TM

905 891 1900www.CAREeducation.ca

info@careeducation.caCommunity Academic Research Education

@weareCARE

ASCO & EHA 2016Commentary and content provided by the CARE Hematology Faculty

HEMATOLOGY

ASCO 2016 - AMERICAN SOCIETY OF CLINICAL ONCOLOGY - CHICAGO, IL - JUNE 3-6, 2016

EHA 2016 - EUROPEAN HEMATOLOGY ASSOCIATION - COPENHAGEN, DNK - JUNE 9-12, 2016

TM

PERSPECTIVES

HIGHLIGHTS FROM ASCO & EHA 2016

Members of the CARE Hematology Faculty recently attended the ASCO & EHA 2016 conferences held in Chicago, Illinois (June 3-7) and Copenhagen, Denmark (June 9-12). CARE was pleased to host the annual resident education meeting in conjunction with ASCO. This meeting brought together a pan-Canadian Faculty of KOLs to showcase news and developments in oncology. Presentations featured cutting edge content with discussion on relevant cases and treatment strategies. CARE at ASCO was attended by over 50 Canadian oncology professionals. Attendees included academic specialists, trainees and residents.

The content that follows is written in the language in which it was presented. The following content is drawn from the abstracts at ASCO and EHA 2016, as well as the presentation made at the CARE at ASCO 2016 meeting by Dr. John Kuruvilla. This report is augmented with content and perspectives from the CARE Hematology Faculty.

CARE HEMATOLOGY FACULTY WHO HAVE CONTRIBUTED TO THIS REPORT:

TM

PERSPECTIVESTM

CONTENTS

1 Multiple Myeloma

4 Chronic Lymphocytic Leukemia

6 Acute Leukemia

7 Mantle Cell Lymphoma

8 Diffuse Large B-Cell Lymphoma

9 Hodgkin's Lymphoma

Email Twitter Facebook LinkedIn Youtube

S TAY CO N N EC TE D WITHTM

www.CAREeducation.ca

ASCO & EHA 2016

David MacDonald, MD Dalhousie University

John Kuruvilla, MD Princess Margaret Cancer Centre

PERSPECTIVES - ASCO & EHA 2016

MULTIPLE MYELOMA

EHA 2016. ABSTRACT LB2236. Phase III randomized controlled study of daratumumab, bortezomib, and dexamethasone (DVd) versus bortezomib and dexamethasone (Vd) in patients (pts) with relapsed or refractory multiple myeloma (RRMM): CASTOR study.

Antonio Palumbo et al.

Results: 498 patients (DVd, 251; Vd, 247) were randomised. Baseline demographics and disease characteristics were well balanced. Patients received a median of 2 prior lines of therapy (range 1-10). 66% received prior bortezomib; 76% received prior immunomodulatory drug (IMiD); 48% received prior proteasome inhibitor (PI) and IMiD; 33% were IMiD-refractory; and 32% were refractory to last line of prior therapy. With a median follow-up of 7.4 months, daratumumab significantly improved median PFS (61% reduction in the risk of progression/death) for DVd versus Vd (Figure). Addition of daratumumab to Vd also significantly delayed median time to disease progression (TTP) versus Vd (not reached [NR] vs 7.3 mo; hazard ratio, 0.30; 95% confidence interval, 0.21-0.43; P <0.0001). Daratumumab significantly increased overall response rate (ORR; 83% vs 63%, P <0.0001), in addition to doubling the rates of very good partial responses (VGPR) or better (59% vs 29%, P <0.0001) and complete responses (CR) or better (19% vs 9%, P = 0.0012) for DVd versus Vd, respectively. The median duration of response was NR for DVd versus 7.9 months for Vd. All planned sensitivity analyses demonstrated that DVd was better than Vd, which was consistent with the results from the primary analysis. In addition, pre-specified subgroup analyses on PFS demonstrated that the treatment effect of DVd over Vd was consistent across all selected subgroups. Most common (>25%) treatment-emergent adverse events (TEAEs; DVd/Vd) were thrombocytopenia (59%/44%), peripheral sensory neuropathy (47%/ 38%), diarrhoea (32%/22%) and anaemia (26%/31%). Most common grade 3/4 TEAEs (>10%) were thrombocytopenia (45%/33%), anaemia (14%/16%), neutropenia (13%/4%). 7%/9% (DVd/Vd) of patients discontinued due to a TEAE. Daratumumab-associated infusion-related reactions (IRR; 45% of patients) mostly occurred during the first infusion (98% of patients with IRR); most were grade 1/2 (grade 3/4, 9%/0%).

Conclusions: Daratumumab significantly improved PFS, TTP, and ORR in combination with Vd versus Vd alone. DVd doubled rates of both VGPR or better and stringent CR/CR versus Vd alone. Safety of DVd is consistent with the known safety profile of daratumumab and Vd. The addition of daratumumab to Vd should be considered a new standard of care for patients with RRMM currently receiving Vd alone.

" T H I S W A S A P R A C T I C E C H A N G I N G T R I A L

. . . F A V O U R I N G D A R A T U M U M A B I N C O M B I N A T I O N

W I T H B O R T E Z O M I B A N D D E X A M E T H A S O N E O V E R

B O R T E Z O M I B A N D D E X A M E T H A S O N E .

CARE FACULTY PERSPECTIVE: This was a practice changing trial that demonstrated an impressive hazard ratio favouring daratumumab in combination with bortezomib and dexamethasone over bortezomib and dexamethasone. Daratumumab represents another exciting option for relapsed/refractory MM patients in Canada.

