1. Vij, Ravi MD

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This year's ASCO Annual Meeting had several exciting presentations focusing on a variety of hematological malignancies. Here, I review what I consider the most significant developments in plasma cell dyscrasias, acute lymphoblastic leukemia, chronic myelogenous leukemia, and chronic lymphocytic leukemia.

RAVI VIJ, MD, is Ass... - Click to enlarge in new windowRAVI VIJ, MD, is Associate Professor of Medicine in the Section of Stem Cell Transplant and Leukemia at Washington University School of Medicine in St. Louis.

Plasma Cell Dyscrasias

The oral session on plasma cell dyscrasias had three presentations looking at combination therapies with the novel proteosome inhibitor carfilzomib. Philippe Moreau et al (first author Brigitte Kolb) reported on a phase I/II study of carfilzomib plus melphalan and prednisone in elderly patients with de novo multiple myeloma (Abstract 8009). Despite the phase I /II nature of the trial, a very promising overall response of 89 percent with a 40 percent very good partial response rate was seen.


Joseph Mikhael reported on a phase I/II trial of cyclophosphamide, carfilzomib, thalidomide, and dexamethasone (CYCLONE) in patients with newly diagnosed multiple myeloma (Abstract 8010). An overall response rate of 96 percent with a 75 percent very good partial response rate was noted.


And Andrzej Jakubowiak presented an update on his trial combining carfilzomib with lenalidomide and dexamethasone with a stringent complete remission rate of 42 percent (Abstract 8011).


In an elegant commentary on the above three abstracts, Robert Orlowski concluded that upfront combination therapies with carfilzomib showed very high rates of response, and it seemed that the depth of response was improved with better tolerability in terms of neuropathy. However, he highlighted that firm conclusions versus bortezomib could not be drawn given the higher number of doses of carfilzomib administered per cycle in combination regimens.


Another exciting compound in development includes the oral proteosome inhibitor MLN9708. Lonial et al presented data from a phase I study of twice-weekly dosing of this agent in patients with relapsed and/or refractory multiple myeloma (Abstract 8017). The drug was generally well tolerated, and a 2 mg/m2 dose was established as the MTD on a twice weekly regimen.


This drug has been found to have a much longer terminal half life of four to six days, in comparison to bortezomib, and despite being a boronate, no grade 3 or 4 peripheral neuropathy was noted. Six out of 53 patients achieved a partial response or better.


In another presentation, Kumar et al reported on once-weekly dosing of MLN9708 in patients with relapsed/refractory disease (Abstract 8034). Here, the maximally tolerated dose was 2.97 mg/m2. In addition, Richardson reported on a regimen of MLN9708, given weekly in combination with lenalidomide and dexamethasone, in patients with previously untreated multiple myeloma. The maximally tolerated dose was determined to be 2.97 mg/m2 (Abstract 8033).


I, on behalf of my co-investigators, presented the outcomes of patients refractory to lenalidomide and bortezomib, treated with pomalidomide with or without low-dose dexamethasone (MM002 study) (Abstract 8016). In this study an overall response rate of 30 percent was seen with pomalidomide and low-dose dexamethasone in the intention-to-treat population with a median progression-free survival of 3.8 months, and a median overall survival of 14.4 months at the time of data cutoff in April 2011.


A preplanned subset analysis of this study showed that the response rates were similar in patients who were refractory to lenalidomide, refractory to bortezomib, and refractory to both lenalidomide and bortezomib, including dual-refractory patients who had had a prior stem cell transplant.


In addition, Rossi et al reported impressive overall response rates and very good partial response rates with a three-drug combination of clarithromycin, pomalidomide, and dexamethasone in relapsed/refractory disease (Abstract 8036).


ASCO 2012 also saw the first presentation of the data from the PANORAMA 2 trial by Alsina et al (Abstract 8012). In this phase II study panobinostat in combination with bortezomib and dexamethasone in patients with relapsed and bortezomib refractory multiple myeloma resulted in an overall response rate of 33 percent.


At a clinical science symposium titled "Immunotherapy for Myeloma," there were presentations on three different monoclonal antibodies in development for the disease. Orlowski et al presented the results of a phase II randomized double-blind placebo-controlled study comparing siltuximab, a chimeric anti-IL-6 monoclonal antibody, plus bortezomib versus bortezomib alone in patients with relapsed/refractory multiple myeloma (Abstract 8018). Although there was a trend for an increase in overall response rates, only marginal and non-significant effects on progression-free survival were noted.


Plesner et al reported encouraging preliminary efficacy data from a multicenter phase I/II study of daratumumab, a CD38 monoclonal antibody, in patients with relapsed/refractory disease (Abstract 8019). The MTD of the drug has not yet been established. However, seven out of 29 heavily pretreated patients had a partial response, and four patients achieved a minimal response.


Moreau et al presented data from a randomized phase II study of elotuzumab with lenalidomide and low-dose dexamethasone in patients with relapsed disease (Abstract 8020). A 92% response rate in patients treated at the 10 mg/kg dose was reported, with the median progression-free survival not being reached at a median follow-up of 17.2 months in that arm.


Ghobrial et al presented long-term results of a phase II trial of the oral mTOR inhibitor everolimus (RAD001) in relapsed or refractory Waldenstrom's macroglobulinemia. In this 60-patient experience, a response rate of over 50 percent was noted in a patient population that had received a median of three prior therapies, suggesting high single-agent activity with this drug.


