Associate Professor of Medicine
Section of Stem Cell Transplant and Leukemia
Division of Medical Oncology
Washington University School of Medicine
St. Louis, Missouri
Hematological malignancies were well represented this year at the ASCO Annual Meeting in the abstracts presented in the sessions on plasma cell disorders, lymphoma, and leukemia.
Dr. Paul Richardson presented results of the PANORAMA-1 study: a randomized double blind phase III study of panobinostat or placebo plus bortezomib and dexamethasone and relapsed/refractory multiple myeloma (Abstract 8510).
Panobinostat is a pan-deacetylase inhibitor which in prior phase I and II studies had demonstrated responses in relapsed and refractory multiple myeloma including bortezomib-resistant disease. In the trial presented at ASCO, 768 patients with relapsed or relapsed/refractory multiple myeloma not refractory to bortezomib who had one to three prior lines of therapy were randomized to treatment with panobinostat, bortezomib, and dexamethasone and compared with a group receiving placebo with bortezomib and dexamethasone. Nearly half the patients enrolled had received at least two prior regimens at time of randomization. After a median follow-up of approximately 125 weeks, the primary end point of progression-free survival was met, with the panobinostat arm having a median progression-free survival of 12 months versus 8.1 months in the comparator arm (p <0.0001). The overall response rate was 60.7 percent in the panobinostat arm versus 54.6 percent in the comparator arm (p =0.087). The CR/near CR rates were 27.6 percent versus 15.7 percent (p = 0.00006), respectively.
The benefit did come at the cost of greater toxicity, with grade III/IV diarrhea observed in 25.5 percent of patients in the panobinostat arm versus eight percent in the comparator arm. Grade III/IV fatigue was seen in 23.9 percent of patients in the panobinostat arm versus 11.9 percent in the comparator arm.
This trial is likely to lead to the approval of panobinostat for the therapy of patients with multiple myeloma allowing for a new option with a novel mechanism of action for patients with the disease. In the future, selective HDAC6 inhibitors like ACY-1215 may be able to demonstrate a better efficacy to toxicity profile.
Additional data with two monoclonal antibodies to CD38 daratumumab and SAR650984, both as single agents and in combination with lenalidomide and dexamethasone, were reported.
Dr. Henk Lokhorst presented data on daratumumab as monotherapy in patients with relapsed or refractory multiple myeloma (Abstract 8513). The results reported earlier from the phase I dose-escalation study had shown impressive responses in patients with refractory disease. The authors here presented preliminary data from the first 50 patients in an ongoing cohort expansion phase of the monotherapy trial. The drug achieved a response rate of 35 percent at a dose level of 16 mg/kg with a median progression-free survival of 23 weeks.
Dr. Thomas Martin reported on a phase IB dose escalation trial of SAR650984 in combination with lenalidomide and dexamethasone in relapsed/refractory myeloma (Abstract 8512). A total of 31 patients were treated, of whom 74 percent were refractory to their last lenalidomide-containing regimen. Twenty nine percent of patients were deemed pomalidomide refractory, 52 percent refractory to bortezomib, and 48 percent refractory to carfilzomib. An overall response rate of 58 percent with a very good partial response rate of 23 percent was observed. A total of 48 percent of patients refractory to lenalidomide responded to the regimen.
Monoclonal antibodies are expected to provide the next big leap in improving the outcomes of patients with multiple myeloma and both of these abstracts provided rationale for the continued enthusiasm about these drugs.
MPT vs. MPR
Dr. A. Keith Stewart reported results of E1A06: an intergroup phase III randomized controlled trial comparing melphalan, prednisone, and thalidomide versus melphalan, prednisone and lenalidomide in newly diagnosed multiple myeloma patients who were not candidates for high-dose therapy (Abstract 8511). The patients received the three-drug induction regimens for a planned 12 cycles and were then continued on thalidomide and lenalidomide respectively until disease progression. A total of 64 percent of patients in the thalidomide arm and 60 percent of patients in the lenalidomide arm had a partial response (p=0.557) with very good partial response rates of 19 and 23 percent (p=0.401), respectively. The progression-free survival was 21 months for the thalidomide arm and 18.7 months for the lenalidomide arm (p=0.19). After a median follow-up of 41 months, the median overall survival was reported to be 52.6 months in the thalidomide arm and 47.7 months in the lenalidomide arm (hazard ratio 0.88). Overall rates of grade III and non-hematological toxicity were lower in the lenalidomide arm.