These findings are results of an interim analysis in which the study met its primary endpoint and the Independent Data Monitoring Committee recommended to stop the trial early.

Data is to be discussed with authorities to prepare for regulatory filings. We will now await the approval and funding process.

DVd: Median (95% Cl) PFS: NE (12.3-NE)

Vd: Median (95% Cl) PFS: 7.2 months (6.2-7.9)

HR (95% Cl): 0.39 (0.28-0.53); P <0.0001

Months since randomizationPatients at risk

Vd 247 182 106 25 5 0

DVd 251 215 146 56 11 0

Vd DVd

Perc

ent o

f pat

ient

s pr

ogre

ssio

n-fr

ee a

nd a

live

00 3 6 9 12 15

20

40

60

80

100

PFS Results

1

PERSPECTIVES - ASCO & EHA 2016

PFS Results:

Conclusions: DRd was superior to Rd alone. A significant reduction in the risk of disease progression/death was demonstrated with DRd vs Rd. DRd induced deep and durable responses, including doubling stringent CR/CR rates and significantly increasing the rate of VGPR or better vs Rd alone. DRd was associated with a manageable safety profile consistent with the known safety profile of D and Rd. The combination of D and Rd potentially represents a new standard of care for pts with >1 prior treatment.

CARE FACULTY PERSPECTIVE: The Pollux study reported the outcome of the addition of daratumumab to lenalidomide and Dexamethasone compared to lenalidomide and dexamethasone. The trial was positive with significantly improved PFS, TTP, ORR and depth of remission. Treatment with the daratumumab combination was also well tolerated. This novel combination represents another important treatment option in patients with relapsed MM. The data from both the Castor and Pollux studies highlight the importance of daratumumab in this patient population and report excellent results with daratumumab in combination with either bortezomib or lenalidomide. It seems clear that daratumumab may have an important role in the treatment of myeloma patients.

E H A 2 01 6 . A B S TR AC T LB 2 2 3 8 . An open-label, randomized phase 3 study of daratumumab, lenalidomide, and dexamethasone (DRD) versus lenalidomide and dexamethasone (RD) in relapsed or refractory multiple myeloma (RRMM): POLLUX

Meletios A Dimopoulos et al.

Results: 569 pts were randomised. Median age of pts was 65 years old. Pts received a median of 1 prior line of therapy (range 1-11), with 19% of pts with ≥3 prior lines of therapy. Eighty-six percent received a prior PI, and 55% received prior IMiD, including 18% prior R, with 44% having received both a PI and an IMiD; 27% were refractory to the last line of prior therapy, 18% were PI refractory, and none were R refractory. After a median follow-up of 13.5 months, D significantly improved median PFS (63% reduction in the risk of progression/death) for DRd vs Rd (Figure). Addition of D to Rd significantly delayed TTP vs Rd (not reached [NR] vs estimated median of 18.4 mo; hazard ratio, 0.34; 95% CI, 0.23-0.48; P<0.0001). D significantly increased ORR (93% vs 76%, P<0.0001) and rates of VGPR or better (76% vs 44%, P<0.0001) and complete response (CR) or better (43% vs 19%, P<0.0001) for DRd vs Rd, respectively. The median duration of response was NR for DRd vs 17.4 months for Rd. All preplanned sensitivity analyses were consistent with results from the primary analysis. Pre-specified subgroup analyses of PFS demonstrated that the treatment effect of DRd over Rd was consistent across all pre-specified subgroups. The most common (<25%) TEAEs (DRd/Rd) were neutropenia (59%/43%), diarrhea (43%/25%), fatigue (35%/28%), upper respiratory tract infection (32%/21%), anemia (31%/35%), constipation (29%/25%), cough (29%/13%), thrombocytopenia (27%/27%), and muscle spasms (26%/19%). Most common grade 3/4 TEAEs (>10%) were neutropenia (52%/37%), thrombocytopenia (13%/14%), and anemia (12%/20%). The rate of Grade 3/4 infections/infestations was 28% in the DRd group and 23% in the Rd group and the most common Grade 3/4 infections/infestations TEAE (≥5%) was pneumonia (8%/8%). Similar rates of treatment discontinuation due to TEAEs were observed (7%/8%). D-associated infusion-related reactions (IRR; 48% of pts) mostly were grade 1/2 (grade 3/4, 5%/0%); most (92% of IRRs) occurred during the first infusion.

" D A T A F R O M B O T H T H E C A S T O R A N D

P O L L U X S T U D I E S H I G H L I G H T T H E

I M P O R T A N C E O F D A R A T U M U M A B I N T H I S

P A T I E N T P O P U L A T I O N . "

DRd: Estimated median (95% Cl) PFS: NE (NE-NE)

Rd: Estimated median (95% Cl) PFS: 18.4 months (13.9-NE)

HR (95% Cl): 0.37 (0.27-0.52): P <0.0001

0 3 6 9 12 15 18 210

20

40

60

80

100

Perc

ent o

f pat

ient

s pr

ogre

ssio

n-fr

ee a

nd a

live

Patients at risk

Rd 283 249 206 179 139 36 5 0DRd 286 266 248 232 189 55 8 0

Months since randomization

Rd DRd

2

PERSPECTIVES - ASCO & EHA 2016

ASCO 2016. ABSTRACT 8000. Upfront autologous stem cell transplantation (ASCT) versus novel agent-based therapy for multiple myeloma (MM): A randomized phase 3 study of the European Myeloma Network (EMN02/HO95 MM trial).Michele Cavo et al.

