ALBERT

Description: Recently, a significant improvement in time to progression (TTP) was reported for pegylated liposomal doxorubicin (PLD) + bortezomib combination therapy vs. bortezomib monotherapy in a phase III randomized trial in relapsed or refractory multiple myeloma (RRMM) (Orlowski, JCO 2007). This pre-specified analysis assessed the efficacy of PLD+bortezomib in RRMM based on the number of prior lines of therapy and previous anthracycline exposure status. Patients with ≥1 prior therapy were randomized to receive PLD at 30 mg/m2 on day 4 and bortezomib at 1.3 mg/m2 on days 1, 4, 8, and 11, or bortezomib alone for up to eight 21-day cycles, or at least 2 cycles beyond CR, or optimal response unless disease progression, or unacceptable toxicities occurred. The baseline beta-2 microglobulin levels were comparable between the subgroup with ≥2 prior treatments and that with 1 treatment (median 3.98 vs. 4.01 mg/L), as well as between anthracycline-exposed and -naïve patients (median 3.91 vs. 4.55 mg/L). The improved TTP reported previously with PLD+bortezomib over bortezomib in the total study population was similarly observed in all four subgroups of patients (patients with ≥2 lines of prior therapy or 1 prior therapy, anthracycline-exposed (median 144 mg/m2 in both treatment arms) or -naïve groups (Table)), indicating a consistent therapeutic benefit favoring the PLD+bortezomib combination. Furthermore, TTP was comparable for the PLD+bortezomib combination between groups with ≥2 lines of prior therapy vs. 1 prior therapy (heterogeneity test, p=0.523), as well as patients who were anthracycline-exposed or -naïve (heterogeneity test, p=0.716). Incidence of treatment-related SAEs, grade 3/4 neuropathy, and symptomatic cardiac events was comparable between treatment arms in each subgroup (Table). PLD-related hand-foot syndrome was also

Description: Investigation of minimal residual disease (MRD) in acute leukemias by immunophenotyping is increasingly used for disease monitoring. Most MRD studies using flow cytometry techniques have focused on patients treated with conventional chemotherapy, while information on its value in patients undergoing allogeneic transplantation is scanty. The aim of the present study is to evaluate whether or not immunophenotypical assessment of MRD could also be a valuable tool in patients undergoing allogeneic transplantation for acute leukaemia. For that purpose we have analysed the level of MRD before and after (month +3) transplantation, by multiparameter flow cytometry, in a series of 38 acute leukaemia patients (26 ALL cases -20 cases in 1st CR and 6 in 2nd CR- and 12 AML cases -all of them in 1st CR), that showed an aberrant immunophenotype at diagnosis. Although the level of MRD in the BM obtained before transplantation showed a tendency to predict RFS, differences did not reached statistical significance. By contrast, the evaluation of the BM obtained 3 months after allo-transplantation had significant prognostic value. Thus, patients with low MRD levels (

Description: Multiple myeloma (MM), like other monoclonal gammopathies, frequently causes impairment of the κ/λ serum free light chain (sFLC) ratio. Based on a short serum half-life of FLC as compared to the complete immunoglobulin (hours versus days), early normalization of κ/λ could predict for response to treatment. As part of a randomized, controlled study, we examined the association between normalization of the κ/λ ratio after one or two 21-day cycles of treatment with bortezomib (B) ± pegylated liposomal doxorubicin (PLD) among patients with relapsed/refractory multiple myeloma. Patients with ≥1 prior therapy were randomized to receive PLD 30 mg/m2 on day 4 and B 1.3 mg/m2 on days 1, 4, 8, and 11, or B alone for up to eight 21-day cycles, or at least 2 cycles beyond complete response (CR) or optimal response, unless disease progression or unacceptable toxicities occurred (Orlowski, JCO 2007). κ/λ measurements were carried out prior to the start of therapy and at the end of each cycle through the entire study period using an immunoassay (Freelite, The Binding Sites, Birmingham, UK). Serial sFLC κ/λ measurements were available on sera from 487 patients with baseline values out of a total of 646 study patients. At baseline, 458/487 patients (94%) had an abnormal κ/λ ratio (1.65). The percentage of patients with normal κ/λ ratio increased from 6% at baseline to 12% after cycle 1, 17% after cycle 2 and 23% by the end of the study. Among patients with a normal κ/λ ratio after cycle 1 (n=54), the median time to progression (TTP) was 345 days compared to 225 days in patients with abnormal ratios (n=395, p=0.0005, HR=0.47 favoring normalization). Following cycle 2, TTP was 325 days vs. 224 days (p≤0.001) in patients with normal (n=72) vs. abnormal (n=348) ratios, respectively. Additionally, patients with normalized sFLC ratios showed significantly higher overall response rates as compared to those with persistently abnormal ratios (≥ partial response [PR] 73% vs. 47%, p=0.001 following cycle 1, and 77% vs. 48%, p

