The 2016 American Society of Clinical Oncology Annual Meeting had more than its fair share of breaking news about advances in a variety of hematological malignancies. There were a lot more sessions dedicated to blood cancers this year and hematological neoplasms were well-represented right from the plenary session to individual tracks on plasma cell dyscrasia to leukemia, myelodysplastic syndromes and allogeneic transplant to lymphoma and chronic lymphocytic leukemia. It is worthwhile to review some of the seminar abstractions and salient findings.
Palumbo et al (Abstract LBA4) presented results of the phase III randomized controlled study of daratumumab, bortezomib and dexamethasone versus bortezomib and dexamethasone in patients with relapsed and refractory multiple myeloma (CASTOR trial) at the plenary session.
Daratumumab is a human CD38 IgG kappa monoclonal antibody currently approved in the United States for the treatment of patients with multiple myeloma who have received at least three prior lines of therapy including a proteasome inhibitor and immunomodulatory agent or are double refractory to a PI and immunomodulatory agent.
The CASTOR study enrolled patients with relapsed and refractory multiple myeloma who had received one or more prior lines of therapy. Patients could be exposed to prior bortezomib, but were not bortezomib refractory. Two hundred fifty-one patients received the three-drug combination of daratumumab, bortezomib, and dexamethasone and 247 patients received bortezomib and dexamethasone. In both arms of this study, the bortezomib and dexamethasone were administered for a total of eight cycles. Daratumumab was given weekly in cycles one through three, every 3 weeks in cycles four through eight, and every 4 weeks thereafter until progression.
With a median follow-up of just 7.4 months, the study reached its primary endpoint demonstrating improvement in progression-free survival (PFS) for patients assigned to the daratumumab, bortezomib, and dexamethasone arm. The 1-year PFS for bortezomib and dexamethasone was 26.9 percent versus 60.9 percent for the three-drug combination with a hazard ratio (HR) of 0.39 (95% CI, 0.28-0.53, p< 0.0001) representing a 61percent reduction in the risk of disease progression or death in favor of the three-drug combination. One-year time to progression was 28.8 percent for bortezomib and dexamethasone and 65.4 percent for daratumumab, bortezomib, and dexamethasone with a hazard ratio of 0.30 (95% CI, 0.21-0.43, P< 0.0001) representing a 70 percent reduction in risk of disease progression in favor of the daratumumab arm.
The overall response rate was 83 percent versus 63 percent (p< 0.0001), > very good partial response rate 59 percent versus 29 percent (p< 0.0001), and CR rate 19 percent versus 9 percent (p=0.0012) for daratumumab, bortezomib, dexamethasone versus bortezomib and dexamethasone alone.
Daratumumab, bortezomib, and dexamethasone was not associated with any accumulative toxicities. The most common treatment emergent adverse events were thrombocytopenia 59 percent in the daratumumab, bortezomib, dexamethasone arm and 44 percent in bortezomib dexamethasone arm. Sensory peripheral neuropathy was seen in 47 percent and 38 percent respectively. No grade 4 or greater infusion reactions were observed in the daratumumab arm. Ninety-eight percent of the infusion-related reactions were experienced on the first infusion and only two patients discontinued treatment due to infusion-related reactions.
The HR for PFS in the CASTOR trial of 0.39 compares very favorably to that reported in other recent phase III studies where bortezomib and dexamethasone were used as a comparator as well. The HR for carfilzomib, and dexamethasone (ENDEAVOR) was 0.53, panobinostat, bortezomib and dexamethasone (PANORAMA-1) was 0.63 and for elotuzumab, bortezomib, and dexamethasone was 0.72.
Richter et al (Abstract 8005) presented updated data from a phase II dose finding trial of single agent isatuximab in relapsed and refractory multiple myeloma. In this trial, isatuximab, a monoclonal antibody also targeting the CD38 antigen was explored at different doses/schedules.
Patients were double refractory to an immunomodulator drug and proteasome inhibitor or had received more than three prior lines of therapy. Patients had received a median of 5 to 5.5 lines of prior therapy and a sizeable proportion of patients were quadruple refractory to lenalidomide, bortezomib, pomalidomide, carfilzomib. The antibody was well tolerated and most infusion reactions were grade 1-2 and occurred during the first infusion. At a dose of greater than or equal to 10 mg/kg, the overall response rate (ORR) was 20 percent to 29 percent, PFS was 3.6 months and overall survival 18.6 months.
Vij et al (Abstract 8009) presented results of a phase I study of isatuximab with lenalidomide and dexamethasone. Again several doses and schedules were explored. The majority of patients were refractory to both an immunomodulator drug and proteasome inhibitor including sizable number of patients who were refractory to carfilzomib and pomalidomide. The ORR was 57 percent including a 54 percent response rate in immunomodulatory drug refractory patients. The median duration of response (DOR) was 7.6 months. Based on this study, it has been decided to pursue 10 mg/kg dose given weekly for the first 4 weeks and every 2 weeks thereafter as the schedule for isatuximab going forth.
