeloma patients who had an incomplete and stalled response to, or had relapsed after, previous immunomodulatory drug-based induction.
Experimental design
Patients received up to six 21-day cycles of bortezomib plus dexamethasone, with added liposomal doxorubicin for patients not achieving partial response or better by cycle 2 or very good partial response or better (≥VGPR) by cycle 4 (DoVeD), followed by bortezomib, high-dose cyclophosphamide, and filgrastim mobilization. Gene expression/signaling pathway analyses were conducted in purified CD34+ cells post-bortezomib-based mobilization and compared against patients who received only filgrastim ± cyclophosphamide. Plasma samples were similarly analyzed for quantification of associated protein markers.
Results
The response rate to DoVeD relative to the pre-DoVeD baseline was 61%, including 39% ≥VGPR. Deeper responses were achieved in 10 of 27 patients who received bortezomib-based mobilization; post-mobilization response rate was 96%, including 48% ≥VGPR, relative to the pre-DoVeD baseline. Median CD34+ cell yield was 23.2 × 106 cells/kg (median of 1 apheresis session). After a median follow-up of 46.6 months, median progression-free survival was 47.1 months from DoVeD initiation;5-year overall survival rate was 76.4%. Grade ≥3 adverse events included thrombocytopenia (13%), hand-foot syndrome (11%), peripheral neuropathy (8%), and neutropenia (5%). Bortezomib-based mobilization was associated with modulated expression of genes involved in stem cell migration.
Conclusion
Bortezomib-based secondary induction and mobilization could represent an alternative strategy for elimination of tumor burden in immunomodulatory drug-resistant patients that does not impact stem cell yield.
doi:10.1158/1078-0432.CCR-12-1429
PMCID: PMC4020015  PMID: 23357980
Bortezomib; CD34+; myeloma; secondary induction; stem cell mobilization
3.  A Phase 1 Study of Bendamustine and Melphalan Conditioning for Autologous Stem Cell Transplantation in Multiple Myeloma 
Bendamustine has efficacy in multiple myeloma with a toxicity profile limited to myelosuppression. We hypothesized that adding bendamustine to autologous stem cell transplant conditioning in myeloma would enhance response without significant additional toxicity. We conducted a phase 1 trial adding escalating doses of bendamustine to the current standard conditioning of melphalan 200mg/m2. Twenty-five subjects were enrolled onto 6 cohorts. A maximum tolerated dose was not encountered and the highest dose level cohort of bendamustine 225mg/m2 + melphalan 200mg/m2 was expanded to further evaluate safety. Overall, there was no transplant related mortality and only 1 grade 4 dose-limiting toxicity was observed. Median number of days to neutrophil and platelet engraftment was 11 (9-14) and 13 (10-21), respectively. Disease responses at day +100 post-transplant were: progression in 5 (21%), partial response in 1 (4%), very good partial response in 7 (33%), complete response in 1 (4%), and stringent complete response in 9 (38%). Six patients (24%) with preexisting high-risk disease died from progressive myeloma during study follow-up, all at or beyond 100 days after ASCT. Bendamustine up to a dose of 225mg/m2 added to autologous stem cell transplant conditioning with high dose melphalan in multiple myeloma did not exacerbate expected toxicities.
doi:10.1016/j.bbmt.2013.02.013
PMCID: PMC3985064  PMID: 23454184
4.  Clarithromycin (Biaxin)-lenalidomide-low-dose dexamethasone (BiRd) versus lenalidomide-low-dose dexamethasone (Rd) for newly diagnosed myeloma 
American journal of hematology  2010;85(9):664-669.
The objective of this case–matched study was to compare the efficacy and the toxicity of the addition of clarithromycin (Biaxin) to lenalidomide/low-dose dexamethasone (BiRd) vs lenalidomide/low-dose dexamethasone (Rd) for newly diagnosed myeloma. Data from 72 patients treated at the New York Presbyterian Hospital–Cornell Medical Center were retrospectively compared to an equal number of matched pair mates selected among patients seen at the Mayo Clinic who received Rd. Case matching was blinded and was performed according to age, gender, and transplant status. On intention-to-treat analysis, complete response (45.8% vs 13.9%, p<0.001) and very-good-partial-response or better (73.6% vs 33.3%, p<0.001) were significantly higher with BiRd. Time-to-progression (median 48.3 vs 27.5 months, p=0.071), and progression-free survival (median 48.3 vs 27.5 months, p=0.044) were higher with BiRd. There was a trend toward better OS with BiRd (3-year OS: 89.7% vs 73.0%, p=0.170). Main grade 3–4 toxicities of BiRd were hematological, in particular thrombocytopenia (23.6% vs 8.3%, p=0.012). Infections (16.7% vs 9.7%, p=0.218) and dermatological toxicity (12.5% vs 4.2%, p=0.129) were higher with Rd. Results of this case-control analysis suggest that there is a significant additive value when clarithromycin is added to Rd. Randomized phase III trials are needed to confirm these results.