Description: Introduction: Liver metabolism has two fundamental types of enzymes. Phase two enzymes include GlutathioneS-transferases (GST), with three main variants: GST-M1, GST-T1 and GST-P1. Individual differences in these enzymes could influence their detoxificating capacity. Aim: To study the influence of several genetic GST liver enzymes variants in the development of liver Sinusoidal Obstruction Syndrome (SOS) in patients with multiple myeloma (MM) that received BUMEL as conditioning regimen for Autologous Stem Cell Transplantation (ASCT). Patients: 91 patients with MM - included in Spanish protocol Myeloma 2000 that had received BUMEL as conditioning schedule for ASCT - have been studied; 12 of them had developed SOS. 62 healthy individuals as well as 12 patients with monoclonal gammapathy of uncertain significance (MGUS) were also studied. Methods: Three genotype variants of GST enzymes were studied: presence or absence of GST-M1, GST-T1 and GST-P1 polymorphism Ile105Val by real time PCR in light cycler v2 or ABI PRISM 7900HT thermocyclers. Associations between variables were studied by X2 and exact Fisher test. Logistic regression analysis was performed to calculate Odds ratios and relative risk of SOS development. Results: Significant differences (p〉0.0001) were found in the prevalence of homozygous genotype GST-P1 Ile105Val comparing the group of patients with MM and SOS (5 of 12, 41%) and the rest of MM patients without SOS (5 of 79, 6%). This genotype was present in 17% of healthy individuals and MGUS. The genotype absence of GST-M1 was observed in 33% (4/ 12) of MM patients with SOS, 46% (37/79) of MM patients without SOS (p=0.38), 56% of controls and 71% of MGUS. The genotype absence of GST-T1 was observed in 50% (6/ 12) of MM patients with SOS, 27% (22/79) without SOS (p=012), 19% (16/62) of healthy individuals and 21% of MGUS. 33% (4/12) of MM patients with SOS presented the absence of GST-T1 genotype and the presence of homozygous GST-P1 Ile105Val and none of the patients with MM without SOS (p=0,000) presented these genotypes. The only factor associated to development of SOS in regression study was the presence of genotype GST-P1 Ile105Val in homozygosis (OR 10.57 CI 2.45–45.6 p=0.002). Conclusions: The genotype absence of GST-T1 together with the homozygous GST-P1 Ile105Val polymorphism, especially the latter, should be considered as new risk factors in the development of SOS in MM undergoing ASCT conditioning regimen with BUMEL.

Description: We explored the ability of the proteasome inhibitor bortezomib, which prevents nuclear factor κB (NF-κB) activation, to block T-cell activation, proliferation, and survival within alloreactive compared with resting T cells. For this purpose, T cells were stimulated with PHA, αCD3/αCD28, or allogeneic dendritic cells or through mixed lymphocyte cultures. NF-κB expression increased in activated T lymphocytes compared with resting T cells. Of interest, the higher the NF-κB expression, the more intense the proliferative blockade induced by bortezomib. Moreover, after mixed lymphocyte reaction (MLR) cultures, alloreactive T cells were 2 logs more sensitive to bortezomib-induced apoptosis than the resting T-cell counterpart. This effect was due to a selective induction of apoptosis among activated T cells that was related to caspase activation and cleavage of the antiapoptotic bcl-2 protein and was partially abolished by the addition of the pancaspase inhibitor Z-VAD-FMK. In addition, after secondary MLR, the number of activated T cells was significantly reduced among T lymphocytes previously cultured with bortezomib when cells from the same donor were used as stimulating cells. By contrast, when third-party donor cells were used as stimulating cells, no significant differences were observed between T lymphocytes previously exposed or not to the drug, indicating a highly specific depletion of T lymphocytes alloreactive against primary donor antigens. The addition of bortezomib decreased not only the proliferation and viability of activated T lymphocytes but also the levels of IFNγ and IL-2, which were significantly decreased among activated T cells cultured with bortezomib at doses ranging from 10 to 100 nM. In conclusion, at concentrations reached in the clinical setting, bortezomib induces selective apoptosis and decreases Th1 response among alloreactive T lymphocytes while it barely affects unstimulated T cells. These results establish the basis for the clinical use of bortezomib in the management of graft-versus-host disease (GVHD).