Acute Lymphoblastic Leukemia

Topp et al presented results of the anti-CD19 BiTE blinatumomab in adult patients with relapsed/refractory B precursor acute lymphoblastic leukemia (Abstract 6500). This bispecific T-cell engager (BiTE) is designed to direct cytotoxic T-cells to CD19-expressive cancer cells. With that given as a continuous IV infusion, the trial established 5 mcg/m2 per day in week 1, and then 15 mcg/m2 per day thereafter, four weeks on and two weeks off, for up to five cycles as the dose for the extension phase of the study.


A 72 percent CR/CRH (CR with partial hematological recovery) rate was demonstrated, with all but two of the responders achieving a complete molecular remission, with a median duration of complete hematological remission of 8.9 months, and a median survival of nine months. The major side effects were a cytokine release syndrome in three out of the 36 patients enrolled, and CNS adverse events in six patients, including three patients with seizures and three with encephalopathy. Two patients had to stop the treatment on account of CNS adverse events.


Jabbour et al presented results with inotuzumab ozogamicin, a CD22 monoclonal antibody conjugated to calicheamicin in patients with relapsed/refractory leukemia (Abstract 6501). Fourteen out of 27 patients (52%) had a response, with three complete remissions, eight CRPs (complete remission without total platelet recovery), and three CRIs (CR with incomplete count recovery) observed.


Eleven out of 27 patients (41%) were rendered MRD-negative with therapy. The majority of side effects were grade 1 to 2, with the grade 3 to 4 adverse events being drug fever in four patients and elevated transaminases in two patients.


Chronic Myelogenous Leukemia (CML)

Cortes et al presented results from the PACE (Ponatinib Ph positive ALL and CML Evaluation) trial in patients resistant to or intolerant of dasatinib on nilotinib or with the p351I mutation (Abstract 6503). This study enrolled 449 patients in a phase II trial with this oral pan bcr/abl tyrosine kinase inhibitor.


A major cytogenetic response was seen in 49 percent of patients with chronic myelogenous leukemia in chronic phase who were relapse/intolerant to dasatinib or nilotinib, and in 70 percent of patients with T531I mutation in chronic phase; 37 percent of patients in the relapsed/-intolerant cohort and 66 percent of patients in the T351I mutation cohort achieved a complete cytogenetic response.


Major molecular responses were seen in 23 and 50 percent of patients, respectively. Overall, the median time to major cytogenetic response was 12 weeks. Most toxicities were grade 1 to 2 in severity. The major grade 3 or greater toxicity was an elevation in lipase seen in 10 percent of patients.


Hochhaus et al presented three-year follow-up data from the DASISION trial comparing dasatinib with imatinib in patients with newly diagnosed CML in chronic phase (Abstract 6504). The cumulative incidence of major molecular response (bcr/abl less than or equal to 0.1%) at 26 months was 68 percent on the dasatinib arm, and 55 percent on the -imatinib arm; 84 percent of patients on the dasatinib arm and 64 percent of patients on the imatinib arm had suppression of the bcr/abl to less than or equal to 10 percent at three months.


In an exploratory analysis, deeper molecular response at three months was associated with a higher probability of progression-free and overall survival and decreased transformation to accelerated and blast phase.


An update with three-year follow-up from the ENESTnd trial of nilotinib versus imatinib in patients with newly diagnosed CML (Abstract 6509) continued to show superiority for nilotinib over imatinib, with 73 percent of patients on the nilotinib at 300 mg p.o. b.i.d. arm being in a major molecular remission, compared with 53 percent on the imatinib arm (P < 0.0001).


Progression to accelerated/blast phase of disease, including events after the discontinuation continued to be lower on the nilotinib arm compared with the -imatinib arm.


An update of the BELA trial of bosutinib versus imatinib in patients with newly diagnosed CML after 30 months of follow-up (Abstract 6512) presented by Gambacorti-Passerini showed cumulative major molecular response rates of 59 percent for bosutinib and 49 percent for imatinib at 24 months of follow-up (P = 0.019). Event-free survival was similar in the two arms of the study.


Nicolini et al presented data on subcutaneous omacetaxine mepesuccinate in patients with chronic-phase or -accelerated-phase CML resistant/intolerant to two or three approved tyrosine kinase inhibitors (Abstract 6513). This first-in-class reversible transient inhibitor of protein elongation showed a major cytogenetic response rate of 16.2 and 11 percent in patients resistant to two or three PKIs, respectively. The median progression-free survival was 10.5 months and 6.5 months in the two cohorts, respectively.


Chronic Lymphocytic Leukemia (CLL)

Byrd et al presented interim results of a phase IB/II study of the Bruton's tyrosine kinase (BTK) inhibitor ibrutinib (PCI-32765) in treatment-naive CLL patients (Abstract 6507). Ibrutinib was given for treatment-naive CLL/SLL patients aged 65 years or older in two separate cohorts at 420 mg per day or 840 mg per day until disease progression.


An overall response rate of 81 percent in 26 patients treated at the 420 mg per day dose, and 40 percent in the five patients who received the 840 mg per day dose, was noted. Three of 26 patients (12%) achieved a complete remission at 420 mg per day, with a median follow-up of 14.4 months. No complete remissions were seen at the dose of 840 mg per day with 7.4 months of follow-up in that cohort of patients.


Treatment resulted in a transient surge in peripheral blood lymphocyte counts with rapid resolution of lymph nodes, suggesting an effect on the microenvironment. The drug was well tolerated with the major toxicities being gastrointestinal, but few grade 3 events were seen, and there were no grade 4 toxicity events.


Phase IB/II studies of ibrutinib in combination with ofatumumab (Jaglowski et al, Abstract 6508) and ibrutinib with bendamustine and rituximab (O'Brien et al, Abstract 6515) in patients with -relapsed and refractory CLL/SLL showed high rates of overall response of 100 and 90 percent, respectively.



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