The practical implications of this study are limited, though, as melphalan-based regimens are now seldom used in newly diagnosed patients in the United States.
Dr. Antonio Palumbo reported on PFS1, PFS2, and overall survival endpoints in patients receiving continuous treatment versus fixed duration of therapy in newly diagnosed multiple myeloma (Abstract 8515). PFS2--defined as progression-free survival from time of initial randomization on a study to a second progression--has emerged as a novel endpoint to assess efficacy of regimens recently. This report included 1,118 patients who had been treated on three phase III trials comparing continuous versus fixed duration of treatment: trials comparing VMPT-VT versus VMP, MPR/MEL 200-R versus MPR/MEL200 and MPR/R versus MPR versus MP.
A one-year landmark analysis showed that the median PFS1 for patients receiving continuous therapy was 32 months versus 16 months for those receiving fixed-duration therapy (p < 0.001). The PFS2 for the continuous- therapy cohort was 55 months versus 40 months for fixed-duration therapy (p < 0.001). Overall survival too was superior in the continuous-therapy cohort: 69 percent versus 60 percent for the fixed-duration therapy cohort (p=0.003).
This presentation provided data that PFS2 could be considered as a surrogate for overall survival in trials of newly diagnosed patients with multiple myeloma.
Leukemia and Myeloproliferative Diseases
Two presentations added to the growing volume of impressive data with the BTK inhibitor ibrutinib in chronic lymphocytic leukemia. Dr. Susan O’Brien presented data on the efficacy and safety of ibrutinib with three years of follow-up in the phase II (PCYC-1102) and extension (PCYC-1103) study (Abstract 7014). This study enrolled 31 patients older than age 65 with treatment-naïve CLL and 101 patients of all ages with relapsed or refractory disease. Median duration of response had still not been reached with single-agent ibrutinib, with best response rates of 87 percent for treatment-naïve and 90 percent for patients with relapsed/refractory disease. Ibrutinib therapy continued to be well tolerated with no new toxicity concerns emerging with longer-term follow-up.
The 13-month progression-free survival was 45.9 percent for patients with deletion 17p, 74.2 percent for patients with deletion 11q, and 89 percent for patients lacking these two cytogenetic abnormalities. The 13-month overall survival figures were 65.9, 84.9, and 93.9 percent, respectively. These figures for patients with deletion 17p are superior to that observed with chemoimmunotherapy that has been standard of care to date.
Dr. John Byrd presented data from the phase III RESONATE trial comparing ibrutinib to ofatumumab in relapsed or refractory chronic lymphocytic leukemia/small lymphocytic lymphoma (Abstract LBA7008). In this trial, the median progression-free survival was 8.08 months in the ofatumumab arm and had not been reached in the ibrutinib arm of the study (p <0.0001). Overall survival, though not reached in either arm, was statistically better for patients treated with ibrutinib (log rank p=0.0049). This represented a 57 percent reduction in the risk of death for patients treated with ibrutinib.
Atrial fibrillation was noted more frequently in patients with ibrutinib (n=10) compared with ofatumumab (n=1). Bleeding-related adverse events were more common with ibrutinib than with ofatumumab (44% vs. 12%). Exposure-adjusted analysis showed a 40 percent relative reduction in grade III/IV infections comparing ibrutinib with ofatumumab.
Dr. Max Topp presented data on a phase II study of the BiTE antibody blinatumomab in patients with relapse refractory B precursor acute lymphoblastic leukemia (Abstract 7005). Data with this investigational bispecific T-cell engaging antibody in patients with primary refractory disease or early relapse or relapsed/refractory disease to first salvage showed a CR/CRh (complete remission with partial hematological recovery) rate of 43 percent, with 82 percent of these patients having minimal residual disease negative remissions.