doi:10.1002/ajh.21777
PMCID: PMC3956597  PMID: 20645430
myeloma; newly diagnosed; therapy; lenalidomide
5.  Targeting BTK with Ibrutinib in Relapsed Chronic Lymphocytic Leukemia 
BACKGROUND
The treatment of relapsed chronic lymphocytic leukemia (CLL) has resulted in few durable remissions. Bruton's tyrosine kinase (BTK), an essential component of B-cell–receptor signaling, mediates interactions with the tumor microenvironment and promotes the survival and proliferation of CLL cells.
METHODS
We conducted a phase 1b–2 multicenter study to assess the safety, efficacy, pharmacokinetics, and pharmacodynamics of ibrutinib (PCI-32765), a first-in-class, oral covalent inhibitor of BTK designed for treatment of B-cell cancers, in patients with relapsed or refractory CLL or small lymphocytic lymphoma. A total of 85 patients, the majority of whom were considered to have high-risk disease, received ibrutinib orally once daily; 51 received 420 mg, and 34 received 840 mg.
RESULTS
Toxic effects were predominantly grade 1 or 2 and included transient diarrhea, fatigue, and upper respiratory tract infection; thus, patients could receive extended treatment with minimal hematologic toxic effects. The overall response rate was the same in the group that received 420 mg and the group that received 840 mg (71%), and an additional 20% and 15% of patients in the respective groups had a partial response with lymphocytosis. The response was independent of clinical and genomic risk factors present before treatment, including advanced-stage disease, the number of previous therapies, and the 17p13.1 deletion. At 26 months, the estimated progression-free survival rate was 75% and the rate of overall survival was 83%.
CONCLUSIONS
Ibrutinib was associated with a high frequency of durable remissions in patients with relapsed or refractory CLL and small lymphocytic lymphoma, including patients with high-risk genetic lesions. (Funded by Pharmacyclics and others; ClinicalTrials.gov number, NCT01105247.)
doi:10.1056/NEJMoa1215637
PMCID: PMC3772525  PMID: 23782158
6.  Stem Cell Mobilization with Cyclophosphamide Overcomes the Suppressive Effect of Lenalidomide Therapy on Stem Cell Collection in Multiple Myeloma 
A total of 28 treatment-naïve patients with stage II or III multiple myeloma (MM) were treated with the combination of clarithromycin, lenalidomide, and dexamethasone (BiRD). Stem cells were collected following granulocyte- colony stimulating factor (G-CSF) or cyclophosphamide (Cy) plus G-CSF mobilization at maximum response. Sufficient stem cells for 2 autologous stem cell transplants were collected from all patients mobilized with Cy plus G-CSF, versus 33% mobilized with G-CSF alone (P<.0001). The duration of prior lenalidomide therapy did not correlate with success of stem cell harvests (P = .91). In conclusion, Cy can be added to G-CSF for stem cell mobilization to successfully overcome the suppressive effect of prior treatment with lenalidomide.
doi:10.1016/j.bbmt.2008.04.008
PMCID: PMC3626097  PMID: 18541199
Autologous stem cell transplantation; Cyclophosphamide; Lenalidomide; Multiple myeloma; Stem cell mobilization
7.  Atypical serum immunofixation patterns frequently emerge in immunomodulatory therapy and are associated with a high degree of response in multiple myeloma 
British journal of haematology  2008;143(5):654-660.
Summary
The M-protein is the major reference measure for response in multiple myeloma (MM) and its correct interpretation is key to clinical management. The emergence of oligoclonal banding is recognized as a benign finding in the post-autologous stem cell transplantation setting (ASCT) for MM but its significance during non-myeloablative therapy is unknown. In a study of the immunomodulatory combination BiRD, (lenalidomide and dexamethasone with clarithromycin), we frequently detected the emergence of mono- and oligo-clonal immunoglobulins unrelated to the baseline diagnostic M-protein. The new M-proteins seen on serum immunofixation electrophoresis were clearly different in either heavy or light chain component(s) from the original M-spike protein and were called atypical serum immunofixation patterns (ASIPs). Overall, 24/72 (33%) patients treated with BiRD developed ASIPs. Patients who developed ASIPs compared with patients treated with BiRD without ASIPs, had a significantly greater overall response (100% vs. 85%) and complete response rates (71% vs. 23%). ASIPs were not associated with new clonal plasma cells or other lymphoproliferative processes, and molecular remissions were documented. This is the first time this phenomenon has been seen with regularity in non-myeloablative therapy for MM. Analogous to the ASCT experience, ASIPs do not signal incipient disease progression, but rather herald robust response.