Description: Introduction Previous results of an open-label, randomized, controlled, multicenter phase III study (DOXIL-MMY-3001) demonstrated that bortezomib+pegylated liposomal doxorubicin (PLD) was superior to bortezomib monotherapy in treating subjects with relapsed or refractory multiple myeloma (MM) whose disease had failed one or more lines of prior therapy. The risk of developing disease progression was significantly reduced by 45% with bortezomib+PLD (median time to progression (TTP) with bortezomib+PLD: 9.3 months, bortezomib: 6.5 months; HR=1.82, 95% confidence interval (CI) [1.41, 2.35]; p=0.000004). In the interim analysis, the 15-month overall survival (OS) rate for bortezomib+PLD was 76% (95% CI [70%, 83%]) compared with 65% (95% CI [58%, 73%]) for bortezomib alone (p=0.03)(Orlowski et al JCO 25: 3892-3901, 2007). A protocol-defined analysis of the final survival data of this study is provided here. Methods Subjects with confirmed MM, ECOG status 0 to 1, platelets ≥75,000/mm3, hemoglobin ≥8.0 g/dL, absolute neutrophils ≥1,000/mm3, and creatinine clearance ≥30 mL/min were randomized to bortezomib (bortezomib 1.3 mg/m2, intravenous, days 1, 4, 8, and 11 of an every 21-day cycle), or bortezomib+PLD (same bortezomib+PLD 30 mg/m2 intravenous on day 4). Randomization was stratified according to serum β2-microglobulin levels (≤2.5, 〉2.5 and ≤5.5, or 〉5.5 mg/L) and response to prior treatment (response followed by progression, or primary refractory). The primary endpoint was TTP; secondary efficacy endpoints included overall survival, progression-free survival (PFS) and overall response rate (complete response [CR] + partial response [PR]). Results A total of 646 subjects (bortezomib+PLD: 324; bortezomib: 322) were randomized between December 2004 and March 2006. In the pre-planned interim analysis, the study met its primary and other secondary end points. The study continued for long-term survival follow-up. At the clinical cutoff of 16 May, 2014, for the final survival analysis with a median follow-up of 103 months, 79% of subjects were dead (bortezomib+PLD: 253 [78%]; bortezomib: 257 [80%]), 6% withdrew consent, 4% were lost to follow-up, and 11% were still alive. Median OS in bortezomib+PLD–treated subjects was 33.0 months (95% CI [28.9, 37.1]) versus 30.8 months (95% CI [25.2, 36.5]) in bortezomib-treated subjects (HR=1.05, 95% CI [0.88, 1.25]; p=0.6068). The types of salvage therapies utilized included dexamethasone (49.1%), thalidomide (31.0%), cyclophosphamide (28.5%), melphalan (22.9%), lenalidomide (21.8%), bortezomib (20.4%) and doxorubicin (8.0%), which were well-balanced between the two treatment groups. Conclusion Despite inducing a superior TTP, long-term follow-up revealed that PLD+bortezomib-treatment did not improve the OS compared with bortezomib alone in subjects with relapsed or refractory MM. The inability to confirm the early survival advantage may be due to the effects of subsequent lines of therapy, and underscores the need for long-term follow-up of phase III trials. Disclosures Orlowski: Onyx Pharmaceuticals: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Millennium Pharmaceuticals: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding. Sonneveld:Orthobiotech;: Consultancy. Bladé:Celgene: Grant support, Grant support Other, Honoraria, Membership on an entity's Board of Directors or advisory committees; Janssen: Grant support Other, Honoraria, Membership on an entity's Board of Directors or advisory committees. Hajek:Janssen: Honoraria; Celgene: Consultancy, Honoraria; Merck: Consultancy, Honoraria. Spencer:Hospira: Research Funding. Robak:MorphoSys AG: Research Funding. Dmoszynska:Johnson & Johnson Pharmaceutical Research & Development: Research Funding. Horvath:Johnson & Johnson Pharmaceutical Research & Development: Consultancy, Research Funding. Sutherland:OrthoBiotech: Consultancy. Xiu:Johnson & Johnson Pharmaceutical Research & Development: Consultancy, Employment, Equity Ownership. Parekh:Johnson & Johnson Pharmaceutical Research & Development: Employment, Equity Ownership. Miguel:Janssen Cilag: Consultancy, Honoraria.