Results: From February 2011 through April 2014, 1503 pts aged ≤65 years with symptomatic newly diagnosed multiple myeloma (NDMM) were registered. Of these, 1308 pts were eligible for R1 and 1266 who were randomized (1:1 ratio; stratification by ISS stage) to bortezomib-melphalan-prednisone (VMP) (512 pts) or high-dose melphalan (HDM) (1±2 ASCT) (754 pts) were analyzed. Median follow up from R1 was 24 months. PFS was significantly prolonged in pts randomized to HDM (HR=0.76; 95% CI=0.61-0.94; P=0.010), a benefit retained across predefined pt subgroups, including those with revised ISS stage III (HR=0.52; CI=0.32-0.84; P=0.008) and high-risk cytogenetics [t(4;14) ± del(17p) ± del(1p) ± 1q gain] (HR=0.72; CI=0.54-0.97; P=0.028). Superior rate of ≥ very good partial response was observed with HDM (84%) vs VMP (74%) (odds ratio=1.90; CI=1.42-2.54; P<0.0001). In a Cox regression analysis, randomization to HDM (HR=0.61, CI=0.45-0.82; P=0.001) was confirmed to be an independent predictor of prolonged PFS. Overall survival was not yet mature and no difference between the treatment groups was evident.

Conclusions: Upfront ASCT still remains the preferred treatment for younger NDMM pts. Further follow-up of the study is needed. Clinical trial information: NCT01208766

CARE FACULTY PERSPECTIVE: With early follow-up, this trial fails to demonstrate any OS difference favouring novel therapy or ASCT. PFS remained superior in patients undergoing ASCT but this may not be an appropriate endpoint to measure in a trial evaluating the role of transplantation. Longer follow-up will be required to determine the best treatment strategy for these patients.

E H A 2 01 6 . A B S TR AC T LB 2 07 1 . Carfilzomib and dexamethasone improves progression-free survival and response rates vs bortezomib and dexamethasone in patients (PTS) with relapsed multiple myeloma (RMM): The phase 3 study endeavorMeletios Dimopoulos et al

Results: In total, 929 pts (Kd: 464; Vd: 465) were randomized. In the Vd arm, 83.6% of pts received SC bortezomib. Median treatment exposure was 39.9 weeks (Kd) and 26.8 weeks (Vd). Kd led to a 47% decrease in the risk of progression or death (hazard ratio, 0.53; 95% confidence interval [CI], 0.44–0.65; P<.0001), with a median PFS of 18.7 months (95% CI, 15.6–not estimable) in the Kd arm vs 9.4 months (95% CI, 8.4–10.4) in the Vd arm. OS data were immature (deaths: Kd=75; Vd=88); pts continue to be followed. The median DOR was 21.3 months (Kd) and 10.4 months (Vd). Treatment discontinuation due to an adverse event (AE) occurred in 14.0% (Kd) and 15.7% (Vd) of pts. An AE led to dose reductions of K or V in 22.5% and 48.0% of pts, respectively; 61.9% of dose reductions in the Vd arm were due to neuropathy-related AEs vs 6.6% in the Kd arm. Rates of grade ≥2 PN (grouped term) were 6.3% in the Kd arm vs 32.0% in the Vd arm (P<.0001). The most common hematologic AEs (preferred terms; all grades) in the Kd and Vd arms, respectively, included anemia (39.3% vs 27.0%) and thrombocytopenia (20.5% vs 17.1%); the most common non-hematologic AEs (preferred terms; all grades) included diarrhea (30.9% vs 38.4%), fatigue (29.4% vs 28.5%), and dyspnea (28.5% vs 13.2%).Grade ≥3 AEs of interest in the Kd and Vd arms, respectively, included hypertension (preferred term; 8.9% vs 2.6%), dyspnea (preferred term; 5.4% vs 2.2%), cardiac failure (grouped term; 4.8% vs 1.8%), and acute renal failure (grouped term; 4.1% vs 2.6%). A total of 3.9% of pts in the Kd arm and 3.4% of pts in the Vd arm died on study owing to AEs.

Conclusions: Carfilzomib and dexamethasone demonstrated statistically significant and clinically meaningful superiority over bortezomib and dexamethasone in RMM, with a 2-fold improvement in median PFS and a favourable benefit–risk profile. These data suggest that carfilzomib could be a best-in-class agent for RMM.

CARE FACULTY PERSPECTIVE: The combination of carfilzomib and dexamethasone continues to be superior to bortezomib and dexamethasone in terms of PFS data and benefit-risk profile.

This data appears promising, however we must determine if the OS data is significant as well. No new toxicities were identified in this study update, however the study highlights a different AE profile for carfilzomib, with decreased peripheral neuropathy but increased hypertension, dyspnea, and cardiac and renal toxicity.

" T H I S T R I A L F A I L S T O D E M O N S T R A T E

A N Y O S D I F F E R E N C E F A V O U R I N G N O V E L

T H E R A P Y O R A S C T . "

3

PERSPECTIVES - ASCO & EHA 2016

CHRONIC LYMPHOCYTIC LEUKEMIA

EHA 2016. ABSTRACT P592. Ibrutinib for relapsed CLL patients older than 75 Years: proven efficacy, toxicities to know Anne-Sophie Michallet et al.