doi:10.1111/j.1365-2141.2008.07374.x
PMCID: PMC3626496  PMID: 18950461
lenalidomide; multiple myeloma; atypical serum immunofixation patterns; M-protein
8.  MAGE-A inhibits apoptosis in proliferating myeloma cells through repression of Bax and maintenance of survivin 
Purpose
The type I Melanoma Antigen GEnes (MAGEs) are commonly expressed in cancers, fueling speculation that they may be therapeutic targets with oncogenic potential. They form complexes with RING domain proteins that have E3 ubiquitin ligase activity and promote p53 degradation. MAGE-A3 was detected in tumor specimens from patients with multiple myeloma and its expression correlated with higher frequencies of Ki-67+ malignant cells. In this report, we examine the mechanistic role of MAGE-A in promoting survival of proliferating multiple myeloma cells.
Experimental Design
The impact of MAGE-A3 expression on survival and proliferation in vivo was examined by immunohistochemical analysis in an independent set of tumor specimens segregated into two groups; newly diagnosed, untreated patients and patients who had relapsed after chemotherapy. The mechanisms of MAGE-A3 activity were investigated in vitro by silencing its expression by shRNA interference in myeloma cell lines and primary cells and assessing the resultant effects on proliferation and apoptosis.
Results
MAGE-A3 was detected in a significantly higher percentage of relapsed patients compared to newly diagnosed, establishing a novel correlation with progression of disease. Silencing of MAGE-A demonstrated that it was dispensable for cell cycling, but was required for survival of proliferating myeloma cells. Loss of MAGE-A led to apoptosis mediated by p53-dependent activation of pro-apoptotic Bax expression and by reduction of survivin expression through both p53-dependent and independent mechanisms.
Conclusions
These data support a role for MAGE-A in the pathogenesis and progression of multiple myeloma by inhibiting apoptosis in proliferating myeloma cells through two novel mechanisms.
doi:10.1158/1078-0432.CCR-10-1820
PMCID: PMC3131419  PMID: 21565982
MAGE; Cancer-Testis Antigen; multiple myeloma; apoptosis; survivin
9.  Durable Responses with the Metronomic Regimen RT-PEPC in Elderly Patients with Recurrent Mantle Cell Lymphoma 
Cancer  2010;116(11):2655-2664.
BACKGROUND
Targeting the tumor microenvironment and angiogenesis is a novel lymphoma therapeutic strategy. We report safety, activity and angiogenic profiling with the RT-PEPC regimen (rituximab with thalidomide, and prednisone, etoposide, procarbazine and cyclophosphamide) in recurrent mantle cell lymphoma (MCL).
METHODS
RT-PEPC includes induction (months 1–3) of weekly rituximab × 4, daily thalidomide (50 mg) and PEPC, then maintenance thalidomide (100 mg), oral PEPC titrated to neutrophil count, and rituximab every 4 months. Endpoints included safety, efficacy, quality of life (QoL), and translational studies including tumor angiogenic phenotyping, plasma VEGF and circulating endothelial cells.
RESULTS
Twenty-five pts were enrolled (22 evaluable) with median age 68 yrs (range 52–81), 24 (96%) stage III/IV, 18 (72%) IPI 3–5, 20 (80%) high risk MIPI, median 2 prior therapies (range 1–7), and 15 (60%) bortezomib progressors. At a median follow-up of 38 months, ORR was 73% (32% CR/CRu, 41% PR, n=22) and median PFS 10 months. Four CRs are ongoing (6+, 31+, 48+ and 50+ months). Toxicities included grade 1–2 fatigue, rash, neuropathy and cytopenias including grade 1–2 thrombocytopenia (64%) and grade 3–4 neutropenia (64%). Two thromboses and 5 grade 3–4 infections occurred. QoL was maintained or improved. Correlative studies demonstrated tumor autocrine angiogenic loop (expression of VEGFA and VEGFR1) and heightened angiogenesis and lymphangiogenesis in stroma. Plasma VEGF and circulating endothelial cells trended down with treatment.
CONCLUSIONS
RT-PEPC has significant and durable activity in MCL, with manageable toxicity and maintained QoL. Novel low-intensity approaches warrant further evaluation, potentially as initial therapy in elderly patients.
doi:10.1002/cncr.25055
PMCID: PMC3004744  PMID: 20235190

Results 1-9 (9)