ALBERT

Description: Abstract 2861 Poster Board II-837 Bcl-2 protein family has the unique capability to balance between the cell survival and death by regulating the expression of its individual members. AT-101 is a BH3 mimetic and a potent inducer of noxa and puma, the natural ligands of BH3 family proteins. It is known to bind and inhibit the anti-apoptotic functions of Bcl-2 family members Bcl-2 and Bcl-XL and Mcl-1. In vitro it has been shown to induce apoptosis in several tumor models systems including multiple myeloma. In this report we investigated the effect of AT-101 on a model cell line, BCWM.1 (a known WM cell line, BCWM.1/WT), representing Waldenström Macroglobulinemia. This disease is characterized by the presence of lymphoplasmacytic cells in the bone marrow and the secretion of IgM monoclonal protein into the serum. Several conventional therapies are available but the disease remains incurable. Therefore there remains a need to develop new therapies for this orphan disease. Recently, bortezomib (a proteasomal inhibitor) has shown promising anti-WM activity with enhanced responses when combined with traditional therapies. But continued treatment with bortezomib result in the development of resistance in the clinic. We developed an in vitro model of bortezomib resistance from BCWM.1 (hereafter referred as BCWM.1/BR). These cells also developed cross resistance to conventional therapies used for WM such as fludarabine and doxorubicin. Biological characterization of this cell line demonstrated Bcl-2 as a potentially important therapeutic target. We therefore assessed the effect of AT-101 to identify preclinically if this could be a potential clinical strategy in future. AT-101 induced a dose and time dependent inhibition in the viability of both BCWM.1/WT as well as BCWM.1/BR cells. Cell death was observed at as low as 1uM concentration of AT-101 and at 10uM a maximum of 50-70% death was observed by 24h. While BCWM.1/WT cells showed a significant death at 12h, treatment with AT-101 induced cell death in BCWM.1/BR cells as early as 6h. These results indicate that AT-101 induced a potent and quick inhibition in viability in BCWM.1/BR cells as compared to their parental wild type cells. Investigation into the mechanism of cell death showed that AT-101 induced apoptosis in a mitochondrial dependent pathway in these cells. A comparative analysis of the signal transduction pathways operated in BCWM.1/WT and BCWM.1/BR cells showed that many of the cellular activation and survival pathways such as AKT, ERK1/2 that are present in BCWM.1 cells are inhibited in the resistant cells. Interestingly, BCWM.1/BR cells expressed a fivefold increase in the Bcl-2 protein as compared to BCWM.1/WT cells suggesting a Bcl-2 dependent survival of these cells in the absence of other cellular activation and survival signals. Increased susceptibility of BCWM.1/BR cells to AT-101 thus can be understood to be a direct consequence of an increased expression of Bcl-2 and a dependence of the resistant cells on Bcl-2 family of anti-apoptotic proteins for their survival. Results presented in this report suggest that AT-101 has a unique therapeutic potential against Waldenström Macroglobulinemia that is independent of resistance to bortezomib. These observations highlight bcl-2 as a potential target, and AT-101 as possible therapeutic avenue for WM patients. Disclosures: Chanan-Khan: Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Millennium: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Immunogen: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau.