Results: At initiation of treatment, the population had frequent vascular comorbidities (hypertension 34%, venous thrombosis 10%, arteritis 7%), heart comorbidities (myocardial infarction, 10.3%, arrhythmias 13.4%, valvular disease 4%), or kidney dysfunction (31.3% with reduced creatinine clearance 30-60ml/min). As such, they required antiplatelet therapy and / or anticoagulant in 30% and 12% of cases, respectively. Baseline CLL characteristics included: advanced Binet stage (stage C 68%), deletion 17p and/or TP53 mutation 53.3%, deletion 11q 21.6%, median of 3 lines of previous treatments (range 1-9). Pts started ibrutinib at 420mg/d in all but one patient, still 55.7% of patients had a dose reduction to 280mg/d due to toxicity during the first year of follow-up, after a median of 8 weeks (range 2-52)). Standard dose was reintroduced in 10/39 pts after resolution of AE, among which 5/10 had to decrease dose from one level again. Ibrutinib was definitively stopped in 34% of pts after a median of 5 months (range 1-16), mainly for AEs (infections 5.6%, cardiac complications 7%, bleedings 11.3%, hematological toxicity), rarely for PD (5.6%). After a median follow-up of 15.1 months, overall response rate at 12 months (45 evaluable patients) was 93.4%, including 75.5% partial remission (35,6% with or 40% without lymphocytosis). Overall survival (OS) and progression-free survival (PFS) rate at 12 months were 92% and 83%, respectively. At last follow-up (median: 15.1mo), 63.4% of patients were alive on treatment, 15.5% alive without ibrutinib, and 21.1% (15/71) died from: infection (7/15), CLL progression (6/15, 3/6 had proven Richter transformation), heart disease (2/15). In statistical analysis, the only factor influencing PFS (HR=6,369; p=0,004) and duration of response (HR= 7,052, P=0,017) but not OS was a previous medical history of arteritis/myocardial ischemia. As reported from clinical trials, a drug hold >7 days tended to be associated with a reduction of the duration of response, but not a dose reduction from 420 to 280mg/d. In this series, estimated median OS was 21 months. Safety profile was fairly known and manageable: grade 1-2 bleeding (19%), cardiac toxicity (7%), diarrhea (24%), myalgia / arthralgia (20%), the frequency of which decreasing over the first 6 months. On the other hand, ibrutinib was associated with a risk of hematologic AE and infection (20 % of pts experienced infection of at least grade 2), irrespectively from date of assessment (3, 6 or 12 months).

Conclusions: In very elderly pts with CLL, Ibrutinib was an effective strategy requiring nevertheless an adequate management of toxicities, dose reduction being often efficient.

CARE FACULTY PERSPECTIVE: Ibrutinib has been studied extensively over the past few years and has continuously had positive survival rates for patients suffering from relapsed/refractory CLL. This study aimed to study patients who were older than 75 years, as the average age in clinical trials is 67 to 71 which isn’t reflective of current practice.

Once again, ibrutinib was effective in this patient group. There are toxicities associated with ibrutinib and specialists should be aware of them and actively manage in order to improve quality of life in addition to extension of life.

" I B R U T I N I B H A S B E E N S T U D I E D E X T E N S I V E LY

O V E R T H E P A S T F E W Y E A R S A N D H A S

C O N T I N U O U S L Y H A D P O S I T I V E S U R V I V A L

R A T E S F O R P A T I E N T S S U F F E R I N G F R O M

R E L A P S E D / R E F R A C T O R Y C L L . "

4

PERSPECTIVES - ASCO & EHA 2016

" U S I N G I B R U T I N I B E A R L I E R I N T H E D I S E A S E

C O U R S E C O U L D T R A N S L A T E T O A N O S

A D V A N T A G E I N P A T I E N T S . "

ASCO 2016. ABSTRACT 7520. Outcomes with ibrutinib by line of therapy in patients with CLL: Analyses from phase III data.

Susan Mary O'Brien et al.

Results: We analyzed data from two phase 3 trials of ibr: PCYC-1115/16 (RESONATE-2) in pts ≥ 65 with treatment naïve (TN) CLL; PCYC-1112 (RESONATE) in previously treated (PT) CLL, excluding pts with del17p for a more homogenous dataset for analysis. Progression-free survival (PFS) and overall response rate (ORR) were assessed by investigator.

In TN vs PT patients, median (med) age was 73 vs 66 yrs. PT patients had med 3 prior therapies including CD20 antibody (93%), purine analog (87%), or alkylating agents (93%; bendamustine 41%). Med PFS and OS were not reached (NR) for TN or PT patients, with 89-92% progression free at 2 yrs for pts treated with ibr in 1st- or 2nd-line. ORR was high regardless of LoT (91% in TN, 92% in PT patients). Most pts continue ibr. Adverse event (AE) profile was similar for both groups. Pts receiving ibr in earlier LoT were less likely to DC ibr due to progression (PD). Med OS post ibr DC is NR for pts who received ibr in 1st- or 2nd-line (n = 23) vs 7-9 m in 3rd-line and beyond (n = 34).

Conclusions: Ibr led to favourable PFS and OS, and high ORR regardless of LoT in pts with CLL. Pts who received ibr in 1st- or 2nd-line were less likely to progress and experienced better post-ibr survival outcomes. Clinical trial information: NCT01578707 and NCT01722487

CARE FACULTY PERSPECTIVE: This trial combines the patients from multiple trials and compares ibrutinib-based therapy with standard therapies. It is not surprising to see that patients treated with ibrutinib as part of primary or second-line therapies appear to have higher rates of PFS compared to patients who receive treatment later in the disease course.

How this impacts overall survival remains unproven. Using ibrutinib earlier in the disease course could translate to an OS advantage in patients. More data with longer follow-up will be needed to confirm this hypothesis.

