Hematologic Malignancies

EditorsFrederick R. Appelbaum, MDDeputy Director and Executive Vice PresidentFred Hutchinson Cancer Research CenterDirectorSeattle Cancer Care AllianceProfessor, Division of Medical OncologyUniversity of Washington School of MedicineSeattle, Washington

A. Keith Stewart, MB ChB, FRCPC, MBADean for Research, Mayo Clinic in ArizonaVasek and Anna Maria Polak Professorship in Cancer ResearchConsultant, Division of Hematology/OncologyMayo ClinicScottsdale, Arizona

John Sweetenham, MD, FRCP Senior Director for Clinical AffairsExecutive Medical DirectorHuntsman Cancer Institute, University of UtahSalt Lake City, Utah

Advances in the Management of Hematologic Malignancies: Highlights from the 2014 ASCO Annual Meeting

An Interactive PDF Newsletter

This activity is supported by independent educational grants from Celgene Corporation and Novartis Oncology.

This activity is sponsored by

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TABLE OF CONTENTS (CLICK THE SECTION YOU WISH TO VIEW)

INTRODUCTION ........................................................................................................................................................ 1

LYMPHOMA .............................................................................................................................................................. 1

DLBCL and FL ............................................................................................................................................................................................ 1

Effect of Lenalidomide Combined With R-CHOP (R2CHOP) on Non-GCB DLBCL ........................................................1

Polatuzumab Vedotin or Pinatuzumab Vedotin Plus Rituximab .......................................................................................3

Prognostic Value of Positron Emission Tomography-Computed Tomography (PET-CT) After Frontline Therapy in FL ..........................................................................................................................................................4

PET-Driven Consolidation Strategy in High-Risk DLBCL .......................................................................................................5

Mantle Cell Lymphoma .......................................................................................................................................................................... 6

R-CHOP Plus Vincristine or Bortezomib in MCL Patients Ineligible for Transplantation ..........................................6

Hodgkin Lymphoma ............................................................................................................................................................................... 7

Brentuximab Vedotin Followed by ABVD in Previously Untreated Hodgkin Lymphoma ........................................7

MULTIPLE MYELOMA ............................................................................................................................................... 8

Newly Diagnosed ..................................................................................................................................................................................... 8

Melphalan, Prednisone, and Thalidomide vs Melphalan, Prednisone, and Lenalidomide ......................................8

Relapsed/Refractory MM ........................................................................................................................................................................ 9

Panobinostat or Placebo Plus Bortezomib and Dexamethasone .....................................................................................9

Daratumumab Monotherapy ...................................................................................................................................................... 10

SAR650984 in Combination With Lenalidomide and Dexamethasone ....................................................................... 11

LYMPHOPROLIFERATIVE DISORDERS ................................................................................................................... 12

Multicentric Castleman’s Disorder ..................................................................................................................................................... 12

Siltuximab in Previously Treated Multicentric Castleman’s Disorder ............................................................................ 12

MYELOPROLIFERATIVE NEOPLASMS .................................................................................................................... 13

Polycythemia Vera ................................................................................................................................................................................ 13

Ruxolitinib Patients With Hydroxyurea Resistance/Intolerance: RESPONSE Trial ..................................................... 13

LEUKEMIA ................................................................................................................................................................ 15

Acute Lymphoblastic Leukemia......................................................................................................................................................... 15

Blinatumomab in Relapsed or Refractory B-Precursor ALL .............................................................................................. 15

Chronic Lymphocytic Leukemia/Small Lymphocytic Leukemia ................................................................................................ 16

Ibrutinib vs Ofatumumab in Relapsed or Refractory CLL/SLL: RESONATE Trial......................................................... 16

Ibrutinib Efficacy 3 Years Post-Initiation of Monotherapy ................................................................................................. 17

Idelalisib in CLL With del(17p) ..................................................................................................................................................... 18

GS-9973, A Selective Syk Inhibitor ............................................................................................................................................ 18

Chronic Myeloid Leukemia .................................................................................................................................................................. 19

Newly Diagnosed CML Treated With Imatinib 400 mg or 800 mg: 10-Year Followup ............................................ 19

CONCLUSION ......................................................................................................................................................... 19

POST-TEST AND EVALUATION ................................................................................................................................ 20

REFERENCES ............................................................................................................................................................ 20

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MEDIA: NEWSLETTEREstimated time to complete activity: 1.0 hourRelease date: Wednesday, August 6, 2014 | Expiration date: Wednesday, August 5, 2015

INTRODUCTIONThe 2014 American Society of Clinical Oncology (ASCO) Annual Meeting held in Chicago, Illinois, provided a comprehensive review of key experimental and clinical data. Included in this newsletter are highlights from the conference covering major plenary sessions, key symposia, and targeted oral and poster presentations on the advances in the management of hematologic malignancies.

EDITORSFrederick R. Appelbaum, MDDeputy Director and Executive Vice PresidentFred Hutchinson Cancer Research CenterDirectorSeattle Cancer Care AllianceProfessor, Division of Medical OncologyUniversity of Washington School of MedicineSeattle, Washington

TARGET AUDIENCE The target audience for this activity is medical oncologists, hematologist/oncologists, hematopathologists, oncology pharmacists, and other allied healthcare professionals caring for patients with hematologic malignancies.

EDUCATIONAL OBJECTIVESAt the conclusion of this activity, participants should be able to:

• Discuss implications of updated efficacy and safety data for clinically available treatment options for patients with hematologic malignancies• Describe potential role of new therapeutic agents or strategies into clinical practice to improve remission and survival rates for patients with hematologic

malignancies• Describe the proposed mechanisms of action of new and emerging therapeutic agents in development for the management of patients with hematologic

malignancies• Differentiate treatment regimens based upon efficacy and toxicity parameters

DESIGNATION OF CREDITPHYSICIAN CONTINUING EDUCATION Accreditation Statement

Educational Concepts Group, LLC is accredited by the Accreditation Council for Continuing Medical Education to provide continuing medical education for physicians.

Credit Designation Statement Educational Concepts Group, LLC designates this enduring material for a maximum of 1.0 AMA PRA Category 1 Credit™. Physicians should claim only the credit commensurate with the extent of their participation in the activity.

METHOD OF PARTICIPATIONThere are no fees for participating and receiving CME credit for this activity. During the period Wednesday, August 6, 2014 through Wednesday, August 5, 2015, participants must 1) read the educational objectives and faculty disclosures; 2) study the educational activity; 3) complete the post-test and evaluation.

CME CREDITPhysicians who complete the post-test with a score of 80% or better may view and print their credit letter or statement of credit via the website, www.ecgcme.com.

A. Keith Stewart, MB ChB, FRCPC, MBA Dean for Research, Mayo Clinic in ArizonaVasek and Anna Maria Polak Professorship in Cancer ResearchConsultant, Division of Hematology/OncologyMayo ClinicScottsdale, Arizona

John Sweetenham, MD, FRCP Senior Director for Clinical AffairsExecutive Medical DirectorHuntsman Cancer Institute, University of UtahSalt Lake City, Utah

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POLICY ON DISCLOSUREIt is the policy of ECG that the faculty, authors, planners, and other persons who may influence content of this CME activity disclose all relevant financial relationships with commercial interests in order to allow ECG to identify and resolve any potential conflicts of interest.

The Following Faculty Members Have Declared Relevant Financial Relationships

Frederick R. Appelbaum, MD Consultant Fees Amgen Inc., Celator Pharmaceuticals, Inc., National Marrow Donor Program, Neumedicines Inc.

A. Keith Stewart, MB ChB, FRCPC, MBA Consultant Fees Array BioPharma , Bristol-Myers Squibb Company, Celgene Corporation, sanofi-aventis

John Sweetenham, MD, FRCP Speakers’ Bureau Seattle Genetics, Inc. STAFF DISCLOSUREPlanners and managers at ECG have no relevant financial relationships to disclose.

ACKNOWLEDGEMENTThe editors wish to thank Sara R. Fagerlie, PhD, CCMEP and Lisa van Devender, PharmD for assistance in writing this document.

DISCLOSURE OF OFF-LABEL USEThis educational activity may contain discussion of published and/or investigational uses of agents that are not indicated by the FDA. ECG does not recommend the use of any agent outside of the labeled indications. The opinions expressed in the educational activity do not necessarily represent the views of ECG. Please refer to the official prescribing information for each product for discussion of approved indications, contraindications, and warnings.

DISCLAIMERParticipants have an implied responsibility to use the newly acquired information to enhance patient outcomes and their own professional development. The information presented in this activity is not meant to serve as a guideline for patient management. Any procedures, medications, or other courses of diagnosis or treatment discussed or suggested in this activity should not be used by clinicians without evaluation of their patient’s conditions and possible contraindications on dangers in use, review of any applicable manufacturer’s product information, and comparison with recommendations of other authorities.