Description: Abstract 2699 Myeloid differentiation factor 88 (MYD88) is an adaptor protein that plays a key role in mediating innate immune response. Upon activation of toll-like (TLRs) or IL-1b receptors, MYD88 activates a signaling cascade that culminates in activation of NF-kB and expression of proinflammatory genes. Activating mutations in MYD88 have been reported in non-Hodgkin's lymphoma (NHL) tumors, including diffuse large B cell and marginal zones lymphoma. The most common MYD88 mutation described thus far is a single base pair mismatch resulting in an amino acid switch from lysine to proline at position 265 (MYD88L265P). MYD88L265P functions as a constitutively active MYD88 protein resulting in dysregulated NF-kB and STAT3 signaling. This mutation has recently been reported to be present in lymphomoplasmacytic lymphoma/Waldenstrom macroglobulinemia (LPL/WM) at a high frequency, ∼ 90% (Xu et al, ASH, #261, 2011). The discovery of MYD88L265P in a high percentage of LPL/WM tumors, and other subtypes of NHL, provides the basis for the identification and targeting of MYD88 dependent pathways. Additionally, the ability of this mutation to drive NF-kB-mediated cytokine expression combined with our finding that LPL/WM patients have elevated serum cytokines suggests that the MYD88 mutation may play a significant role in LPL/WM pathogenesis. We first wanted to confirm the incidence of the MYD88L265P mutation in LPL/WM and other subtypes of indolent lymphoma. Using Sanger sequencing we found that 57% (n=58) of LPL, 4% of MALT (n=23), 5% of nodal marginal zone (n=34), and 6% of splenic marginal zone (n=34) lymphomas harbor the MYD88L265P mutation, with all but 1 case being heterozygous. When we specifically looked at the LPL cases with WM, we found that 70% of WM tumors have the MYD88L265P mutation. In a validation cohort of WM (n=41), we found a similar mutation rate of 68%. Additionally, the WM cell line MWCL1 and the IgM secreting cell line BCWM.1 also harbor the MYD88L265P mutation. The prevalence of the MYD88L265P mutation in NHL, specifically WM and LPL, suggests that it may be a novel driver of lymphoma pathogenesis and a potential therapeutic target. However, it is not yet clear if this mutation correlates with activation of signaling pathways, or cell growth and survival in LPL/WM. To address these questions we first explored the possibility that the MYD88 signaling pathway is constitutively active in cells that express MYD88L265P. Upon activation of TLRs or IL-1b receptors, MYD88 forms a homodiamer and recruits IRAK1/4 and TRAF6 into a complex resulting in association and phosphorylation of TAK1 followed by activation of NF-kB. Using three cell lines that express MYD88L265P (BCWM, MWCL1, and OCI-Ly3), we looked for complex formation of MYD88, IRAK1/4, TRAF6, and TAK1. Immunoprecipitation of either endogenous IRAK1 or TAK1 revealed constitutive association with both TRAF6 and MYD88. We also detected phosphorylation of TAK1, and taken together, these data suggest that the MYD88 pathway is activated in cells that harbor the MYD88L265P mutation. We next wanted to confirm the significance of the MYD88 pathway on lymphoma cell growth. Using our cell lines we tested the effect of IRAK1/4, TAK1, and NF-kB inhibitors on cell proliferation. All MYD88L265P expressing cell lines were sensitive to the TAK1 and NF-kB inhibitors in a dose dependent manner (0–10 uM), however, we only saw inhibition of cell proliferation with the IRAK1/4 inhibitor at the highest dose (10 uM) in the BCWM cell line. These data suggest that cell proliferation is dependent on the MYD88 signaling pathway, with some variation being detected between cell line models and inhibitors. Because the MYD88 pathway has also been shown to drive cytokine secretion we next tested the impact of the IRAK1/4, TAK1, and NF-kB inhibitors on expression of IL-10. Using drug doses that were shown to inhibit cell proliferation, but not impact survival, we found that all three inhibitors reduced the level of IL-10 secreted by each of cell lines. In summary, our data confirm the high incidence on the MYD88L265P mutation in LPL/WM, we find that the MYD88 signaling pathway is constitutively activated in cells the harbor the mutation, and we show that cell proliferation and cytokine secretion are dependent on MYD88 signaling targets. These studies highlight the biologic significance of the MYD88L265P mutation in LPL/WM and suggest that the MYD88 signaling pathway may be a novel therapeutic target. Disclosures: No relevant conflicts of interest to declare.