A global phase III trial of isatuximab is expected to be initiated soon.
Mateo et al (Abstract 8010) presented the final efficacy and safety analysis of phase I/II study of pembrolizumab in combination with lenalidomide and low-dose dexamethasone for relapsed refractory multiple myeloma.
The PD pathway is exploited by tumors to evade immune surveillance. PD-1 is increased among T-cells of patients with relapsed refractory multiple myeloma. Lenalidomide is known to reduce PD-L1 and PD-1 expression on multiple myeloma cells and myeloid-derived suppressor cells. It enhances the checkpoint blockade induced effector cytokine production in multiple myeloma bone marrow and induced cytotoxicity against multiple myeloma cells in preclinical models.
This trial (KEYNOTE-023) enrolled a total of 51 patients. Efficacy data was presented for 40 patients who completed three cycles of treatment or discontinued for progressive disease. Patients had received a median of four prior lines of therapy with 75 percent of patients' refractory to lenalidomide. The ORR was 50 percent in the overall efficacy population and 38 percent in the 29 patients who had lenalidomide refractory disease. With a median duration of follow-up of 9 months, the median DOR was 11.3 months.
Phase III studies of pembrolizumab have been initiated in patients with both untreated (KEYNOTE-185) and relapsed refractory (KEYNOTE-183) multiple myeloma.
Autologous Stem Cell Transplantation:
Cavo et al (Abstract 8000) presented results of randomized phase III study of the European Myeloma Network (EMN02/H095MM Trial) of autologous stem cell transplantation versus novel agent based therapy for multiple myeloma.
Patients on this trial received induction chemotherapy with bortezomib, cyclophosphamide, and dexamethasone and thereafter underwent mobilization of stem cells with cyclophosphamide/G-CSF and then were randomized to either four cycles of bortezomib, melphalan, and prednisone (VMP), or one to two course of high-dose melphalan. Thereafter, there was a second randomization to two consolidation cycles of bortezomib, lenalidomide, and dexamethasone versus no consolidation therapy. All patients were subsequently placed on maintenance therapy with lenalidomide.
The trial enrolled 1,510 patients. This interim analysis reported on 1,192 patients who had been randomized to stem cell transplantation versus VMP chemotherapy. With a median follow-up of 26 months, median PFS had not been reached in the ASCT arm and was 44 months in the VMP arm with a 3-year PFS of 66.1 percent and 57.5 percent (HR 0.73, 95% CI 0.59-0.90, p= 0.003). ASCT had superior results even in patients with high-risk cytogenetics with a median PFS of 42 months versus 32 months for VMP (HR 0.69, 95% CI 0.52-0.92, p= 0.010).
This trial, once again, reaffirmed that upfront high-dose melphalan and ASCT continues to be the reference treatment of choice in patients with newly diagnosed multiple myeloma, even in the era of novel agents.
Attal et al presented results of a meta-analysis of overall survival of patients receiving lenalidomide maintenance after high-dose therapy and autologous stem cell transplantation. This was pooled analysis of primary source patient data. The three studies included in the meta-analysis were the IFM 2005-02 trial, CALGB-00104, and the Gimema-RVMM-PI-209 studies.
In all, 605 patients received lenalidomide maintenance and 604 patients received no maintenance therapy. The median overall survival in the lenalidomide arm was not reached and was 85 months for the control arm. The 7-year OS was 62 percent for lenalidomide maintenance versus 50 percent for the control arm, with a HR of 0.74 (95% CI 0.62-0.89, p=0.001).
This represented a 25 reduction in risk of death and an estimated 2.5 year increase in median survival with maintenance lenalidomide.
Lancet et al (Abstract 7000) presented the final results of a phase III randomized trial of CPX-351 versus 7+3 in older patients with newly diagnosed high-risk (secondary) acute myeloid leukemia (AML).
CPX-351 uses a nanoscale delivery complex for 5:1 molar ratio cytarabine to daunorubicin encapsulated in 100 nanomolar bilaminar liposomes. A phase I trial of CPX-351 in advanced acute leukemias had shown that a fixed molar ratio was maintained for 24 hours after the final dose and drug exposure was maintained for 7 days. An earlier randomized phase II study of CPX-351 versus 7+3 in patients older than 60 with previously untreated AML had shown that in patients with secondary AML event free survival (EFS) increased from 1.3 months to 4.5 months and OS from 6.1 months to 12.1 months with CPX-351.