Please refer to the official prescribing information for each product or consult the Physicians’ Desk Reference for discussion of approved indications, contraindications, and warnings.

ACKNOWLEDGEMENT OF COMMERCIAL SUPPORTThis activity is supported by independent educational grants from Celgene Corporation and Novartis Oncology.

CME INQUIRIESFor further information, please contact:Educational Concepts Group, LLC 1300 Parkwood Circle SE, Suite 325Atlanta, Georgia 30339Phone: 1.866.933.1681 | Fax: 1.866.933.1692www.ecgcme.com

None of the contents may be reproduced in any form without prior written permission from the publisher. This activity may be accessed at www.ecgcme.com.

http://www.ecgcme.com


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INTRODUCTION“Science and Society” was the theme of the 2014 American Society of Clinical Oncology (ASCO) Annual Meeting, held in Chicago, Illinois May 30-June 3, 2014. Providing the largest international multidisciplinary forum for cancer research, ASCO gathers clinicians from around the globe to present and discuss cutting-edge outcomes in multiple oncology specialties. Further optimization of current treatments and the development of important novel therapies continued to be intense areas of investigation. Data and information from notable ASCO presentations on hematological malignancies are highlighted in this newsletter.

LYMPHOMA The National Cancer Institute estimates that there will be approximately 71,000 new cases and 19,000 deaths from non-Hodgkin lymphoma (NHL) in the US in 2014.1 Although the combination of rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone (R-CHOP) has been an accepted standard of care for the most common B-cell malignancies, including several NHL subtypes, there is still a relatively high rate of relapse after treatment with R-CHOP. Therapeutic agents that continue to show promise in the treatment of NHL include monoclonal antibodies, immunomodulatory drugs, antibody-drug conjugates (ADCs), and therapies that target key cellular pathways. Clinical trials that evaluated some of these approaches for the treatment of relapsed/refractory NHL are discussed below.

DLBCL and FLEffect of Lenalidomide Combined With R-CHOP (R2CHOP) on Non-GCB DLBCLDespite advances in the treatment of diffuse large B-cell lymphoma (DLBCL), approximately 40% of patients will relapse after treatment with R-CHOP, and, unfortunately, the majority of patients with relapsed DLBCL will die from the disease. There is evidence that, for patients who are not eligible for stem cell transplantation, salvage therapy has little impact on improvement of outcomes in patients with DLBCL. However, autologous hematopoietic cell transplantation can cure a substantial fraction of patients with DLBCL who suffer an initial relapse. Two distinct biological and molecular subtypes of DLBCL are recognized ─ germinal center B-cell (GCB) and activated B-cell (ABC; also referred to as non-germinal center B-cell, or non-GCB).2 Patients with the ABC subtype of DLBCL have significantly worse outcomes in terms of both progression-free survival (PFS) and overall survival (OS). Despite this, R-CHOP or R-CHOP-like chemotherapy is standard of care for patients with both GCB and ABC subtypes.

Recent evidence suggests that B-cell receptor signaling is a critical driver of ABC subtype of DLBCL, and studies with the immunomodulatory agent, lenalidomide, have demonstrated the synthetic lethality of lenalidomide in ABC DLBCL is related to downstream inhibition of B-cell receptor signaling.3,4 In the clinical setting, treatment of DLBCL with lenalidomide yields an overall response rate (ORR) of about 30%,5 and data in relapsed DLBCL suggest that the activity of lenalidomide occurs mainly in the non-GCB subtype, in terms of both response rate and progression.

In phase I studies lenalidomide in combination with standard R-CHOP therapy (R2CHOP) was found to be safe and effective.6 At the 2014 ASCO Annual Meeting, Dr Nowakowski presented the results of the phase II study, which evaluated the efficacy of this combination in patients with newly diagnosed, untreated

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DLBCL and analyzed the outcomes based on DLBCL subtype.7 Eligible patients received lenalidomide at 25 mg days 1-10 with standard dose R-CHOP every 21 days for 6 cycles. All patients received pegfilgrastim support and prophylactic aspirin (325 mg daily). Of the 64 patients enrolled, 25% were over age 70, 60% had stage IV disease, and 52% had high-intermediate or high International Prognostic Index (IPI).

With 60 patients evaluable for response, the ORR was 98% (complete response [CR] 80% and partial response [PR] 18%) as defined by PET criteria. At 24 months, the PFS and OS rates were 59% and 78%, respectively. In a non-randomized case match control analysis, R2CHOP patients appear to compare favorably to R-CHOP alone with regard to 24-month PFS (52% vs 59%) and OS (65% vs 78%). In patients treated with R-CHOP alone those with non-GCB subtype had significantly reduced 24-month PFS rates (28% vs 64%; P < 0.001) and OS (46% vs 78%; P < 0.001). In contrast, there was no difference in 24-month PFS or OS between GCB and non-GCB subtypes treated with R2CHOP (60% vs 59%, P = 0.83 and 83% vs 75%, P = 0.61, respectively) and patients with non-GCB subtype did better with R2CHOP (Figure 1).

Grade 3 or higher toxicity was mainly hematological; with grade 3 or 4 neutropenia occurring in over 80% of patients and thrombocytopenia occurring in over 40% of patients. Neutropenic complications (febrile neutropenia and bleeding) were rare. Thrombosis occurred in 1 patient and there was 1 death from a bowel perforation and subsequent sepsis.

Overall, the use of R2CHOP regimen in the treatment of DLBCL shows promising activity and may ameliorate the negative effect of non-GCB on outcome. A randomized study to further evaluate R-CHOP vs R2CHOP utilizing DLBCL subtype is underway.

Figure 1. (A) Progression-free and (B) overall survival in DLBCL patients with non-GCB subtype treated with R-CHOP or treated with R-CHOP or lenalidomide with R-CHOP (R2CHOP).

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20

30

40

50

60

70

80

90

100

Non-GCB: Progression-Free Survival by Treatment

+ Censor

R2CHOP12 Month (95% CI): 72% (55-94)24 Month (95% CI): 60% (41-87)R-CHOP12 Month (95% CI): 39% (25-62)24 Month (95% CI): 28% (15-51)

0 6 12 18 24 30

22 20 14 10 5 428 17 11 8 6 3

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+ Censor

R2CHOP12 Month (95% CI): 95% (87-100)24 Month (95% CI): 83% (67-100)R-CHOP12 Month (95% CI): 61% (45-82)24 Month (95% CI): 46% (30-69)

0 6 12 18 24 30

22 21 18 13 6 628 23 17 14 11 5

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Polatuzumab Vedotin or Pinatuzumab Vedotin Plus Rituximab Polatuzumab vedotin (PoV) and pinatuzumab vedotin (PiV) are antibody drug conjugates (ADC), consisting of the potent microtubule inhibitor monomethyl aurostatin E (MMAE) and targeting CD79b (PoV) and CD22 (PiV). Both have shown clinical activity in phase I studies. Preliminary results of the ROMULUS study, which compared PoV with rituximab to PiV with rituximab in relapsed/refractory DLBCL and follicular lymphoma (FL), were presented by Dr Morschhauser.8

In this multicenter, phase II study, patients were randomized to receive rituximab (R 375 mg/m2) with PoV or PiV (2.4 mg/kg) every 21 days up to 1 year (FL, N = 41; DLBCL, N = 81). The ORR was similar between treatment groups in the DLBCL cohort (PiV 57% vs PoV 56%) and in the FL cohort (PiV 62% vs PoV 70%; Table 1). However, the CR rate was better in the PoV + rituximab regimen compared to PiV with R (40% vs 10%, respectively) in the FL group. In the DLBCL cohort, the mean duration of response was 6 months for PiV + rituximab and not reached for PoV + rituximab; in the FL cohort, the mean duration of response was 5.8 months for PiV + rituximab and not reached for PoV + rituximab. Median PFS was nearly identical between the ADCs in the DLBCL group (PiV + rituximab, 5.4 months vs PoV + rituximab, 5.2 months). Median PFS was not reported for the FL group due to insufficient duration of followup. Pharmacokinetic profiles were similar for both ADCs across DLBCL and FL with no free MMAE accumulation.

Neutropenia and peripheral neuropathy were the principal toxicities, with neutropenia being the most common grade 3-4 treatment-emergent adverse event (AE). Although febrile neutropenia was reported in 4% of study patients, only one patient discontinued study treatment for neutropenia. Peripheral neuropathy was the most common AE leading to study treatment discontinuation.