Description: Introduction: Lenalidomide (L) is a compound in a new group of drugs called ImiDs® which have Immunomodulatory properties and with anti-tumor activity reported in multiple myeloma and MDS. Although the exact mechanism of action of L is unknown, they are reported to affect the tumor microenvironment through modulation of critical cytokines such as TNF-a, VEGF and IL-6. These cytokines also play an important role in pathogenesis of CLL. Based on these properties we have investigated and previously reported on the anti-leukemic activity of thalidomide in CLL. We subsequently conducted a phase II study with L, to evaluate its clinical activity in pts with relapse (rel) or refractory (ref) CLL. Here we present the results of this study. Patients and Methods: CLL pts with rel or ref disease were eligible. L was given at 25mg PO QD x 21 days followed by 7 days rest on a 28 day cycle. Absolute lymphocyte counts (ALC) were measured at Day 0, 7 and 30. Response was assessed at day 30 and monthly thereafter using the NCI-WG 1996 criteria. Pts with stable disease (SD) or better response were continued on therapy for a maximum of 12 months while those with progressive disease (PD) were to receive rituximab (R) (375mg/m2) added to L. Pts were considered evaluable for response if they completed at least 2 months of treatment. Target enrollment is 29 patients. Results: Twenty nine pts, median age of 64 years (range: 47–75) were enrolled. All pts are available for toxicity and 17 out of 29 pts available for response evaluation. Three pts on treatment are too early for response assessment while 9 pts are off study (2 withdrew consent and 5 got 〈 2 months of therapy due to toxicity). Response is reported based on evaluable pts. Complete remission (CR) was noted in 2/17 (11.7%) pts while partial remission (PR) was noted in 9/17 (52.9%) pts. Additional 5/17 (29.4%) pts, currently on treatment, achieved stable disease (SD). ORR (CR+PR) in the intent to treat population is 42.3% (11/26, excluding pts currently too early for response assessment). To date only 1 pt has PD after 3 months of L and is on LR per protocol. Toxicity: Flare reaction (tender swelling of lymph nodes and/or rash) was the most common SE noted in almost all pts. Other important SE were tumor lysis syndrome (n=2); grade 3/4 hematologic toxicities (n=7) and febrile neutropenia (n=3). Conclusion: This is the first study to report the clinical activity of L in pts with CLL. Our findings are encouraging and provide evidence of the anti-CLL activity of L. Although some of the pts did achieve a CR, longer follow-up will determine the durability of responses noted to date. Update results of this study along with toxicity profile of L in CLL will be presented at the meeting.

Description: Background: IMGN901 (huN901-DM1) is a novel conjugate of the cytotoxic maytansinoid, DM1, with the humanized CD56-binding monoclonal antibody, N901. Once bound to CD56 on a cancer cell, the conjugate is internalized and releases DM1. About 70% of multiple myeloma (MM) cases have surface expression of CD56. Preclinical investigations demonstrated significant in vitro and in vivo anti-myeloma activity of IMGN901. Objectives: To determine the maximum tolerated dose (MTD), the dose-limiting toxicities (DLTs), and pharmacokinetics (PK) of increasing doses of IMGN901 given for MM on a weekly schedule. Methods: Patients with relapsed or relapsed/refractory MM who have failed at least one prior therapy and have CD56-expressing MM received a single IV infusion of IMGN901 on 2 consecutive weeks every 3 weeks. Patients are enrolled in cohorts of 3 at each dose level, with DLT triggering cohort expansion. Results: Eighteen patients have received IMGN901 to date in this study - 3 patients each at 40, 60, 75, 90, 112, and 140 mg/m2/week. One patient experienced a DLT (grade 3 fatigue) on 140 mg/m2/week, and this cohort is being expanded to enroll up to 6 patients. No patients have experienced serious hypersensitivity reactions or evidence of presence of humoral responses against the huN901 antibody component (HAHA) or against the DM1 component (HADA). Preliminary PK results indicate an approximately linear relationship between dosing and observed maximal serum concentration. A confirmed minor response (MR) was documented in 3 heavily pretreated patients (1 patient each at 60, 90, and 112 mg/m2/week) using the European Bone Marrow Transplant criteria. Durable stable disease was reported at doses of 60, 90, 112, and 140 mg/m2/week. Of the 18 patients treated in the study, eight patients remained on treatment with IMGN901 for at least 15 weeks, five of these 8 patients remained on treatment for at least 24 weeks, and two of these 5 patients remained on treatment for at least 42 weeks. This phase I study provides preliminary evidence of safety as well as clinical activity of IMGN901 in patients with CD56-positive MM who have failed established MM treatments. Updated results of this ongoing study will be presented.