Description: One randomized trial showed that tandem transplant resulted in a significantly longer EFS and OS in patients failing to achieve CR or near-CR with a single transplant. However, other studies failed to show benefit from a second transplant. The aim of our study was to investigate the efficacy in terms of response improvement and survival from a second transplant intensification in patients with chemosensitive disease who failed to achieve CR or near-CR with a first high-dose procedure. Patients diagnosed with MM from Oct 1999 to Dec 2004 younger than 70 years received 6 courses of VBMCP/VBAD and responding patients were intensified with busulphan/melphalan or MEL-200 followed by stem cell support. Patients not achieving CR or near-CR were planned to undergo a second transplant (second auto with CVB - cyclophosphamide, etoposide and BCNU - or MEL-200 intensification or an allo-RIC with Fludarabine/MEL-140 conditioning, if sibling donor available). Eighty-eight patients received a second autologous transplant while 26 underwent an allo-RIC. Thirty-seven percent of the patients given a second autologous transplant improved their response status (CR 11%, near-CR: 6%, PR: 9% and MR 11%) while 63% showed “no change”, progressive disease or early death. A response was observed in 45% of patients undergoing the allo-RIC (CR: 33%, PR: 4%, MR: 8%). The CR rate was significantly higher with allo-RIC (33% vs. 11%, p= 0.02). There was a trend towards a higher TRM with the allo-RIC (5% vs. 16%, p=0.09). Although the median EFS (26 vs 19 m) and OS (57 m vs not reached in allo-RIC) from the second high-dose procedure were not significantly different, there is a plateau in the “allo-RIC” group beyond 3 years of the second procedure not observed in the autologous arm. Conclusions: an allo-RIC transplant after an autologous procedure results in a significantly higher CR rate than a second autologous transplant, and despite the lack of significant differences in survival between the two transplant modalities, there is a plateau in the allogeneic group not observed in the autologous arm.

Description: Reduced-intensity allogeneic hematopoietic cell transplantation (HCT) is increasingly considered as a therapeutic option for young patients with advanced chronic lymphocytic leukemia (CLL). We report 59 consecutive CLL patients who underwent allogeneic HCT following fludarabine and melphalan conditioning at four different institutions. For graft-versus-host disease (GVHD) prophylaxis, 38 patients (Cohort 1) received alemtuzumab (20–100 mg) and cyclosporine; and 21 patients (Cohort 2) received cyclosporine plus methotrexate or mycophenolate. Donors were 47 HLA-matched siblings and 12 unrelated volunteers, 6 of whom were mismatched. Median age at transplant was 53 (range, 34–64) years and median number of previous chemotherapy regimens was 3 (1–6), with 39% of patients being refractory to fludarabine. Nine patients had previously failed an autologous HCT. Fluorescent in-situ hybridization and IgVH mutation status data were available in 33 (56%) and 31 (53%) patients, respectively, being unfavorable (17p- or 11q-) in 22 (67%) and unmutated in 24 (77%) of them. All but 1 patient engrafted, and the median interval to neutrophil recovery (〉 0.5 × 109/l) was 14 (range, 10–36) days. Twenty patients (34%), mostly from Cohort 1, received escalated donor lymphocyte infusions due to mixed chimerism or disease relapse. The overall complete response rate among 53 patients with measurable disease at the time of transplantation was 70%, whereas 21% had stable disease. Grade II-IV acute GVHD was observed in 14 (37%) and 12 (57%) patients from Cohorts 1 and 2, respectively (P = 0.17). Extensive chronic GVHD was observed in 3 (8%) and 10 (48%) patients from Cohorts 1 and 2, respectively (P 〈 0.01). The incidence of cytomegalovirus reactivation was not significantly different between cohorts (67% vs 47%, P = 0.23). With a median follow-up of 36 (range, 3–99) months for survivors, 18 (30%) patients have died, 3 of progressive disease and 15 of transplant-related complications. The 3-year overall survival (OS), progression-free survival (PFS) and non-relapse mortality were 66% (95% CI 48–84%), 38% (20–56%) and 21% (8–34%), respectively, for Cohort 1 and 65% (44–86%), 54% (32–76%) and 29% (10–48%) for Cohort 2 (P = 0.66; P = 0.33; and P = 0.53). Despite low patient numbers, alemtuzumab seemed particularly effective for unrelated donor recipients, with a 3-year OS and PFS of 54% and 40% for Cohort 1; and 33% and 0% for Cohort 2 (P = 0.02 and P = 0.07). In conclusion, results with reduced-intensity allogeneic HCT are promising for these poor-prognosis patients. Furthermore, the alemtuzumab-based regimen was effective in reducing the chronic GVHD rate with no negative effect on NRM, PFS or OS.