In conclusion, both ADCs in combination with rituximab had similar and generally acceptable safety profiles and acceptable pharmacokinetics. Importantly, positive responses occurred in patients who were refractory to their last therapy, those who were heavily pretreated, and patients refractory to rituximab. Combination studies of PoV with chemotherapy and strategies to evaluate and reduce peripheral neuropathy are ongoing or planned.

Table 1. Investigator-assessed best responses in relapsed or refractory DLBCL or FL patients treated with pinatuzumab vedotin or polatuzumab vedotin.

R/R DLBCL R/R FL

PiV + R(N = 42)

n (%)

PoV + R(N = 39)

n (%)

PiV + R(N = 21)

n (%)

PoV + R(N = 20)

(%)

Objective response

Complete response

Partial response

24 (5)

10 (24)

14 (33)

22 (56)

6 (15)

16 (41)

13 (62)

2 (10)

11 (52)

14 (70)

8 (40)

6 (30)

Stable disease 3 (7) 4 (10) 6 (29) 6 (30)

Progressive disease 7 (21) 11 (30) 1 (5) 0

Unable to evaluate 8 (19) 2 (5) 1 (5) 0

Median duration of response (mos) 6.0 NR 5.8 NR

R/R, relapsed/refractory; PiV, pinatuzumab vedotin; PoV, polatuzumab vedotin; R, rituximab; NR, not reached; R/R relapsed refractory; DLBCL, diffuse large B-cell lymphoma; FL, follicular lymphoma.

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Prognostic Value of Positron Emission Tomography-Computed Tomography (PET-CT) After Frontline Therapy in FLFollicular lymphoma has a very indolent histology, yet a significant minority (~ 15%) of patients will die within 5 years of diagnosis. High-risk Follicular Lymphoma International Prognostic Index (FLIPI) and FLIPI-2 scores alone fail to identify this high-risk population.9,10 Moreover, there are limitations of computed tomography (CT) response assessment in predicting OS.11 Despite specific recommendations against the routine use of positron emission tomography (PET)-CT for FL in the 2007 International Harmonization Project (IHP) criteria, PET-CT is commonly used in response assessment.12 More recently, the predictive value of PET assessment after first-line rituximab chemotherapy for high tumor burden FL was reported in the PRIMA, FOLL05, and PET Folliculaire trials13-15; however, each of these trials had certain limitations. To provide more precise survival estimates from a larger patient cohort with longer followup, a pooled analysis of centrally reviewed scans in these 3 studies was conducted by Trotman and colleagues.16

Another aim of this study was identification of the best cut-off for survival when applying the Five-Point Scale (5PS) for response assessment of FDG-avid lymphoma.17,18

Patient data and conventional CT-based response assessment were recorded for all patients undergoing central PET review in the GELA (PRIMA and PET Folliculaire) and FIL (FOLL05) studies. Postinduction PET-CT scans were assessed independently by 3 reviewers using the 5PS. PET status was compared with patient characteristics, CT-based assessment, and survival endpoints of PFS and OS.

Within the studies, 246 patients with reviewed postinduction PET-CT were identified. CT response was predictive of PFS principally because of the markedly higher rate of progression in patients with stable or progressive disease (Figure 2). The incidence of postinduction PET positivity was 68 (28%) with a cutoff ≥ 3 (FDG uptake > mediastinum) and 41 (17%) with a cutoff ≥ 4 (uptake moderately > liver).

Patient and baseline disease characteristics did not differ significantly between PET+ and PET- patients; a FLIPI score of 3-5 was associated with PET+ status. While both PET cutoffs were highly predictive of PFS and OS, the cutoff ≥ 4 had better reporter concordance and was used for subsequent analyses. With this cutoff, the HR for PFS in PET+ vs PET- patients was 3.9 (P < 0.0001) and 6.7 (P = 0.0002) for OS. Four-year PFS was

23% vs 63% (P < 0.0001) for PET+ and PET- patients, respectively; 4-year OS was 87% vs 97% (P < 0.0001), respectively. Being PET+ and having stable or progressive disease were highly predictive of progression, whereas obtaining PR was weakly predictive of progression by multivariate analysis.

Figure 2. Progression-free survival by CT-assessed response in patients with follicular lymphoma.

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113556210

35% (39)47% (26)55% (34)80% (8)

66% (74)53% (29)45% (28)20% (2)

NR584011

Log Rank P < 0.0001

1: CR2: CRu3: PR4: SD+PD

CT, computed tomography; CR, compete response; CRu, CR unconfirmed; PR, partial response; SD, stable disease; PD, progressive disease; NR, not reached.

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The results of this analysis confirm that postinduction PET-CT status is strongly predictive of PFS/OS, and PET-CT using the 5PS should be the new gold standard for therapeutic response assessment. Thus, postinduction PET-CT is a platform to study response-adapted therapy.

PET-Driven Consolidation Strategy in High-Risk DLBCLThe GELA standard treatment for patients under 60 years old with high-risk DLBCL (aaIPI 2-3) is R-ACVBP (rituximab-doxorubicin, cyclophosphamide, vindesine, bleomycin, prednisone) induction plus consolidation BEAM and autologous stem cell transplantation (ASCT).19 Early ASCT improved PFS among patients with high-intermediate risk or high-risk aggressive NHL who had a response to induction therapy.20 Studies have shown that patients who achieve interim PET- status after 2 or 4 cycles of induction therapy have a better prognosis.21-23 Based on a hypothesis that first-line ASCT may not improve outcome for patients who achieve PET- status early in their induction therapy, Dr Casasnovas and his colleagues designed a phase II randomized trial to test both an induction regimen and a PET-driven consolidation strategy in DLBCL patients with an aaIPI 2-3.24

The study randomized 222 patients (median age 46 years) to 4 cycles of either R-ACVBP or R-CHOP14 induction therapy. Consolidation treatment was driven by centrally reviewed PET assessment (IHP visual criteria) after 2 (PET2) and 4 (PET4) induction cycles. PET2-/PET4- patients received sequential immunochemotherapy consolidation, PET2+/PET4- patients underwent ASCT, and PET4+ patients were eligible for salvage therapy. The primary endpoint was CR rate after 4 induction cycles according to IWG 2007 criteria.

The incidence of PET negativity by treatment arm is outlined in Table 2. For PET2-/PET4- patients, 96% received planned rituximab/chemotherapy consolidation. For those PET2-/PET4+ 83% received the planned ASCT. Among PET4+ patients, more patients on the R-CHOP14 arm received salvage therapy (39% vs 27%, P = 0.048).

Of the 211 evaluable patients (R-ACVBP, n = 109; R-CHOP, n = 102), a CR was achieved by 47% of patients in the R-ACVBP arm compared to 39% of patients in the R-CHOP arm. Although more patients in the R-CHOP arm received salvage therapy, 4-year PFS and OS was similar between the 2 treatment arms. Event-free survival (EFS) was longer for patients on R-ACVBP (43% in R-ACVBP vs 31% in R-CHOP14). In the PET2-/PET4- population, 4-year PFS was 71% and 79% and 4-year OS was 83% and 96% for R-CHOP14 and R-ACVBP arms, respectively.

Table 2. PET status of high-risk DLBCL patients treated with R-ACVBP or R-CHOP14 after 2 or 4 induction cycles.

R-ACVBPn = 109

R-CHOP14n = 102

All

n % n % %

PET2-/PET4- 28 26 18 18 22

PET2+/PET4- 30 28 24 24 26

PET4+ 45 41* 55 54* 47

Premature withdrawal 6 6 5 5 5

*P = 0.07. R-ACVBP, rituximab-doxorubicin, cyclophosphamide, vindesine, bleomycin, prednisone; PET, positron emission tomography; PET2, after 2 cycles; PET4, after 4 cycles.

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Due to missing data of bone marrow reassessment in the R-ACVBP arm, the primary objective (CR after 4 cycles > 50%) was not reached. Four-year PFS and OS rates were similar to those observed in the 2003-3B study, in which all patients responding to 4 cycles of R-ACVBP received ASCT as consolidation treatment. Progression-free survival and OS were similar between treatment arms, but, given the higher frequency of salvage therapy in the R-CHOP14 arm, PET-guided strategy may equalize the efficacy level observed between the 2 treatment regimens.