Description: Loss of function of ATM gene is associated with higher incidence of leukemia and lymphoma. ATM localized to 11q22.3-q23.1, is a tumor suppressor gene and plays an important role in cell cycle arrest, DNA repair mechanisms, and apoptosis. The incidence of deletion of ATM in MM remains unknown. Using a new commercially available fluorescently labeled DNA probe, we investigated the incidence of homozygous and heterozygous deletions of the ATM gene locus to explore its potential role in the pathogenesis of multiple myeloma (MM). Fifty-three MM pts were evaluated by fluorescence in situ hybridization (FISH) using the Vysis, Inc. LSI ATM (11q22.3) probe to assess the status of the ATM gene. LSI ATM (11q22.3) is a ~500 kb probe that hybridizes to the 11q22.3 region of chromosome 11 and spans the entire ~184 kb ataxia telangiectasia mutated (ATM) gene and several others. Probe copy number was assessed in each patient after analyzing at least 200 interphase nuclei. Only pts with〉 10% bone marrow involvements with malignant plasma cells were analyzed. Heterozygous ATM deletion was noted in 2/53 (3.7%) patients. These patients had 82% and 20% involvement of bone marrow (BM) with malignant plasma cells. Twenty-eight of 53 (%) patients showed an extra signal suggestive of trisomy 11, while no abnormality (2 signals) was noted in 23/53 (%) pts. There was no significant difference in the stage, B2M or extent of marrow involvement among patient with or without aberration of ATM gene. Up to 15–20% of the pts with B-cell lymphoproliferative disorders (CLL, mantle cell and other NHL) are reported to have ATM deletion suggesting a possible role of ATM protein in the pathogenesis of at least a subset of these disorders. Even though MM is a B-cell disorder, in our observation the prevalence of ATM deletion in these pts is uncommon and thus unlikely to be a major factor in the pathogenesis of MM.

Description: Atiprimod (N-N-diethl-8, 8-dipropyl-2-azaspiro [4,5] decane-2-propanamine) is an orally bioavailable cationic amphilic compound that inhibited STAT 3 activation in MM cells. It effectively blocked the signaling pathway of interleukin-6, resulting in activation of caspase 3 and apoptosis (Amit-Vazina et al, Br J Cancer, 2005). Atiprimod has also induced cytotoxicity in dexamethasone, doxorubicin, and melphalan resistant MM cell lines (Hamasaki et al, Blood, 2005). Based on these encouraging in vitro data, we initiated a multi-center, phase I trial of atiprimod for patients (pts) with refractory or relapsed MM who had 2 prior lines of therapy and serum creatinine less than 2 mg/dl. Primary objectives were to evaluate the safety of atiprimod in MM pts and to identify the maximum tolerated dose (MTD). Each cycle of treatment consisted of 14 consecutive days of oral atiprimod followed by 14 consecutive days without treatment. A standard phase I dose escalation was used to determine MTD with atiprimod dose levels at 30 mg, 60 mg, 90 mg, 120 mg, and 180 mg. To date, 14 pts from 4 centers have been enrolled with evaluable data in 12 patients. Median age was 60 (range 44–64); median prior lines of therapy were 4 (range 3–7); median duration from initial treatment to registration to this trial was 36 months (range 19–76). Cohorts of 3 patients have been treated at 30, 60, 90,120 mg/day and 2 patients have been enrolled at the 180 mg/day level; no cohorts have been expanded because of dose-limiting toxicity. Median number of cycles received by MM pts was 2 (range 1–5). Common Grade 1 toxicity events included diarrhea, liver enzyme elevation and dyspepsia. There were two Grade 2 toxicity events with 1 neutropenia at the 90 mg/day level and 1 diarrhea at the 120 mg/day level. One pt had Grade 3 transaminase elevation (peak AST 402, ALT 469 units/L, bilirubin 0.5 mg/dl) during the second cycle that resolved on its own during the 14 day period off treatment. Two patients with rapidly rising serum M proteins prior to enrollment had a transient but clear reduction of their M proteins (30% and 80%) after the first 14 days of atiprimod. Two pts at higher dose levels noted subjective improvement in their bone pain. Atiprimod was generally well tolerated in this heavily treated group of MM pts. The MTD has not been reached. Although there has been no response to date, clinical activity is not expected until higher dose levels are evaluated (240 mg/day, 300 mg/day, and 360 mg/day). After the MTD has been established, the study of atiprimod combinations should be considered based on the in vitro assessment of synergy with other active agents.