ASCO 2016. ABSTRACT 7525. Ibrutinib (I) plus bendamustine and rituximab (BR) in previously treated chronic lymphocytic leukemia/small lymphocytic lymphoma (CLL/SLL): a 2-year follow-up for the HELIOS study.

Graeme Fraser et al.

Results: Median follow up is 25.4 months. I + BR continues to show improvement in PFS vs P + BR (investigator [INV]-assessed median: not reached [NR] vs 14.2 months; HR [95% CI]: 0.199 [0.15, 0.26], p< 0.0001; 2-yr rate: 74.8% vs 20.9%). Median OS is still NR in either arm (HR [95% CI]: 0.670 [0.44, 1.02], p = 0.0587; 2-yr rate: 86.2% vs 81.5%); 142 pts (49.1%) in the P + BR arm with confirmed PD have crossed over to receive I, as permitted by protocol. The updated INV-assessed ORR is 87.2% for I + BR vs 66.1% for P + BR (p< 0.0001); updated rates of CR/CRi are 33.9% vs 7.2% (rates at first analysis: 21.4% vs 5.9%). Rates of MRD -ve response for the intent-to-treat population are 18.0% (52/289) for I + BR and 4.8% (14/289) for P + BR (p< 0.0001) (rates at first analysis: 12.8% vs 4.8%). Median PFS2 is unreached in both arms, but PFS2 is significantly longer for pts assigned to I + BR vs P + BR, despite crossover (HR [95% CI]: 0.622 [0.42, 0.92], p= 0.0162). Safety is consistent with first analysis.

Conclusions: I + BR continues to demonstrate superiority vs P + BR with significantly longer PFS and higher ORR. Responses continue to deepen with continuous ibrutinib therapy with rates of CR/CRi and MRD -ve response increasing over time. At every MRD level (<0.01% or ≥10% CLL+), I + BR showed a more sustained PFS than P + BR. These 2-year follow-up data confirm the important role of ibrutinib in pts with previously treated CLL. Clinical trial information: NCT01611090

CARE FACULTY PERSPECTIVE: As expected, further follow-up of the HELIOS study continues to demonstrate superiority for ibrutinib in combination with BR versus BR in previously treated CLL. The increase in MRD negative response from 12.8% to 18% with a longer follow-up period points to patients with increasing depth of response as duration of ibrutinib exposure increases. This may suggest that the original HELIOS report underestimated the benefit of adding ibrutinib to BR.

Longer follow-up to look at the impact of combination therapy with ibrutinib on OS is still awaited as the median OS for either arm has not been reached. The role of chemotherapy in this setting remains unclear, particularly in patients with high risk disease or early treatment failure.

5

PERSPECTIVES - ASCO & EHA 2016

ACUTE LEUKEMIA

ASCO 2016. 7000. Final results of a phase III randomized trial of CPX-351 versus 7+3 in older patients with newly diagnosed high risk (secondary) AMLJeffrey E. Lancet et al.

Results: A total of 309 patients were randomized (153 to CPX-351 + 156 to 7+3) and were well balanced for sex, race, age, performance status, AML-subtype, MDS-related cytogenetics and prior HMA therapy. After minimum follow-up of 13.7 months final analysis began.CPX-351 treatment resulted in superior overall survival (HR=0.69; P=0.005; median OS 9.56 vs. 5.95 months), EFS (HR=0.74; P=0.021), and CR+CRi response (47.7% vs. 33.3%; P=0.016). 60-day mortality favored CPX-351 (13.7% vs. 21.2%). Grade 3-5 AEs were equal (92% vs. 91%) and were similar in frequency and severity in both arms. Similar numbers of patients were transplanted in both arms.

Conclusion: CPX-351 treatment significantly improved overall survival, event free survival, and response without an increase in 60-day mortality or AE frequency or severity. CPX-351 should become the standard of care for older patients with secondary AML. Clinical trial information: NCT01696084

CARE FACULTY PERSPECTIVE: Older patients do not experience very good outcomes with first-line 7+3 and thus new therapy options are required. This study looked at CPX-351, a therapy designed to provide fixed ratios of doxorubicin and cytarabine via an IV liposomal delivery system, in older patients with high risk secondary AML. Results from this trial showed a superior OS of approximately 4 months for CPX-351 when compared with 7+3 treatment regimen (cytarabine & daunorubicin). While the toxicity was similar, improved response rates, post-transplant outcomes, PFS and OS highlight the activity and safety of CPX-351. The study highlighted poor outcomes with standard therapy in this setting and CPX-351 is now a treatment showing survival advantages for these high risk patients.

Even with 4-month OS advantage, prognosis for elderly high-risk AML patients still remains poor. More research needs to be conducted in this field by incorporating newer targeted therapies in order to improve patient outcomes.

EHA 2016. ABSTRACT LB2073. Efficacy and safety of inotuzumab ozogamicin (INO) vs standard of care (SOC) in salvage 1 or 2 patients with acute lymphoblastic leukemia (ALL): An ongoing global phase 3 studyDaniel J. DeAngelo et al.