Mantle Cell Lymphoma R-CHOP Plus Vincristine or Bortezomib in MCL Patients Ineligible for Transplantation Mantle cell lymphoma (MCL) is an aggressive subtype of NHL with a generally poor prognosis.25,26 R-CHOP has been the standard frontline therapy for patients with MCL considered ineligible for intensive treatment and stem cell transplantion, but relapse is common.27,28 The proteasome inhibitor, bortezomib, is currently approved for the treatment of relapsed MCL. Therefore, a randomized, open-label, phase III study evaluating the safety and efficacy of R-CHOP vs VR-CAP (vincristine replaced with bortezomib) in newly diagnosed, BMT-ineligible MCL patients was conducted by Cavalli and colleagues.29

Adult patients with newly diagnosed, measurable stage II-IV MCL were randomized 1:1 to 6-8 21-day cycles of rituximab (375 mg/m2), cyclophosphamide (750 mg/m2), doxorubicin (50 mg/m2) all IV d 1, and prednisone (100 mg/m2 PO days 1-5) plus either vincristine (1.4 mg/m2 [max 2 mg] IV day 1) (R-CHOP) or bortezomib (1.3 mg/m2 IV days 1, 4, 8, 11) (VR-CAP). The primary endpoint was PFS by independent review committee (IRC) secondary endpoints included ORR, CR, time to progression (TTP), time to next treatment (TTNT), OS, and safety.

A total of 487 patients were randomized to treatment (R-CHOP, n = 244; VR-CAP, n = 243), with a median age of 66 years, 74% male, and 74% stage IV MCL. Patients received a median of 6 treatment cycles.

After 40 months median follow-up (298 PFS events), median PFS by independent review was 14.4 months for R-CHOP vs 24.7 months for VR-CAP (P < 0.001; Table 3). The OS data for this trial are not yet mature.

Table 3. Primary and secondary outcomes of MCL patients ineligible for bone marrow transplant after treatment with R-CHOP or VR-CAP.

Primary and Secondary Outcomes (mo)

R-CHOP(N = 244)

VR-CAP(N = 243)

HR P Value

PFS IRC TTP IRC Investigator

Median TTNT

Median OS 4-year OS (%)

14.4

16.116.8

24.8

56.354

24.7

30.535.0

44.5

NR64

0.63

0.580.47

0.50

0.80-

< 0.001

< 0.001< 0.001

< 0.001

0.173-

OR

CR + CRu (%) IRC Investigator

4128

4842

1.41.9

0.0750.002

R-CHOP, rituximab, cyclophosphamide, doxorubicin, vincristine, prednisone; VR-CAP, rituximab, cyclophosphamide, doxorubicin, bortezomib, prednisone; PFS, progression-free survival; IRC, independent review committee; TTP, time to progression; TTNT, time to next treatment; OS, overall survival; CR, complete remission; CRu, complete remission/unconfirmed.

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At least 3 AEs were reported in patients treated with VR-CAP vs R-CHOP (93% vs 85%, respectively). Serious AEs were also more common with VR-CAP (38% vs 30%). Nine percent of patients on VR-CAP discontinued treatment due to AE compared with 7% on R-CHOP. Treatment-related deaths occurred in 2% of patients on VR-CAP and 3% of patients treated with R-CHOP.

In conclusion, PFS was significantly longer in newly diagnosed MCL patients treated with VR-CAP compared to R-CHOP. Secondary efficacy endpoints also consistently improved with VR-CAP vs R-CHOP. VR-CAP was associated with additional but manageable toxicity compared to R-CHOP, but toxicity was consistent with known side effects of bortezomib and the R-CAP backbone.

Hodgkin Lymphoma Brentuximab Vedotin Followed by ABVD in Previously Untreated Hodgkin LymphomaPatients with limited/intermediate stage Hodgkin lymphoma (HL) do particularly well, and most of them can be cured with combined-modality treatment. CD30, a defining feature of HL, is an attractive target that is highly expressed on the surface of Reed-Sternberg cells, with limited expression on normal cells. Brentuximab vedotin, an ADC consisting of anti-CD30 conjugated to MMAE, selectively induces apoptotic death of CD30-positive cells. Thus far, the majority of patients who have received brentuximab vedotin have achieved significant tumor regression, confirming very promising activity for this compound. Therefore, Federico and colleagues conducted a pilot phase II study to determine the efficacy and safety of 2 courses of brentuximab vedotin before the start of a standard program with ABVD +/- radiotherapy (RT) in patients with limited/intermediate stage HL.30

The study enrolled 12 patients with previously untreated CD30-positive HL (stage IA, IIA, or IIIA). The primary endpoint was response to brentuximab vedotin assessed by FDG/PET, defined as reduction of Deauville Score (DS), or, if no change in DS, any reduction in standardized uptake value (SUV) intensity compared with basal SUV. Baseline and PET-2 images were assessed by a panel of 3 external independent reviewers.

Between April and October 2013, enrolled patients (median age 36 years; 11 in stage II and 1 in stage III) received 2 cycles of brentuximab vedotin (1.8 mg/kg intravenously every 3 weeks over 30 minutes as an outpatient infusion), followed by 3-6 cycles of ABVD, depending on disease stage. After the 2 cycles of brentuximab vedotin, all but 1 patient (92%) responded (10 CR and 1 partial metabolic response). All 7 patients with early favorable HL achieved a complete metabolic response. The non-responsive patient had disease progression. The majority of patients tolerated treatment well. Grade 3 AEs were transient and asymptomatic increase in liver transaminases (n = 3) and gamma glutamyl transpeptidase (n = 2).

These are clearly very preliminary results, but demonstrate the single-agent activity of brentuximab vedotin in the first-line setting. Future studies are likely to investigate whether there is a very favorable group of patients with early stage HL in whom treatment with chemotherapy can be avoided.

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MULTIPLE MYELOMA Expanded active treatments for multiple myeloma (MM) over the past 15 years have led to improved survival. Frontline and salvage regimens generally include an immunomodulatory agent (lenalidomide, thalidomide, or pomalidomide) and/or a proteasome inhibitor (bortezomib or carfilzomib). Frontline treatment continues to be optimized, and a number of other agents are being tested to further optimize histone deacetylase (HDAC) inhibitors (eg, panobinostat) and monoclonal antibodies (eg, elotuzumab, daratumumab, and SAR650984). New research findings from the 2014 ASCO Annual Meeting related to these agents in MM are discussed below.

Newly DiagnosedMelphalan, Prednisone, and Thalidomide vs Melphalan, Prednisone, and Lenalidomide In the treatment of transplant-ineligible, newly diagnosed patients with MM, the combination of melphalan, prednisone, and thalidomide (MPT) improved survival over MP with a median PFS of 20 months and OS of 39 months. The combination of melphalan, prednisone, and lenalidomide was also shown to be highly active in phase I/II clinical trials with a median PFS of 25 months.31 Other clinical trials have demonstrated that continued therapy with thalidomide32 or lenalidomide33 beyond induction improves PFS. Based on the hypothesis that MP with lenalidomide may be a superior regimen to MPT with improved PFS and lower toxicity, a phase III trial comparing these combinations in induction followed by maintenance with either thalidomide (MPT-T) or lenalidomide (mPR-R) in patients with untreated, symptomatic, transplant-ineligible MM was conducted by ECOG and presented by Dr Stewart.34

The study included a non-inferiority design with a superiority alternative. The primary objective was PFS for MPT-T vs mPR-R in newly diagnosed MM patients. Patients were stratified by ISS stage (I-II vs III) and age (< 65 vs ≥ 65). Enrolled patients (n = 306) received MPT (M, 9 mg/m2 and P, 100 mg po each on days 1-4; T, 100 mg daily) or mPR (m, 5 mg/m2 and P, 100 mg po each on days 1-4; R, 10 mg po, days 1-21). MPT or mPR therapy was continued for 12 28-day cycles, followed by maintenance thalidomide (100 mg) or lenalidomide (10 mg daily) until relapse (Figure 3).

The median patient age was 75.7 years. Median time on therapy was 12 months. A total of 46% of patients started maintenance therapy, with median time on maintenance of 10.5 months. Presently, 275 patients are off-treatment (42% for AE/complications; 34% for PD; 10% for patient withdrawal). Median followup was 40.7 months.

Response rates were similar between the 2 arms, with PR rates of 75% with MPT-T vs 70% with mPR-R, and there was little difference in Very Good Partial Response rates (VGPR; 19% MPT-T vs 23% mPR-R) between the 2 arms. Median PFS was not significantly different (21 months MPT-T vs 18.7 months mPR-R).

Figure 3. Trial schema for the E1A06 trial: MPT-T vs mPR-R in patients with newly diagnosed, transplant ineligible multiple myeloma.

Induction Maintenance

EnrollmentN = 306

Thal 100 mg po daily

Len 10 mg po daily

(Planned Twelve Cycles)(Until Disease Progression)

MPT-T

mPR-R

• Melphalan 9 mg/m2 po days 1-4• Prednisone 100 mg po days 1-4• Thalidomide 100 mg po days 1-28

• Melphalan 5 mg/m2 po days 1-4• Prednisone 100 mg po days 1-4• Lenalidomide 10 mg po days 1-21

All patients received EC aspirin 325 mg po daily

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No significant differences in PFS were identified among the evaluated subgroups. At 41 months median followup, median OS was 52.6 months MPT-T and 47.7 months mPR-R.