Description: Lenalidomide is an immunomodulatory drug that has demonstrated therapeutic activity in 2 independent phase II trials in patients with relapsed or refractory chronic lymphocytic leukemia (CLL). Based on those data a new phase II trial (CC-5013-CLL-001) was designed to compare 25 mg versus 10 mg, the doses used in those completed phase 2 studies. Patients were randomized in the initial protocol design to treatment with either 25 mg of lenalidomide daily for 21 out of each 28-day cycle, or with 10 mg of lenalidomide daily for 28 out of each 28–day cycle. However, when 5 out of 18 patients enrolled developed tumor lysis syndrome (TLS) resulting in 2 fatalities the protocol was amended to a phase I/II trial to determine a safe dose and schedule (Moutouh-de Parseval et al. J Clin Oncol2007, 25: 5047). In this ongoing phase I dose escalation study the safety of several lenalidomide doses was investigated. Patients with prior treatment with an alkylating agent and who have failed fludarabine were started on 2.5 mg of lenalidomide daily, followed by slow intra-patient dose escalation to 5 mg after 28 days. Doses were then escalated as tolerated by 5 mg every 28 days by initial cohort of 6 patients, until the maximum tolerated dose escalation level (MTDEL) was defined or a maximum dose of 25 mg daily. Patients were treated until disease progression, and all patients received TLS prophylaxis with hydration starting 3 days prior to lenalidomide treatment and continuing for at least the first 3 cycles. Seventeen patients, with a median age of 66 years (range 50–76), have been enrolled on the amended protocol. Patients had a median of 4 prior therapies (range 2–14), 56.3% of patients were refractory to fludarabine and 31.3% had prior alemtuzumab therapy. Among these, 77% of patients had bulky lymphadenopathy. Treatment is continued in 13 patients, while 4 patients have discontinued treatment (2 lack of therapeutic effect, 1 grade 4 thrombocytopenia at 2.5 mg every other day in a patient with preexisting thrombocytopenia, and 1 withdrew consent). During therapy, common toxicities included ≥ grade 3 neutropenia [4/17 (23.5%) at 2.5 mg; 3/7 (42.9%) at 5 mg; 2/3 (66.7%) at 10 mg], ≥ grade 3 thrombocytopenia [2/17 (11.8%) at 2.5 mg daily], and tumor flare reaction [TFR; 4/17 (23.5%) at 2.5 mg; 1/7 (14.3%) at 5 mg]. TFR ≥ grade 3 occurred in 2 patients, in one patient at the 2.5 mg dose and in one at the 5 mg dose which was effectively managed with non-steroidal anti-inflammatory drugs, corticosteroids and/or temporary interruption of treatment. On the amended protocol, TLS has not been observed in any patient except 1 in whom laboratory findings consistent with TLS was observed at the 2.5 mg dose. The patient was able to continue treatment without TLS recurrence. To date, the MTDEL has not been reached. At the time of data collection patients were not yet evaluable for clinical response. Preliminary data presented here demonstrate the safety of lenalidomide therapy administered by a step-wise dose escalation with an initial 2.5 mg starting dose in patients with heavily treated CLL. We further observe that use of prophylaxis, as well as frequent monitoring of patients, was effective in decreasing the incidence of TLS. Further data are needed to confirm the optimal dose for lenalidomide in the treatment of CLL. Additional safety data observed in the patients treated on this study will be presented at the meeting.