In this current phase III study, previously untreated patients aged 60 to 75 years of age, able to tolerate intensive chemotherapy were accrued. Patients were eligible if they had therapy-related AML, AML with history of MDS/CMML, or de novo AML with MDS karyotype. Patients in both arms received induction chemotherapy for one to two cycles and consolidation for an additional one to two cycles.
One hundred and fifty-three patients were assigned to CPX-351 and 156 patients to 7+3 chemotherapy. The median OS for patients with CPX-351 was 9.56 months compared to 5.95 months with 7+3 (HR 0.69, p=0.005). EFS also favored the CPX-351 arm with a median of 2.53 months versus 1.31 months (HR 0.74, p= 0.021). The CR rates (37.3% versus 25.6%, p= 0.04) and CR plus CRi rates (47.7% versus 23.3%, p= 0.016) also favored CPX-351. The 30 and 60 day mortality rates were lower in the CPX-351 arm compared with 7+3 (5.9% versus 10.6% and 13.7% versus 21.2% respectively).
Thirty-four percent of patients in the CPX-351 arm and 25 percent in the 7+3 arm underwent allogeneic hematopoietic stem cell transplantation. A sensitivity analysis was performed for median OS for patients censored at the time of transplant. The patients in the CPX-351 arm had a median OS of 7.75 months versus 5.55 months for patients receiving 7+3 (HR 0.81, p=0.165). A landmark survival analysis at time of transplant showed that the median OS was not reached for the CPX-351 arm versus 10.25 months for the 7+3 arm (HR 0.46, p= 0.0046).
Cortes et al (Abstract 7008) presented results on crenolanib besylate, a type 1 pan-FLT3 inhibitor, in patients with multiple relapsed FLT3-ITD and D835 AML. Crenolanib inhibits both FLT3-ITD and FLT3 TKD mutations in the active confirmation. Substitution of D835 in the activation loop with increasingly hydrophobic amino acids like valine, isoleucine, and phenylalanine result in increased resistance to type 2 FLT3-TKIs.
Sixty-nine patients were enrolled in two parallel trials. There were three cohorts of patients presented, cohort 1 with no prior exposure to FLT3-TKI (n= 19), cohort 2 with prior exposure to FLT3-TKI (n= 39), and cohort with secondary AML (n= 11).
Cohort 1 had a CR/CRi rate of 37 percent with median duration of CR/CRi of 51 days. Median OS of this cohort was 238 days. Patients in cohort 2 had failed up to three TKIs, including sorafenib, crizotinib, pexidartinib, midostaurin, gilteritinib and FLX-925. The CR/CRi rate in this population was 15 percent with a median duration of 47.5 days. Median OS was 94 days. There were no CR/CRi seen in the secondary AML cohort. Overall responses were seen in FLT3-ITD, D835, ITD+D835, as well as FLT3-A833, D839 and N841.
Secondary FLT3 resistant mutations were not seen at the time of relapse. Grade 3 or greater intestinal hemorrhage was seen in 17 percent of patients. Two patients discontinued crenolanib due to adverse events.
Frey et al (Abstract 7002) presented data on 30 adults with relapsed refractory acute lymphoblastic leukemia (ALL) treated with CAR T-19 (CTL-019). This chimeric antigen receptor consists of the antigen binding domain of CD19 linked to the 4-1BB costimulatory domain and the CD3-zeta chain signaling domain and is delivered to the T-cells using a retroviral vector. Four treatment cohorts were presented. Cohort 1 utilized high dose (5 x10e8 T-cells) split over day 1 (10%), day 2 (30%), and day 3 (60%) schedule. Cohort 2 received the same high dose but over a single infusion on day 1. Cohort 3 received low dose (5 x 10e7 T-cells) using the same split dosing schedule where-as cohort 4 got low dose as a single infusion. It was felt that the high dose split schedule was the best with an 86% response rate and no treatment related mortality.
Park et al (Abstract 7003) presented data on the impact of disease burden on long-term outcomes of 19-28z CAR modified T-cells in adult patients with relapsed, refractory B-cell ALL. These CAR T-cells generated using a retroviral vector were administered to 51 adult patients. Thirty-one (61% of patients) had morphologic disease at the time of T-cell infusion and 20 patients (39%) had minimal disease. After a median follow-up of 8.5 months, the CR rate was 77 percent for patients with morphological disease and 90 percent for patients with minimal disease with MRD negative rates in 90 percent and 78 percent respectively.
Sixteen of 41 CR (39%) patients proceeded to allogeneic hematopoietic stem cell transplant after achieving complete remission to CAR T-cells, 9 of 23 (39%) of the morphological disease cohort and 7 of 18 (39%) of the minimal disease cohort. Fifteen out of 33 MRD negative CR (45%) relapsed with 4 of 15 (27%) relapses being CD19 negative/undetectable. Nine of 33 (27%) of patients were disease free for greater than 1 year. After a median follow-up of 13 months, the median overall survival was not reached in the minimal disease cohort and was 9 months in the morphological disease cohort (p= 0.35). Patients with minimal disease at the time of T-cell infusion experienced significantly less severe CRS and neurological toxicities.