Adverse events were more common with the MPT-T regimen (≥ grade 3 AE 73% vs 59%, P = 0.007; ≥ grade 3 non-hematologic toxicity: 58% vs 40%, P = 0.001). Thrombolic events occurred in 8.8% of patients on MPT-T and 6.7% of patients on mPR-R. The rate of secondary primary malignancies was 7.4% (9.5% MPT-T and 5.3% mPR-R). There were 10 hematological malignancies in the thalidomide-containing arm and 4 in the lenalidomide-containing arm, possibly reflecting the higher dose of melphalan in the MPT-T arm. Quality of life analysis favored mPR-R by the end of induction (P = 0.007).

In summary, this trial was statistically inconclusive, since it did not prove inferiority or non-inferiority of mPR-R compared with MPT-T. There were no clinically significant differences in response rate, depth of response, time on therapy, PFS, or OS. However, overall toxicity was less with mPR-R, and patient-reported quality of life was better with mPR-R at the end of induction.

Relapsed/Refractory MMPanobinostat or Placebo Plus Bortezomib and DexamethasonePanobinostat is a potent pan-HDAC inhibitor that increases acetylation of proteins involved in multiple oncogenic pathways and thus normalizes epigenetic function in malignant cells.35 In preclinical studies of MM, panobinostat activity was synergistic with bortezomib and dexamethasone.36-38 Early phase I and II studies demonstrated durable responses in relapsed or relapsed MM with the combination of panobinostat, bortezomib, and dexamethasone even in bortezomib-refractory disease.39,40 Thus, a randomized, double-blind, phase III study (PANORAMA 1) was initiated to assess panobinostat or placebo + bortezomib and dexamethasone.41

In this study, 768 patients with relapse or refractory MM who had received 1 to 3 prior regimens were randomized to IV bortezomib (1.3 mg/m2 days 1, 4, 8, 11) during weeks 1-2 and oral dexamethasone (20 mg on the days of and day after bortezomib in 8 3-week cycles) with oral panobinostat (20 mg) or placebo 3 times per week (Treatment Phase I). Patients who benefitted from therapy could proceed to Treatment Phase II (cycles 9-12), with panobinostat dosing maintained and bortezomib/dexamethasone less frequent. The primary endpoint was PFS with response assessed by modified European Group for Blood and Marrow Transplant criteria.42,43 Overall survival was a key secondary endpoint.

Median age for the randomized patients was 63 years and 48% had received at least 2 prior regimens. The relative dose intensity of panobinostat decreased to 78.2% at cycle 3 and remained stable through the rest of the study.

In the panobinostat vs placebo-containing arms, the ORR was 61% vs 55%, respectively with an improved CR/near CR (nCR) rate of 28% vs 16% (P = 0.00006). Median PFS was 12 months for panobinostat-bortezomib-dexamethasone compared to 8.1 months for placebo-bortezomib-dexamethasone (P < 0.0001; Figure 4). The PFS benefit was maintained across all subgroups analyzed. There were no significant differences in OS detected in this interim analysis.

10 Table of Contents


Diarrhea (25% vs 8%), peripheral neuropathy (18% vs 15%), and asthenia (24% vs 12%) were the most common grade 3/4 non-hematological AEs and were higher with the addition of panobinostat. On the panobinostat-containing arm, 4.5% of patients discontinued due to diarrhea and 2.9% discontinued because of fatigue. Grade 3/4 hematological AEs were also increased with the addition of panobinostat and included thrombocytopenia (67% vs 31%), lymphopenia (53% vs 40%), and neutropenia (34% vs 11%; grade 4, 7% vs 2%), with low rates of discontinuation. Toxicities were generally managed with dose reduction and supportive care. There were 11 (3%) deaths possibly related to study drug on the panobinostat-containing arm and 7 (2%) on the placebo arm.

Overall, the combination of panobinostat, bortezomib, and dexamethasone significantly improves PFS in patients with relapsed or relapsed MM, but the regimen was associated with increased toxicity, particularly diarrhea, fatigue, and thrombocytopenia.

Daratumumab MonotherapyDaratumumab is a human IgG1k monoclonal antibody with a broad spectrum of mechanisms of action that include complement-dependent cytotoxicity, antibody-dependent cellular cytotoxicity, antibody-dependent cellular phagocytosis, and apoptosis induction and inhibition of enzymatic activity.44,45 A dose escalation study of daratumumab in patients with relapsed or refractory MM resulted in a PR in 5 of 12 patients treated with 4-24 mg/kg with good tolerability.46 Preliminary results of the ongoing cohort expansion of this study, which has completed enrollment, were presented by Dr Lokhorst.47

Figure 4. Median progression-free survival of relapsed or refractory multiple myeloma patients treated with bortezomib and dexamethasone with or without panobinostat.

0

20

40

60

80

100

0 642 10 16148 12 18 24 30Months

Prog

ress

ion-

Free

Sur

viva

l Pro

babi

lity

(%)

Number of Patients at Risk

panobinostat, bortezomib dexamethasoneplacebo, bortezomib, dexamethasone

Panabinostat

Placebo

2220 28 34 363226

387 202241288 143 6989171 113 52 26 103544 13 3 0518

381 185235296 114 4264143 89 32 12 31824 5 0 025

207/387

260/381

12.0(10.3, 12.9)

8.1(7.6, 9.2)

0.63(0.52-0.76)

< 0.0001

Events P valueHR(95% CI)

Median PFS(95% CI)months

panobinostat, bortezomibdexamethasone

placebo, bortezomib,dexamethasone

Bortezomib +Dexamethasone +

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The primary objective of this study was to establish the safety profile of daratumumab in the treatment of patients with relapsed or refractory MM, with evaluation of efficacy as a secondary objective. Eligible adults who were relapsed or refractory to at least 2 prior lines of therapy were enrolled in 4 cohorts at 2 dose levels of 8 mg/kg and 16 mg/kg. Patients received 8 weekly doses, followed by 8 doses twice monthly, then monthly dosing up to 24 months or until disease progression. Thirty patients received 8 mg/kg and 20 patients received 16 mg/kg. Patients at 8 mg/kg received 10.5 full infusions, whereas those in the 16 mg/kg cohort received 11.5 full infusions.

Serious AEs occurred in 40% of patients in the 8 mg/kg cohort (majority of these related to infections) and in 25% of patients in the 16 mg/kg cohort. No severe infusion-related reactions were observed with all being grade 1 or 2 across both dosing groups, which were reduced by greater dilution of daratumumab. Infusion times could be reduced to approximately 3.4 hours as of the third infusion.

The majority of patients had a decrease over baseline in the M-protein, with more pronounced decreases at 16 mg/kg. The ORR was 35% among patients in this subgroup, compared with 10% among those treated at 8 mg/kg. Median PFS was 14.9 weeks at 8 mg/kg and 23 weeks at 16 mg/kg.

Overall, daratumumab toxicity was manageable. A higher ORR was achieved in the 16 mg/kg cohort vs the 8 mg/kg cohorts, with a deeper response in the higher-dose group in part 2 of this study. Findings of a study that evaluated the safety and efficacy of daratumumab combined with lenalidomide and dexamethasone in patients with relapsed or refractory MM demonstrated a favorable safety profile with manageable toxicities and an ORR of 75% (15/20 patients).48 Further clinical development of daratumumab is warranted.

SAR650984 in Combination With Lenalidomide and DexamethasoneSAR650984 (SAR) is a humanized IgG1 monoclonal antibody that binds selectively to a unique epitope on the human CD38 receptor. CD38, a 45kD type II transmembrane glycoprotein, is widely expressed in many hematologic malignancies.49-51 SAR kills tumor cells via antibody-dependent cellular-mediated cytotoxicity, complement-dependent cytotoxicity, direct apoptosis induction without secondary crosslinking, and allosteric inhibition on CD38 enzymatic activity. Both SAR and lenalidomide have shown single-agent activity, and a combination regimen of SAR-lenalidomide resulted in additive tumor growth inhibition in an RPMI-8226 xenograft model.52 A phase I dose escalation trial of SAR in 40 patients with relapsed or refractory MM (ongoing expansion cohort n = 18) showed a favorable safety profile in heavily pretreated patients and an ORR of 32% at doses ≥ 10 mg/kg.53 A subsequent phase Ib dose escalation trial was undertaken to determine the maximum tolerated dose of SAR in combination with lenalidomide and dexamethasone in adult patients with relapsed or refractory MM.54

Eligible patients had received at least 2 prior therapies. A standard 3+3 dose escalation design was used, in which SAR at 3, 5, or 10 mg/kg IV was given on days 1 and 15 per 28-day cycle with lenalidomide (25 mg, days 1-21), and dexamethasone (40 mg, days 1, 8, 15, and 22). Prophylactic therapy for infusion reactions included methylprednisolone (100 mg IV), diphenhydramine (50 mg IV), ranitidine (50 mg IV), and acetaminophen (650-1000 mg PO). Disease assessment occurred every 8 weeks. The maximum tolerated dose was not observed, and an expansion cohort of 18 additional patients was enrolled at the SAR 10 mg/kg dose every other week.