Description: In the past, the most common initial combination chemotherapy regimen used by most oncologists to treat B-cell lymphoma was the CHOP regimen. Although doxorubicin (DOX) is a major component of CHOP, it is associated with myelosuppression, alopecia, and potential cardiotoxicity. In vitro data has demonstrated synergistic activity between rituximab and certain drugs, including DOX. Because of D’s unique liposomal encapsulation, delivery, and toxicity profile, it may prove to be a more effective, less toxic anthracycline to combine with R. A formal Phase I/II trial to evaluate the safety and efficacy of R+D in pts with relapsing B-cell lymphoma was undertaken. R (375 mg/m2/dose) was given on day 1 and D (30 mg/m2/dose) on day 3 on q 21 day cycles for 6 cycles. Thirteen pts have completed therapy to date: 9F, 4M; Follicular lymphoma, grade 1 (n=6), grade 2 (n=1), grade 3 (n=3), DLBCL (n=3); med age = 63 (38–78); median number of prior Rx’s = 3 (range 1–8); prior anthracycline exposure (n=8). Overall, the combination of R + D was well-tolerated. Transient grade 3 cytopenias were noted in 3 pts with limited bone marrow reserve and grade 3 palmar/plantar erythrodysesthesia seen in 2 pts. All 13 pts completed the planned 6 courses of Rx. Objective responses were seen in 85% (11 of 13 pts), including 54% CR, 31% PR. Median time-to-progression has not been reached at 7+ months (range 4.5+ to 19+ months). No cardiac toxicity was seen and comparison of pre-Rx to post-Rx LVEF remained unchanged in 9, increased in 2, and decreased in 2 (yet still remaining 〉 50%). D + R immunochemotherapy is a well-tolerated, unique, non-cardiotoxic, and apparently effective salvage therapy for relapsed B-cell lymphoma. The study will continue until accrual of 42 pts has been reached.

Description: Despite the improved outcome in patients with DLBCL treated with rituximab (R) in combination with systemic chemotherapy (R + chemotherapy), a significant number of patients either relapse or fail to respond as a consequence of resistant disease. HDC and ASCT is the best therapeutic strategy to rescue relapsed/refractory DLBCL. It has been postulated that R+chemotherapy may lead to the selection of highly resistant lymphoma cells diminishing the clinical benefit of HDC and ASCT. Preliminary data from the CORAL study (Gisselbrecht et al Blood2007; 11:517a) suggest that overall response rates (ORR) and 2-year event free survival (EFS) are lower in R+chemotherapy relapsed/ refractory DLBCL when compared to DLBCL treated with chemotherapy alone. However the second randomization of this study to observation versus R-maintenance may affect the interpretation of the data. We retrospectively studied the difference in the outcomes of relapsed/refractory DLBCL patients following HDC and ASCT according to the front line therapy utilized (R+chemotherapy versus chemotherapy). Using the Roswell Park Cancer Institute (RPCI) Tumor Registry and the RPCI Blood and Marrow Transplant (BMT) Database we identified 130 patients with relapsed/refractory NHL who underwent for HDC + ASCT from 1991 to 2008. After excluding patients with a diagnosis other than B-cell DLBCL (patients with transformed NHL were excluded) and those patients receiving allo-BMT after progression from ASCT, the analysis included 63 refractory/ relapsed DLBCL. Demographic characteristics, clinical data, treatment history in the front line and salvage setting were collected. In addition response to salvage therapy and disease status at day +100 from ASCT was recorded for each subject. Progression free and overall survival were calculated from ASCT. Differences in clinical outcomes between patients receiving R as part of first line or salvage treatment and those treated with chemotherapy alone were evaluated by multivariate analysis, adjusting for significant univariate predictors of survival. The patient cohort included 34 males and 29 females with median age of 46 yrs (14.4 to 69.4). Two-thirds of the patients had advance disease and the majority had a Karnofsky performance status (KPS) of 80–100% at diagnosis. R+chemotherapy was given in the front line setting to 25 pts and while 38 received chemotherapy alone. In the salvage setting, 35 pts (55%) received R+chemotherapy. Most relapses (44 pts) occurred within 6 months of completion of front line therapy (17 pts with vs. 27 pts without R). The use of R in the front line setting was associated with significantly higher response rates (PR + CR) to salvage chemotherapy (P = 0.036) and better disease control on day +100 post-ASCT (P = 0.016) when compared to chemotherapy alone. In our cohort, there have been 32 deaths, 23 in chemotherapy treated DLBCL in contrast to 9 deaths in R+chemotherapy treated patients There was a significantly higher response rate post-ASCT for R+chemotherapy treated (as front-line or salvage) DLBCL versus chemotherapy alone (P = 0.007). A multivariate analysis demonstrated that achieving a CR pre-ASCT was the most important predictor of post-ASCT progression free and overall survival . In summary, our data suggest that the use of R + chemotherapy during frontline therapy and in the salvage setting yields better disease control and less incidence of chemo-resistant disease at the time of BMT. Applying the natural selection theory, the use of R+chemotherapy is expected to result in the development of resistant lymphomas. The length of time and the amount of R therapy that will render lymphoma cells resistant to chemo-immunotherapy remain to be determined. Standard doses of R (6 to 8 doses) do not appear to affect response to salvage therapy or autologous BMT outcomes. In our single institution analysis over the last 18 years, it appears that HDC + ASCT is an effective and viable option for patients with R +/− chemotherapy relapsed/refractory DLBCL.

Description: BACKGROUND: Bortezomib (btz, VELCADE®), a selective and reversible proteasome inhibitor, is approved for the second-line treatment of multiple myeloma (MM). There is a tendency for reactivation of varicella zoster virus (VZV;herpes zoster) among patients (pts) receiving immunosuppressive agents for cancer. Rates of VZV reactivation during btz therapy in phase 2 studies were reported to be 11% in SUMMIT and 13% in CREST. To investigate whether btz increases the incidence of VZV reactivation, data were reviewed from the phase 3 APEX trial of btz vs high-dose dexamethasone (dex) in pts with relapsed MM following 1–3 prior therapies. METHODS: The APEX trial was described previously [Richardson et al. N Engl J Med2005;352:2487–98]. Use of prophylactic anti-virals and anti-bacterials was not mandated by this protocol. RESULTS: Baseline characteristics, including age, prior ASCT, β2-microglobulin, and disease stage, were comparable between the btz and dex arms. The incidence of VZV reactivation was significantly higher with btz vs dex (13% [42/331] vs 5% [15/332], respectively; p=0.0002). Most VZV reactivation events in both arms were grade 1/2. Notably, the incidence of grade 3/4 events was similar between the two arms (1.8% [6/331] vs 1.5% [5/332]), as was the rate for serious adverse events (1.5% [5/331] vs 0.9%, [3/332], respectively). The incidence of other opportunistic infections, including VZV, was comparable between the btz and dex arms; 23% vs 20%, respectively. There were no deaths due to VZV reactivation in either arm. Median time to onset of VZV reactivation tended to be shorter in the btz arm vs dex, though this was not statistically significant (31 vs 51 days; p=0.221). At first assessment post VZV reactivation event, median ALC was significantly lower in the btz vs dex arm (1050 vs 1750 cells/μL; p=0.028). However, immediately prior to the event, median ALC was similar between arms (1030 vs 1100 cells/μL; p=0.529). CONCLUSIONS: Btz was associated with a higher incidence of VZV reactivation events than dex. The reasons for this are unclear and require further study. Preliminary evidence from recent studies has shown that this adverse event of btz could be overcome with the use of prophylactic acyclovir [Mateos et al. Blood 2006; Epub ahead of print].