Results: Per protocol, the first 218 of 326 pts randomized were included in the primary intent-to-treat (ITT) analysis (for InO vs SOC [n=109 each]: CR1 duration ≥12 mo, 43% vs 35%; age <55 y, 61% vs 63%; Salvage 1, 67% vs 63%); CR/CRi rate was significantly better in the InO vs SOC arm (see Table for efficacy). Safety was assessed in 259 pts who received ≥1 dose of study drug; pts received InO (n=139) for median 8.3 (range, 0.1–26.4) wks vs SOC (n=120) for median 0.9 (0.4–15.1) wks; 83% vs 89% discontinued, primarily due to CR in InO (35%) vs resistant ALL in SOC (40%) arms. Most common grade (Gr) ≥3 AEs were hematologic cytopenias. For InO vs SOC, Gr≥3 hepatobiliary AEs occurred in 9% vs 3% pts; any grade veno-occlusive liver disease (VOD) occurred in 15 vs 1 pts (Gr≥3, 13 vs 1 pts). More patients proceeded to allogeneic SCT with InO (n=48) vs SOC (n=20); in the InO arm, 5 VOD cases (2 in pts with prior SCT) occurred during treatment and 10 after subsequent SCT (2 fatal).

Efficacy Results

% (95% CI) InO (n=109) SOC (n=109) 1-sided P-Value

CR/CRia 80.7 (72–88) 33.3 (24–44) <0.0001

S1 87.7 31.3 <0.0001

S2 66.7 37.9 0.0104

Median DOR, mo 4.6 (3.9–5.4) 3.1 (1.4–4.9) 0.0169

MRD-neg in pts with CR/CRi

78.4 (68–87) 28.1 (14–47) <0.0001

aModified ITT analysis excluding 13 untreated SOC pts; assessed

perindependent endpoint adjudication committee

Conclusions: CR/CRi, DOR, and MRD-neg rates were significantly greater with InO vs SOC. InO safety profile is consistent with previous studies; liver toxicities and VOD were more common with InO; additional VOD analyses characterizing risk factors and management considerations will be presented. Trial is ongoing to allow survival data to mature.

CARE FACULTY PERSPECTIVE: This study demonstrates that inotuzumab is a better option than the current standard of care for patients with ALL. Additionally, another late breaking abstract presented at EHA 2016 (LB2233) by Kantarjian et al. provided evidence of a longer OS and significantly longer PFS data for adult patients with R/R ALL. Given this positive data, we should expect this agent to be introduced into the Canadian landscape in the near future. Despite the improvements, the median duration of response remains disappointing, and more work is needed to make a meaningful impact on refractory ALL, perhaps incorporating this agent into novel combinations.

" O L D E R P A T I E N T S D O N O T E X P E R I E N C E

V E R Y G O O D O U T C O M E S W I T H F I R S T - L I N E

7 + 3 A N D T H U S N E W T H E R A P Y O P T I O N S

A R E R E Q U I R E D . "

6

PERSPECTIVES - ASCO & EHA 2016

MANTLE CELL LYMPHOMA

ASCO 2016. ABSTR ACT 7503. Two years rituximab maintenance vs. observation after first-line treatment with bendamustine plus rituximab (B-R) in patients with mantle cell lymphoma: First results of a prospective, randomized, multicenter phase II study (a subgroup study of the StiL NHL7-2008 MAINTAIN trial).Mathias J. Rummel et al.

Results: A total of 120 patients were evaluable for the analysis, 59 (49%) were randomized to maintenance with rituximab and 61 (51%) to observation, respectively. Patient characteristics were comparable for both groups. Median patient age was 70 years, median time of observation was 54.2 months at the time of this analysis (January 2016). No significant difference in PFS between both arms could be observed (p = 0.130, 47 events, HR 0.64, 95% CI 0.36 – 1.14). The median for R maintenance was not yet reached, whereas for the observation arm the median was 54.7 months (95% CI 40.1. – n. y. r.). The results for overall survival showed no difference (p = 0.271, 27 events, HR 1.53, 95% CI 0.73 – 3.32) with a median of 69.6 months for R maintenance versus a median not yet reached in the observation arm.

Conclusions: After a median observation time of 4.5 years, the results are yet inconclusive. Up to date we were not able to demonstrate statistical evidence supporting the benefit of R maintenance after B-R in the treatment of patients with MCL. Longer follow-up is needed before final results can be presented. Clinical trial information: NCT00877214

CARE FACULTY PERSPECTIVE: Most Canadian centres use the combination of bendamustine and rituximab as treatment of patient with MCL, particularly those ineligible for SCT. This is often followed by maintenance rituximab although there are no data examining maintenance post B-R. While this trial looks at this question prospectively, it did not demonstrate an advantage for rituximab maintenance in patients that had received B-R.

Whether this is due to the smaller sample size of the trial (particularly compared to the European MCL network study) or if there could be a reason for the lack of benefit for maintenance rituximab following bendamustine instead of CHOP remains unclear. While these findings are interesting, we do not suggest changing practice at this time, given the limitations to this study.

EHA 2016. ABSTRACT S438. Overall Survival Outcomes in Patients with Mantle Cell Lymphoma (MCL) treated with Ibrutinib in a Pooled Analysis of 370 Patients from 3 International Open-Label Studies Simon Rule et al.