Patients had received a median of 6 (range 2-12) prior therapies, 23 patients (74%) were refractory to their last lenalidomide-containing regimen, and 25 patients (81%) were refractory to an immunomodulatory agent. At the time of presentation,17 patients were receiving ongoing therapy and 14 were off treatment (12 due to disease progression, 2 due to AEs). Three deaths occurred, all due to disease progression.

For all patients, the ORR was 58%, with 23% achieving a VGPR and 35% a PR. The clinical benefit rate (≥ marginal response [MR]) was 65% (Figure 5). For patients who received SAR at 10 mg/kg the ORR was 63% and 48% of lenalidomide-refractory patients achieved a response. The median time on treatment was 20 weeks.

The most common treatment-emergent AEs (all grades, ≥ 10%) were nausea, fatigue, diarrhea, and upper respiratory tract infection. Grade 3/4 AEs occurring in at least 10% of patients included neutropenia and febrile neutropenia. Most infusion reactions were grade 1/2, occurred at cycle 1, and did not lead to treatment discontinuation.

In conclusion, the combination of SAR with lenalidomide and dexamethasone demonstrated significant clinical activity and minimal toxicity in patients with relapsed or refractory MM who were heavily pretreated. The maximum tolerated dose was not reached up to the highest tested dose of SAR and further clinical development is ongoing.

LYMPHOPROLIFERATIVE DISORDERSMulticentric Castleman’s DisorderSiltuximab in Previously Treated Multicentric Castleman’s DisorderMulticentric Castleman’s Disease (MCD) is a rare lymphoproliferative disorder with a high morbidity whose signs and symptoms are driven by dysregulated interleukin 6 (IL-6) production.55,56 Siltuximab is a chimeric IgG1k monoclonal antibody that specifically binds human IL-6 with high affinity and prevents IL-6 from interacting with the IL-6 receptor.57 IL-6 plays a crucial role in the pathogenesis of MCD by increasing B-cell growth, driving vascular endothelial growth factor (VEGF) production, dysregulating the immune system, and increasing the inflammatory response.58 van Rhee and colleagues conducted a multinational, double-blind, randomized, placebo-controlled study in MCD to assess durable tumor and symptom response with siltuximab.59

Adult patients with MCD who were HIV and HHV-8 negative (treatment-naïve or previously treated) were randomized 2:1 to siltuximab 11 mg/kg (n = 53) or placebo (n = 26) IV every 3 weeks and were stratified by corticosteroid use at randomization. All patients received best supportive care, and treatment was continued until treatment failure. Treatment groups were similar in terms of number of prior regimens (45% of patients who received siltuximab were treatment naïve).

Figure 5. Response of relapsed or refractory multiple myeloma patients to SAR650984, lenalidomide, and dexamethasone.

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Minimal ResponsePartial ResponseVery Good Partial Response

3(n = 4)

5(n = 3)

10(n = 24)

Overall(n = 31)

SAR650984 dose level, mg/kg q2W

25%

25%

ORR 25%CBR 50%

ORR 58%CBR 65%

23%

35%

6%

67%

25%

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ORR 63%CBR 67%

ORR 67%

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Durable tumor and symptomatic responses, median time to treatment failure, and durable complete symptomatic response are outlined in Table 4. Durable tumor and symptomatic responses were similar for pretreated and treatment-naïve siltuximab patients vs placebo (34.5% vs 0% and 33.3% vs 0%, respectively), and median time to treatment failure was not reached for siltuximab in either treatment group. Secondary endpoints consistently favored siltuximab in both subgroups.

Despite double the treatment duration in the siltuximab arm, the frequency of AEs, grade 3 or higher AEs, and SAEs was similar to placebo. Siltuximab was well tolerated in both previously treated and treatment-naïve patients.

In conclusion, this study met its primary objective of demonstrating that siltuximab plus best supportive care is superior to placebo plus best supportive care in terms of durable tumor and symptomatic response in patients with MCD. Siltuximab demonstrated efficacy in both treatment experienced and treatment-naïve patients and appears to be well tolerated. Based on these results, siltuximab was recently approved by the US Food and Drug Administration for the treatment of patients who are HIV- and HHV-8-negative.

MYELOPROLIFERATIVE NEOPLASMSPolycythemia Vera Ruxolitinib Patients With Hydroxyurea Resistance/Intolerance: RESPONSE TrialPolycythemia vera is a myeloproliferative neoplasm characterized by increased erythrocytosis, debilitating symptoms (eg, pruritus), and cardiovascular complications due to thrombosis or hemorrhage.60,61 Controlling hematocrit (HCT) is a key therapeutic goal, and maintaining HCT less than 45% has been shown to significantly decrease the risk of cardiovascular death and major thrombotic events.62 Ruxolitinib,

Table 4. Responses of previously treated patients with Multicentric Castleman’s Disease to siltuximab.

Endpoint Placebo(%)

Siltuximab(%)

P Value

Durable tumor and symptom response (by investigator)

All patients Previously treated Treatment naïve

000

34 34.533.3

0.00120.00750.0731

Median time to treatment failure

Previously treated Treatment naïve

184 days106 days

Not reachedNot reached

0.22960.0051

Durable complete symptomatic response


000

251733

0.00370.14150.0731

Hemoglobin increase > 1.5 g/dL in anemic patients


000

615964

0.00020.01880.0824



a potent JAK1/JAK2 inhibitor, was well tolerated and effectively controlled HCT and reduced splenomegaly in a phase II study of patients with polycythemia vera.63 Therefore, Verstovsek and colleagues conducted the phase III RESPONSE study to evaluate ruxolitinib compared to best available therapy in patients with polycythemia vera and hydroxyurea resistance/intolerance.64

Phlebotomy-dependent patients with splenomegaly (> 450 cm3) and hydroxyurea resistance/intolerance were randomized 1:1 to ruxolitinib 10 mg bid (n = 110) or investigator-selected monotherapy (hydroxyurea, interferon/pegylated interferon, anagrelide, pipobroman, immunomodulatory agents, or observation; n = 112). The primary endpoint was the percentage of patients who achieved both HCT control without phlebotomy from week 8 to 32 (with ≤ 1 phlebotomy from week 0 to 8) and a ≥ 35% reduction in spleen volume from baseline. Key secondary endpoints included the percentage of patients who maintained primary response at week 48 and the percentage of patients who achieved complete hematologic remission at week 32. Patients on the control arm could cross over to ruxolitinib at week 32 if they failed to meet the primary endpoint, or later in case of progression. The primary analysis occurred when all patients reached week 48 or discontinued.

Of patients treated with best available therapy, 94% crossed over to ruxolitinib between weeks 32 and 48. Median exposure on randomized treatment was 81 weeks with ruxolitinib and 34 weeks with best available therapy. The primary response at week 32 is shown in Figure 6. Twenty-one percent (21%) of ruxolitinib patients achieved the primary endpoint compared to 1% of patients on best available therapy (P < 0.0001); 77% of ruxolitinib patients met at least 1 component of the primary endpoint. Of those who achieved the primary endpoint, 91% had a confirmed response at week 48. The phlebotomy rate between weeks 8 and 32 was more than 3 times higher in the best available therapy arm compared with the ruxolitinib arm (62.4% vs 19.8%). At week

32, complete hematologic response was achieved by 24% of patients on ruxolitinib and 9% of patients on the best available therapy (P = 0.003); 49% vs 5%, respectively, had at least a 50% improvement in the Myeloproliferative Neoplasm Symptom Assessment Form (MPN-SAF) score. At a median followup of 81 weeks, 85% of ruxolitinib patients remained on treatment.

Ruxolitinib was generally well tolerated. Thromboembolic events (all-grade) occurred in 1 ruxolitinib and 6 best available therapy patients. The exposure-adjusted rates of serious AEs per 100 patient-years were comparable between treatment arms (15.3 ruxolitinib vs 13.7 best available therapy).

Overall, ruxolitinib was superior to best available therapy in controlling HCT without phlebotomy, normalizing blood cell count, and reducing spleen volume in polycythemia vera patients with hydroxyurea resistance/intolerance, making it a valuable new treatment option for this patient population.