Description: Initial analysis of the Assessment of Proteasome Inhibition for Extending Remissions (APEX) trial of relapsed multiple myeloma patients showed significantly longer time to progression, higher response rate, and improved survival with single-agent bortezomib versus high-dose dexamethasone. In this updated analysis (median follow-up: 22 months), survival was assessed in both arms, and efficacy updated for the bortezomib arm. Median survival was 29.8 months for bortezomib versus 23.7 months for dexamethasone, a 6-month benefit, despite substantial crossover from dexamethasone to bortezomib. Overall and complete response rates with bortezomib were 43% and 9%, respectively; among responding patients, 56% improved response with longer therapy beyond initial response, leading to continued improvement in overall quality of response. Higher response quality (100% M-protein reduction) was associated with longer response duration; response duration was not associated with time to response. These data confirm the activity of bortezomib and support extended treatment in relapsed multiple myeloma patients tolerating therapy. This study is registered at http://clinicaltrials.gov (Study ID NCT00048230).

Description: All transretinoic acid (ATRA) followed by daunorubicin (DNR)-AraC chemotherapy (CT) has improved the outcome of acute promyelocytic leukemia (APL) by comparison to CT alone. In a randomized trial, (1) we compared 2 induction schedules (ATRA followed by CT [ATRA→CT] and ATRA plus CT [ATRA+CT, with CT added on day 3 of ATRA treatment]) and (2) we assessed the role of maintenance treatment. Four hundred thirteen patients ≤75 years of age and with newly diagnosed APL were included. Induction treatment was stratified on white blood cell (WBC) count and age: patients ≤65 years of age and with an initial WBC count of ≤5,000/μL (n = 208) were randomized between ATRA→CT and ATRA+CT (initially randomized patients); patients with a WBC count greater than (high WBC count group, n = 163) and patients 66 to 75 years of age with a WBC count greater than 5,000/μL (elderly group, n = 42) were not initially randomized and received ATRA+CT from day 1 and ATRA →CT, respectively. All patients achieving CR received 2 additional DNR-AraC courses (only 1 in patients 66 to 75 years of age) and were then randomized for maintenance between no treatment, intermittent ATRA (15 days every 3 months) for 2 years, continuous low-dose CT (6 mercaptopurine + methotrexate) for 2 years, or both, using a 2-by-2 factorial design. Overall, 381 (92%) of the patients achieved complete remission (CR), 31 (7%) suffered an early death, and only 1 patient had leukemic resistance. ATRA syndrome occurred in 64 patients (15%) and was fatal in 5 cases. The CR rate was similar in all induction treatment groups. Event-free survival (EFS) was significantly lower in the high WBC group (P = .0002) and close to significance in the elderly group (P = .086) as compared with initially randomized patients. Relapse at 2 years was estimated at 6% in the ATRA+CT group, versus 16% in the ATRA→CT group (P = .04, relative risk [RR] = .41). EFS at 2 years was estimated at 84% in the ATRA+CT group, versus 77% in the ATRA→CT group (P = .1, RR = .62). Two hundred eighty-nine patients were randomized for maintenance. The 2-year relapse rate was 11% in patients randomized to continuous maintenance CT and 27% in patients randomized to no CT (P = .0002) and 13% in patients randomized to intermittent ATRA and 25% in patients randomized to no ATRA (P= .02). An additive effect of continuous maintenance CT and intermittent ATRA was seen, and only 6 of the 74 patients who received both maintenance treatments had relapsed. Overall survival was improved in patients who received maintenance CT (P = .01), and there was a trend for better survival in patients who received maintenance ATRA (P = .22). Our findings strongly suggest that early addition of chemotherapy to ATRA and maintenance therapy combining continuous CT and intermittent ATRA can reduce the incidence of relapse in APL. This effect already translates into significantly better survival for maintenance treatment with continuous CT.