Results: Overall, 370 patients were included in this analysis (PCYC-1104, n=111; SPARK, n=120; RAY, n=139); median age was 67.5 years, 94% had ECOG 0-1, 45% and 32% had intermediate and high-risk sMIPI, most patients had 1-3 prior lines of therapy (27%, 29%, 22% had 1, 2, 3 prior lines of therapy, respectively), 49% had bulky disease (>5 cm) and 88% had non-blastoid histology. Overall response rate (ORR) was 66% (20% CR; 46% PR), with a median DOR, PFS and OS of 18.6, 12.8 and 25.0 months, respectively. ORR (CR) for patients with 1, 2 and ≥3 prior lines of therapy was 77.8% (34%), 71% (24%) and 64% (16%). Of patients who achieved a CR, 70% were progression-free and 90% were alive at 2 years. Univariate analyses showed that patients with 1 vs >1 prior line of therapy had significantly longer OS, with longer OS also observed in those who were younger and had non-blastoid histology, non-bulky disease or better sMIPI score. Patients with blastoid and non-blastoid histology had similar ORR (55 vs 72%) and time to best response (2.2 vs 2.1 months); however, DOR (8.6 vs 18.8 months), PFS (5.1 vs 14.6 months) and OS (12.8 vs not reached) were significantly shorter in patients with blastoid histology. Multivariate analyses identified ECOG, sMIPI, bulky disease and blastoid histology as impacting OS, and sMIPI, bulky disease, blastoid histology and 1 prior line of therapy as impacting PFS.

Conclusion: Here we show that OS is significantly longer in ibrutinib-treated patients who are younger and who have fewer prior lines of therapy, better sMIPI scores, non-bulky disease and non-blastoid histology. While PFS and OS in patients with blastoid vs non-blastoid histology are shorter, these rates are higher than seen with other agents, indicating that ibrutinib is an effective agent to achieve a response and potentially provide a bridge to transplant. Multivariate analyses indicate that traditional poor prognostic factors adversely impact OS, suggesting that worsening OS in later lines of therapy is associated with disease characteristics rather than an impact of ibrutinib on post progression survival. Data support the preferential use of ibrutinib after initial vs later relapse, as PFS and OS are longer in patients receiving 1 vs >1 prior line of therapy.

CARE FACULTY PERSPECTIVE: Ibrutinib clearly appears to be the preferred strategy for patients with relapsed/refractory mantle cell lymphoma. This study highlights the inferior outcomes of multiply treated MCL and supports the use of active agents such as ibrutinib earlier in the disease course.

" T H I S T R I A L . . . D I D N O T D E M O N S T R A T E

A N A D V A N T A G E F O R R I T U X I M A B

M A I N T E N A N C E I N P A T I E N T S T H A T H A D

R E C E I V E D B - R . "

7

PERSPECTIVES - ASCO & EHA 2016

DIFFUSE LARGE B-CELL LYMPHOMA

EHA 2016. LB705. PILLAR-2: A randomized, double-blind, placebo-controlled, phase III study of adjuvant everolimus (EVE) in patients (pts) with poor-risk diffuse large B-cell lymphoma (DLBCL).

Franco Cavalli et al.

Results: DFS + OS Outcomes

Number of patientsEVE/PBO

EVE vs PBO HR (95% CI)

DFS*

Overall (n = 742) 372/370 0.92 (0.69–1.22)†

IPI 4+5 (n = 313) 148/165 0.65 (0.42–1.01)

Male (n = 372) 168/204 0.68 (0.45–1.05)

Age <65 years (n=398)

192/201 0.79 (0.52-1.21)

OS*

Overall (n = 742) 372/370 0.75 (0.51–1.10)

IPI 4+5 (n = 313) 148/165 0.63 (0.37–1.07)

Male (n = 372) 168/204 0.55 (0.32–0.94)

Age <65 years (n=398)

192/201 0.62 (0.34-1.13)

LSS* (n = 742) 372/370 0.64 (0.39–1.04)

* Median duration not estimable. †Log-Rank p = 0.276.

Conclusion: Adjuvant EVE for 1 year did not improve DFS in poor-risk pts with DLBCL who achieved a CR after R-chemo. Trends favoring adjuvant EVE for DFS and OS in selected pt subgroups and for LSS in the overall population suggest that EVE may provide anti-lymphoma activity in poor-risk DLBCL that warrants further investigation. Clinical trial information: NCT00790036

VISIT TH E C AR E YO UTU B E CHAN N E L

FOR AN UPDATE FROM C ARE H EMATOLOGY FACU LT Y M EM B ER

DR . JOHN KURUVILL A

CARE FACULTY PERSPECTIVE: This was another fairly large RCT with no significant advantage for a maintenance strategy in DLBCL. However, it appears that everolimus provided some benefit in terms of OS and lymphoma-specific survival (LSS) in two patient subgroups: males & those with IPI 4+5.

We can expect further investigation with everolimus in these patient groups to determine whether it could positively affect their life span for high-risk DLBCL. In the future, we may see studies with different populations, different therapies, and perhaps no more maintenance trials.

" I T A P P E A R S T H A T E V E R O L I M U S

P R O V I D E D S O M E B E N E F I T I N T E R M S O F

O S A N D LY M P H O M A - S P E C I F I C S U R V I V A L

I N T W O P A T I E N T S U B G R O U P S : M A L E S &

T H O S E W I T H I P I 4 + 5 . "

8

PERSPECTIVES - ASCO & EHA 2016

HODGKIN’S LYMPHOMA

ASCO 2016. ABSTRACT 7555. Pembrolizumab for relapsed/refractory classical Hodgkin lymphoma (R/R cHL): phase 2 KEYNOTE-087 study.Robert W. Chen et al.

Results: At time of data cutoff (Feb 1, 2016), 60 pts were evaluable for cohorts 1 and 2. Median (range) age was 36 (19-64) years in cohort 1 and 33 (20-71) in cohort 2. 67% received ≥ 4 prior lines of therapy, and by design 100% failed prior BV. ORR among 30 pts in cohort 1 is 70% (95% CI, 51-85). 6 pts (20%) achieved CR (residual mass permitted if PET negative), 15 (50%) PR, and 6 (20%) stable disease as best response. ORR among 30 pts in cohort 2 is 80% (95% CI, 61-92). 8 pts (27%) achieved CR, 16 (53%) PR, and 4 (13%) stable disease as best response. With a median of 6 treatment cycles, most common treatment-related AEs in the combined cohorts are pyrexia (13%), diarrhea (8%), fatigue, back pain, platelet count decrease, dry skin, and cough (7% each).