Lymphoma & Chronic Lymphocytic Leukemia (CLL)
Diffuse Large B-Cell Lymphomas (DLBCL)
Lugtenburg et al (Abstract 7504) presented results on a phase III study of early intensification of rituximab in combination with 2-weekly CHOP chemotherapy followed by rituximab or no maintenance in patients with DLBCL for the HOVON-NORDIC lymphoma group. Five hundred and seventy-five patients were randomized to R-CHOP-14 with Rituxan given on day 1 for four cycles or CHOP-14 with Rituxan administered on day 21 and 8 for four cycles. Rituximab intensification early during treatment did not improve the CR rate, PFS or OS.
Witzig et al (Abstract 7506) presented results on PILLAR-II, a randomized double blind placebo-controlled phase III study of everolimus in patients with poor-risk DLBCL. Patients received induction chemotherapy with either R-CHOP (n= 725) or R-EPOCH (n= 17) and were randomized to either everolimus 10 mg daily for 1 year or placebo for 1 year. In this patient population, there was no disease-free survival benefit of up to 1 year of everolimus maintenance.
Rummel et al (Abstract 7503) presented date from the StiL NHL7-2008 MAINTAIN trial, looking at 2 years of rituximab maintenance versus observation after front-line treatment with bendamustine plus rituximab in patients with mantle cell lymphoma. In this relatively small study, 168 patients were randomized. Rituximab maintenance did not improve PFS or OS after bendamustine/Rituxan.
Trumper et al (Abstract 7500) presented results of the international ACT-2 phase III study of alemtuzumab added to CHOP for treatment of peripheral T-cell lymphoma in the elderly. In this trial, patients were randomized to either CHOP or alemtuzumab with CHOP chemotherapy, both given for 6 cycles. Alemtuzumab added to CHOP-14 resulted in increased response rates in elderly patients but did not improve EFS, PFS, and OS.
Rubenstein et al (Abstract 7502) presented results on a phase I trial of lenalidomide with Rituxan followed by lenalidomide maintenance in patients with recurrent CNS diffuse large B-cell lymphoma. Patients with recurrent or relapsed refractory CNS non-Hodgkin lymphoma involving brain, CSF/meninges, and/or intraocular compartments were eligible for the study. Patients received 1 cycle of lenalidomide monotherapy and were restaged. Those that had stable disease or better continued with a second cycle of lenalidomide monotherapy. Patients who had disease progression after the first cycle had rituximab added to their treatment on days 1, 8, 15 and 22 of the second cycle. A total of 14 patients were recruited to the study. Five patients had intraocular involvement, seven had CSF/leptomeningeal involvement and 10 involvement of the brain parenchyma.
Lenalidomide was found to penetrate the ventricular CSF and responses to lenalidomide were detected in nine of 13 available patients. A retrospective analysis of maintenance after salvage therapy in patients with CNS lymphoma showed that the approach was feasible and associated with enhanced progression-free survival.
Dartigeas et al (Abstract 7505) presented results from the randomized CLL-2007SA trial from the French FILO group, which studied rituximab maintenance after induction with abbreviated FCR in previously untreated elderly CLL patients.
Five hundred and forty-two patients were enrolled and 409 patients were randomized, 202 patients to rituximab and 207 patients to observation. Rituximab maintenance resulted in improved PFS 59.3 months versus 49 months for observation (HR 0.597, 95% CI 0.437-0.814). Benefits were observed in patients with unfavorable characteristics including deletion 11q and unmutated IGHV and was independent of MRD status at time of initiation of maintenance. However, it was associated with a higher incidence of infections (18.8% versus 10.1%, p= 0.0126) and neutropenia (52% versus 35.7%, p= 0.0009).
The data presented in several of these abstracts have clinical relevance for the practicing physician. For our patients with myeloma once daratumumab gets FDA approval in the earlier line of treatment based on the CASTOR study, it will move from the relapsed/refractory third-line setting, where it is currently being used, to the second-line setting. The value of high dose therapy even in the era of modern agents and maintenance lenalidomide was once again reaffirmed. Check-point inhibitors may be the next class of drugs to be added to the armamentarium. CPX-351 is likely to get FDA approval for patients with secondary AML in the near future. Midostaurin may prove to be the first Flt-3 inhibitor to make it to market but it is gratifying to note that even better drugs in the class may follow. Lenalidomide has activity is CNS lymphomas. Also, CAR-T cells too may be here sooner than you think!Wolters Kluwer Health, Inc. All rights reserved.
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