The median relapse-free survival was 5.9 months, with an overall survival of 6.1 months. A total of 52 percent of patients had neuropsychiatric issues, but only 13 percent were grade II or higher. A random open-label phase III study of blinatumomab in this patient population is currently underway.
Dr. Srdan Verstovsek presented results of the RESPONSE trial, a prospective randomized open-label phase III study of ruxolitinib in polycythemia vera patients resistant to or intolerant of hydroxyurea (Abstract 7026). Patients were randomized to ruxolitinib at a dose of 10 mg twice daily titrated up to 25 mg twice daily or investigator-selected best alternative treatment. The composite primary endpoint of percentage of patients who achieved both hematocrit control and greater than 35 percent reduction from baseline of spleen volume by MRI at week 32 was 21 percent in the ruxolitinib arm and one percent in the control arm. The probability of maintaining primary response for one year was 94 percent in the study arm.
A total of 19.8 percent of patients required phlebotomy between weeks 8 and 32 on study in the ruxolitinib arm and 62.4 percent in the comparator arm. Forty nine percent of patients had greater than 50 percent improvement in symptom scores at week 32 in the ruxolitinib arm versus five percent in the control arm. Although a higher proportion of patients in the ruxolitinib arm had a history of prior thromboembolic events at baseline (35.5% vs. 29.5%), there was only one additional event in the ruxolitinib arm over the course of the treatment compared with six additional events in the control arm. Most adverse events were grade I/II and few patients developed grade III/IV cytopenias and no patients discontinued ruxolitinib because of anemia or thrombocytopenia.
These data demonstrate that ruxolitinib is a potentially valuable treatment option in this population of patients with polycythemia vera.
Dr. Franco Cavalli on behalf of the LYM-3002 investigators presented results on a randomized phase III study of rituximab, cyclophosphamide, doxorubicin and prednisone plus vincristine (R-CHOP) or bortezomib (VR-CAP) in newly diagnosed mantle cell lymphoma patients ineligible for bone marrow transplantation (Abstract 8500). In this large study, 486 patients were randomized between the two treatment arms of R-CHOP and VR-CAP. After a median follow-up of 14 months, the median progression-free survival was 14.4 months for R-CHOP and 24.7 months for VR-CAP (p < 0.001).
The CR plus CRu (unconfirmed CR) rates were 42 percent for R-CHOP and 53 percent for VR-CAP (p=0.007). The four-year overall survival rate was 53.9 percent for R-CHOP patients and 64.4 percent for VR-CAP patients.
There was a greater rate of grade III thrombocytopenia in the VR-CAP arm: 57 percent versus six percent. However, there was no difference in bleeding events in the two arms. Grade III or higher neuropathy occurred in 4.1 percent of patients in the R-CHOP arm and 7.5 percent of patients in the VR-CAP arm. The neuropathy seemed to resolve more frequently and more quickly in the VR-CAP arm.
In addition, two studies targeting CD19 were presented at the meeting. Dr. Andres Forero-Torres from the University of Alabama presented interim analysis of a phase I open-label dose-escalation study of SGN-CD19A in patients with relapsed or refractory B lineage non-Hodgkin lymphoma (Abstract 8505). No dose-limiting toxicities were observed, and an overall response rate of 30 percent with a CR rate of 16 percent were noted.
Dr. Trneny presented phase II data on coltuximab ravtansine (SAR3419) in patients with relapsed/refractory diffuse large B cell lymphoma (Abstract 8506). This antibody to CD19 conjugated to DM4, a highly potent tubulin blocker, showed an overall response rate of 43.9 percent with a CR rate of 14.6 percent. In a patient population that had received a median of two prior regimens, the median progression-free survival was 4.4 months and overall survival 9.2 months. Few grade III/IV adverse events were noted, and no grade III/IV peripheral neuropathy was seen.
All of these abstracts are proof that the relentless march of progress against hematological malignancies continues with exciting new therapeutic options continuing to emerge for patients.