Conclusions: PD-1 blockade with pembrolizumab shows early responses in heavily pretreated cHL pts. Of note, pembrolizumab shows an unprecedented high ORR (80%) in pts who were not candidates for ASCT and failed previous BV therapy. Clinical trial information: NCT02453594

CARE FACULTY PERSPECTIVE: In April, the FDA granted breakthrough designation therapy to pembrolizumab as a treatment for patients with relapsed/refractory classical HL, based on the early findings from the KEYNOTE-13 study as well as the unpublished findings from the KEYNOTE-87 trial. ASCO reported on the results from the latter, showing that pembrolizumab has very high response rates even in heavily pre-treated, refractory patients. We look forward to this agent being approved in Canada.

ASCO 2016. 7535. Checkmate 205: Nivolumab (nivo) in classical Hodgkin lymphoma (cHL) after autologous stem cell transplant (ASCT) and brentuximab vedotin (BV)—A phase 2 studyAnas Younes et al.

Results: The main characteristics of 80 treated cHL pts were: median age 37 y, median (range) 4 prior regimens (3–15). 90% of pts had drug-related AEs: 25% G3–4, 1% G5 (multi-organ failure). Most common drug-related AEs were fatigue (25%), infusion reaction (IR; 20%) and rash (16%). Most common SAEs were pyrexia, tumor progression, arrhythmia, IR, septic meningitis, and pneumonia ( ≤ 4% each). Select immune-related AEs, all G1–2, occurred in 26%. At database lock (DBL; October 2015), median (range) follow-up was 8.9 mo (1.9–11.7). 64% of pts remained on therapy; main reason for discontinuation was disease progression (16%). IRRC ORR (95% CI) was 66% (54.8–76.4); CR and PR rates were 8.8% (3.6–17.2) and 57.5% (45.9–68.5), respectively. Inv ORR, a pre-specified secondary endpoint, was 73% (61.4–81.9); CR and PR rates were 27.5% (18.1–38.6) and 45.0% (33.8–56.5). 62% (33/53) of IRRC responders remained in response at DBL. 6 pts elected to stop nivo and undergo stem cell transplant, all of these pts were alive at data cut-off. IRRC 6-mo PFS was 77%; OS was 99%. In 43 pts who had no prior BV response, nivo treatment resulted in an IRRC ORR of 72% (31/43).

Conclusions: Nivo demonstrated a high response rate, long-lasting responses, and an acceptable safety profile in pts with cHL after ASCT and BV, including pts with no prior BV response. PFS and OS are encouraging in this heavily pretreated population. Clinical trial information: NCT02181738

CARE FACULT Y PERSPECTIVE: Nivolumab represents an important new treatment for patients with relapsed/refractory cHL post ASCT and brentuximab. This is now FDA approved and hopefully will be available to patients in Canada shortly.

" I N A P R I L , T H E F D A G R A N T E D

B R E A K T H R O U G H D E S I G N AT I O N T H E R A P Y

T O P E M B R O L I Z U M A B A S A T R E A T M E N T

F O R P A T I E N T S W I T H R E L A P S E D /

R E F R A C T O R Y C L A S S I C A L H L . "

9

TM

CHC 2016C A N A D I A N H E M A T O L O G Y C O N F E R E N C E

C O N F É R E N C E C A N A D I E N N E S U R L ’ H É M A T O L O G I E

D O N ' T M I S SE A R L Y B I R DR E G I S T R A T I O N

C O S T S

T H E C A R E F A C U L T Y I S W O R K I N G O N A S E T O F R E G I O N A L M E E T I N G S C O M I N G S O O N T O A C I T Y N E A R Y O U !

C H C – W E S T C A L G A R Y , O C T O B E R 2 0 1 6

C H C – A T L A N T I C H A L I F A X , N O V E M B E R 2 0 1 6

C H C – Q U É B E C Q U É B E C C I T Y , T B D

P R E S E N T E D B Y :

S E P T E M B E R 2 3 - 2 4 , 2 0 1 6 I N T E R C O N T I N E N T A L T O R O N T O - Y O R K V I L L E H O T E LT O R O N T O , O N

P L E A S E V I S I T W W W. C A R E E D U C AT I O N . C A / C H C - 2 0 1 6 T O R E G I S T E R T O DAY !

J U L Y 3 1 D E A D L I N E !

This CARE PUBLICATION provides educational updates on current trends in medicine. Content reflects the opinions, output and analyses of experts, investigators, educators and clinicians ("CARE Faculty"), whose activities, while independent, are commercially supported by the noted sponsor(s).Program content is developed independently of sponsor(s). This content is intended for educational value only; to make scientific information and opinions available to health professionals, to stimulate thought, and further investigation. Decisions regarding diagnosis and/or management of any individual patient or group of patients should be made on individual basis after having consulted appropriate sources. Opinions expressed herein reflect the opinions and analyses of the experts who have authored the material. Support for the distribution of this report was provided by Janssen Inc. and Novartis Canada Inc. Copyright © 2016 by CARE. All rights reserved. This publication or any portion thereof, in print, electronic copy or any other form, cannot be reproduced without the express written consent of CARE. Any information, data, analysis, or results reproduced from another source remains the property of its authors.