Figure 6. Response of patients with polycythemia vera after treatment with ruxolitinib or best available therapy.

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70

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(%)

RuxolitinibBAT

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21%

1% 1%

38%

Primary Composite Endpoint

≥ 35% Reduction in SV

Individual Components ofPrimary Endpoint

Hct Control

P < 0.0001or, 28.64

(95% CI, 4.50-12.06)

60%

20%

SV, spleen volume; Hct, hematocrit; BAT, best available therapy.

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LEUKEMIAAcute Lymphoblastic Leukemia Blinatumomab in Relapsed or Refractory B-Precursor ALLThe outcome for patients with relapsed acute lymphoblastic leukemia (ALL) is poor, with a median OS of 6 to 8 months.65-67 Blinatumomab, an investigational bispecific T-cell engaging antibody, redirects cytotoxic T-cells to lyse CD19-positive malignant and non-malignant B-cells.68 CD19 is expressed in virtually all of tested B-lineage ALL cells and throughout B-cell development.69,70 The results of a phase II exploratory study of blinatumomab in 36 adults with relapsed or refractory ALL showed a complete remission/complete remission with partial hematologic recovery of peripheral blood counts (CR/CRh) rate of 69% and a median OS rate of 9.8 months.71,72 Based on these findings, the same investigators designed a single-arm, multicenter, phase II study to evaluate blinatumomab in relapsed or refractory ALL.73

Eligible patients (N = 189) received blinatumomab by continuous IV infusion (4 weeks on, 2 weeks off ) for up to 5 cycles (cycle 1 only: 9 mg/d on days 1-7; then 28 mg/d). The primary endpoint was CR or CRh within the first 2 cycles. The study population was predominantly male (n = 119), a fairly high percentage of patients had multiple prior salvage therapy (2 for 22%, ≥ 3 for 17%), and 56% of patients had ≥ 75% bone marrow blast count.

Primary and secondary endpoints are shown in Table 5, with 43% (81/189) of patients achieving CR/CRh within the first 2 cycles. CRs/CRh were observed in all subgroups. The median relapse-free survival was 5.9 months and the median OS was 6.1 months. An interim analysis on day 77 showed a median OS of 9.9 months in patients with CR/CRh, compared with 2.7 months in those with no CR/CRh.

Regardless of causality, the most frequent grade ≥ 3 AEs were febrile neutropenia (25%), neutropenia (16%), and anemia (14%). The most common grade ≥ 3 neurologic AEs were encephalopathy (3%), confusional state (2%), ataxia (2%), and nervous system disorder (2%). Serious AEs considered treatment related were attributed to sepsis (n = 2) and candida infection (n = 1). Fatal AEs were seen in a single patient with uncontrolled leukemia.

This study confirmed the antileukemia activity of blinatumomab in patients with Ph-negative, B-precursor relapsed or refractory ALL, and showed a CR/CRh rate of 43%. Responses were observed in all subgroups of patients, but AEs were common with 25% of patients having febrile neutropenia. A randomized, open-label, phase III study of blinatumomab in this population is currently underway.

Table 5. Response for relapsed/refractory ALL patients treated with blinatumumab.

Endpoint Patients (N = 189) n (%)

Primary CR/CRh during first 2 cycles 81 (43)

Secondary CR CRh Blast-free hypoplastic or aplastic bone marrow Failure to respond to therapy No response data available* HSCT after CR/CRh 100-day transplant-related mortality rate

63 (33)18 (10)17 (9)

73 (39)18 (9)

32 (40)11

Exploratory MRD response during the first 2 cycles 60 (82)

*Death before the first response assessment (n = 8) or adverse events leading to treatment discontinuation before the first response assessment (n = 10). CR, complete remission/complete remission with partial hematologic recovery of peripheral blood counts; HSCT, hematopoietic stem cell transplantation; MRD, minimal residual disease.



Chronic Lymphocytic Leukemia/Small Lymphocytic Leukemia Ibrutinib vs Ofatumumab in Relapsed or Refractory CLL/SLL: RESONATE TrialWhile outcomes have improved for patients with chronic lymphocytic leukemia (CLL) and small lymphocytic leukemia (SLL), for those patients with a short response to initial therapy, over 65 years of age, or with del(17p) outcomes remain poor and treatment options are limited.74-76 The oral Bruton’s tyrosine kinase inhibitor, ibrutinib, received recent FDA approval for the treatment of MCL and CLL after 1 prior therapy.77,78 In relapsed or refractory CLL/SLL, ibrutinib demonstrated a 71% response rate and 75% progression-free rate at 2 years.78 Results of the RESONATE trial, which compared ibrutinib to ofatumumab in relapsed or refractory CLL/SLL, were presented by Dr Byrd.79

This phase III study randomized patients with previously treated CLL/SLL to oral ibrutinib (420 mg daily until progressive disease, n = 195) or ofatumumab (300/2000 mg IV x 12 doses over 24 weeks, n = 196). Four months after enrollment ended, patients who received ofatumumab were allowed to cross over to daily ibrutinib therapy after confirmation of progressive disease (n = 57) by independent review. The primary endpoint was PFS assessed by an independent review committee. Secondary endpoints included OS, independent review committee-assessed ORR, and safety and tolerability.

As shown in Figure 7, ibrutinib significantly prolonged PFS (median not reached vs 8.08 months) compared to ofatumumab (HR 0.215, P < 0.0001) and reduced the risk of progression to death by 78%. Ibrutinib significantly improved OS, with a 57% reduction in risk of death (HR 0.434; P = 0.0049) compared to ofatumumab. Independent review committee assessed ORR was 63% for ibrutinib and 4% for ofatumumab, whereas investigator assessment ORR was 85% for ibrutinib and 23% for ofatumumab. The best response by independent review (without the required second CT confirmation), was 76% for ibrutinib and 11% for ofatumumab.

The most frequent AEs for ibrutinib and ofatumumab were diarrhea (48% vs 18%), fatigue (28% vs 30%), and nausea (26% vs 18%). Infusion-related reactions occurred in 28% of ofatumumab-treated patients (none for ibrutinib). Grade 3 or higher infections occurred in 24% treated with ibrutinib and 22% treated with ofatumumab. Exposure-adjusted analysis showed no difference in any grade infection and a 40% relative reduction in grade 3/4 infections comparing ibrutinib with ofatumumab. Atrial fibrillation of any grade occurred more frequently in ibrutinib-treated patients (n = 10) vs ofatumumab-treated patients (n = 1). Bleeding-related AEs of any grade were more common with ibrutinib than ofatumumab (44% vs 12%).

Figure 7. Progression-free survival of patients with relapsed or refractory CLL/SLL treated with ibrutinib or ofatumumab.

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0 3 6 9 12 15Months

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IbrutinibOfatumumab

Ofatumumab Ibrutinib8.08 NR

0.215

< 0.0001(0.146-0.317)

Hazard RatioMedian Time (mo)

Log Rank P value

NR, not reached.

(95% CI)

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In this study, ibrutinib significantly improved PFS, OS, and response compared to ofatumumab demonstrating that ibrutinib is an effective new single-agent therapy for CLL/SLL. Moreover, the effect of ibrutinib was observed regardless of baseline characteristics or molecular features. Overall survival benefit was observed despite patient crossover after independent review committee-confirmed progression.

Ibrutinib Efficacy 3 Years Post-Initiation of MonotherapyIbrutinib has shown single-agent activity and mild toxicity in treatment-naïve CLL80 and in relapsed or refractory CLL in a phase Ib/II study (PCYC-1102).78 An independent assessment of efficacy data, 3 years after initiation of monotherapy in patients with CLL/SLL (including deletion 17p [del(17p)] disease), sought to further characterize the durability of response (DOR).81

The PCYC-1102/1103 phase II trial studied 132 patients with CLL/SLL (treatment-naïve ≥ 65 years n = 31; relapsed or refractory n = 101) treated with oral, once-daily ibrutinib (420 or 840 mg/day). The relapsed or refractory group included patients with high-risk CLL/SLL (progression of disease < 24 months after initiation of a chemotherapy regimen or failure to respond). Del(17p), a poor prognostic abnormality, was present in 34% of relapsed or refractory patients and in 6% of treatment-naïve patients.

Investigator-assessed best response was 87% for treatment-naïve and 90% for relapsed or refractory patients. Independent review committee- and investigator-assessed responses were 90% concordant. The median time to first response was 1.9 months and median time to best response was 7.3 months; responses to ibrutinib improved over time (Figure 8). Thirty-month PFS was 96.3% in treatment-naive patients compared to 68.4% in relapsed or refractory patients; median PFS has not been reached in either treatment group. In the relapsed or refractory population, the only group that reached PFS were del(17p) patients (28.1 months). Notably, the median PFS in most published trials for del(17p) patients is 12 months.

Grade 3 or higher AEs occurred at a higher rate among relapsed or refractory patients compared with treatment-naïve patients (82% vs 61%), as did serious grade ≥ 3 AEs (66% vs 29%). The most common grade ≥ 3 AEs were hypertension and pneumonia. The onset of AEs diminished over time.

Figure 8. Response of CLL/SLL patients to ibrutinib monotherapy over time.

0%

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100%

0 3 6 9 12 15 18 21 24 27 30 33 36Months From Initiation of Study Treatment

Patie

nts

With

Res

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e (%

)

CR/PRPR-L

Median Time to FirstResponse:

1.9 months (range, 1.4-23.2)

7.3 months (range, 1.7-31.8)Median Time to BestResponse:92% of Patients who Archived a PR-L Converted to Better Response

56101215

2920

4221

4248

5867

7377 80 83 85



Three-year followup showed that rapid and durable responses were achieved with ibrutinib in this study population, with median DOR not yet reached. Ibrutinib therapy was well tolerated with no unexpected late AEs observed.

Idelalisib in CLL With del(17p)Phosphoinositide 3-kinase (PI3K) plays a critical role in a number of key pathways known to be dysregulated in indolent NHL. PI3K-delta (PI3Kδ) is highly expressed in many B-cell malignancies and its signaling is critical for activation, proliferation, and survival of B-cells. Idelalisib is a highly selective oral inhibitor of PI3Kδ. Preclinical studies have suggested that idelalisib inhibits proliferation, homing, and retention of malignant B-cells. Results of a phase III study comparing rituximab alone to rituximab with idelalisib in CLL found improved ORR (82% with idelalisib vs 16%), PFS (median not reached with idelalisib vs 5.5 months with rituximab alone), and OS (HR = 0.28, P = 0.003).82 Analysis of poor prognostic subpopulations including del(17p), TP53 mutations, and IGVH mutation showed that the addition of idelalisib to rituximab dramatically improved treatment for all subpopulations analyzed.83

On July 23, 2014 the US FDA approved idelalisib in combination with rituximab for patients with relapsed CLL for whom rituximab alone would be considered appropriate therapy. Idelalisib was also approved as a monotherapy for patients with relapsed FL and SLL who have received at least 2 prior systemic therapies. The approval included a boxed warning for the following fatal and serious adverse reactions: hepatotoxicity, severe diarrhea or colitis, pneumonitis, and intestinal perforation.

GS-9973, A Selective Syk Inhibitor Targeted B-cell receptor signaling inhibition in CLL has been established as an effective means for treating patients with this disease. The signaling cascade begins with the enzyme spleen tyrosine kinase (Syk) and is followed by downstream activation of BTK and PI3 kinase.84 The initial demonstration of efficacy of targeting this pathway in patients with CLL was demonstrated by the drug R406.85 It was the relative specificity of GS-9973, a selective inhibitor of SYK (Kd 7.6 nM), that led to the hypothesis that this compound would enable more targeted inhibition of B-cell receptor signaling with perhaps fewer side effects. Results of a phase II trial of GS-9973 in patients with lymphoid malignancies were presented by Sharman and colleagues.86

Five patient cohorts were enrolled (CLL, MCL, DLBCL, FL, and Other Indolent [LPL, SLL, MZL]) and treated with GS-9973 800 mg BID. Following the initial evaluation of 10 patients treated in each cohort, a futility analysis was performed that would result in termination of a cohort if responses were not seen in that group. If responses were seen, accrual could continue through 40 patients in each cohort. To date, all cohorts have passed their futility analysis and continue accrual (cohorts of CLL and FL have fully accrued). Median age was 70 and 61% were male. The median number of prior regimens was 3. In the CLL subset (N = 41), 19 patients remain on study at a median duration of exposure of 32 weeks.

The primary endpoint, PFS, at 24 weeks was 70%, and the ORR was 49%. Among patients who experienced a response, 75% had duration of response in excess of 6.5 months with ongoing followup for all patients.

In the safety cohort of 145 patients, fatigue, nausea, and diarrhea were the most common AEs. No pneumonitis was seen in this population. Anemia, neutropenia, and thrombocytopenia were the most common lab abnormalities. GS-9973 interacts with the UGT-1A1 hepatic enzyme, and expected increased

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bilirubin levels occurred. Grade 3/4 reversible ALT/AST elevations occurred in 14% of patients. In the CLL cohort, 5 of 6 patients who experienced this were able to resume the drug at the same or reduced dosage with no further elevations in liver function tests. Lymphocytosis, which is characteristic of this family of agents, peaked at day 8, resolved to baseline at 3 months, and continued to improve over time. Nineteen deaths occurred in the total safety cohort, 12 due to disease progression and 7 due to AEs.

In conclusion, GS-9973 showed promising activity in CLL and was well tolerated in patients with lymphoid malignancies. Current study plans include new treatment cohorts of patients with relapsed CLL following prior treatment with B-cell receptor targeted therapies.

Chronic Myeloid Leukemia Newly Diagnosed CML Treated With Imatinib 400 mg or 800 mg: 10-Year FollowupThe tyrosine kinase inhibitor imatinib is considered standard therapy for patients with chronic myeloid leukemia (CML) in chronic phase (CML-CP). To determine whether higher-dose imatinib can outperform standard-dose imatinib over the long term, Sasaki and colleagues evaluated long-term followup data of patients treated sequentially in non-randomized trials with high-dose imatinib (minimum follow-up 8 years).87

Patients with newly diagnosed CML-CP received daily imatinib 400 mg (n = 70) or imatinib 800 mg (n = 201) in consecutive clinical trials. Patients were assessed for cytogenetic and molecular response, OS, EFS, transformation-free survival (TFS), and failure-free survival (FFS). Median age was 48 years and median followup was 118 months.

Time-based (3-12 months) and molecular landmark-based (major and “complete” molecular [3-4.5 log reduction]) responses were higher in imatinib 800 patients compared to imatinib 400 patients. Additionally, imatinib 800 yielded significantly higher 10-year EFS and 10-year TFS, but 10-year OS was high and not significantly different between the 2 doses.

CONCLUSION At the 2014 ASCO Annual Meeting, meaningful clinical trial results in the field of hematology were presented.

In the lymphomas, the addition of lenalidomide to R-CHOP therapy may ameliorate the negative effect of the non-GCB phenotype of DLBCL. Two novel ADCs, PoV and PiV, when combined with rituximab, produced positive responses in patients with refractory DLBCL. In terms of imaging, PET-CT after frontline therapy was determined to have a high prognostic value in predicting PFS/OS in patients with FL. Another study demonstrated that a PET-driven treatment of high-risk DLBCL patients is feasible; however, the primary endpoint of CR after 4 cycles > 50% was not reached and the PFS and OS were similar between the R-ACVBP and R-CHOP14 arms. In newly diagnosed MCL patients, the replacement of vincristine in R-CHOP with bortezomib significantly prolonged PFS. In previously untreated HL, 2 cycles of brentuximab induced a complete metabolic response in the majority of patients.

In MM, clinical trial data of several newer investigational agents showed quite promising results. In the PANORAMA 1 trial in relapsed or refractory patients, the HDAC inhibitor panobinostat plus bortezomib plus dexamethasone demonstrated a statistically significant PFS compared with placebo plus bortezomib plus dexamethasone. Moreover, the PFS benefit was maintained across all



subgroups. Treatment with monoclonal antibodies in patients with relapsed or refractory MM has also shown encouraging results. In one of these studies, SAR650984 combined with lenalidomide and dexamethasone demonstrated good efficacy in heavily pretreated patients. In another study, daratumumab monotherapy demonstrated good efficacy and manageable toxicity.

In the leukemias, ruxolitinib showed superiority to best available therapy in patients with polycythemia vera with hydroxyurea resistance in controlling HCT. Blinatumomab confirmed antileukemia activity in patients with relapsed or refractory ALL. Results of the RESONATE trial were particularly striking for ibrutinib, which significantly improved response rate and extended PFS and OS, compared with ofatumumab, in patients with relapsed or refractory CLL/SLL disease. Ibrutinib was associated with rapid and durable responses in these patients 3 years post-initiation therapy. The selective Syk inhibitor, GS-9973, showed promising activity in several cohorts of patients with lymphoid malignancies. Finally, a long-term follow-up study of imatinib in patients with CML showed that this agent was associated with higher time-based and molecular landmark-based responses when given at doses of 800 mg vs standard-dose 400 mg.

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