EHA 2017: News in Hematology

Multiple Myeloma

EHA 2017. LB2236. Daratumumab, Bortezomib and Dexamethasone (DVd) vs Bortezomib and Dexamethasone (Vd) in Relapsed or Refractory Multiple Myeloma (RRMM): Efficacy and Safety Update (CASTOR)

Antonio Palumbo et al.

Results: PFS Data

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.


ASCO 2017. 8006. Efficacy of Daratumumab in Combination with Lenalidomide Plus Dexamethasone (DRd) or Bortezomib Plus Dexamethasone (DVd) in Relapsed or Refractory Multiple Myeloma (RRMM) Based on Cytogenetic Risk Status

Katja Weisel et al.

Results: Samples from 311/569 pts in POLLUX and 353/498 pts in CASTOR were assessed via NGS. In POLLUX, the median duration of follow-up was 17.3 months. Significantly longer median PFS and numerically higher ORR were observed with DRd vs Rd among high-risk patients, and significant improvements in these outcomes were observed in std-risk patients. In CASTOR, the median duration of follow-up was 13.0 months. Significantly longer median PFS and higher ORR were observed with DVd vs Vd among both high- and std-risk pts. Concordance rates for t(4;14), t(14;16), and del17p were high (88%-98%) between NGS and FISH. Updated data, including subgroup analyses, will be presented. 

Conclusions: In RRMM pts, the addition of D to standard-of-care regimens improved outcomes regardless of cytogenetic risk status. Targeting CD38 by combining D with Rd or Vd appears to improve the poor outcomes associated with high-risk cytogenetic status. Clinical trial information: NCT02136134 and NCT02076009

CARE Faculty Perspective: These data (LB2236 & 8006) reinforce the benefit of daratumumab and dexamethasone in combination with bortezomib or lenalidomide for patients who have received at least one prior therapy. These regimens were approved by Health Canada in April 2017.

The combination of daratumumab with pomalidomide and dexamethasone received FDA approval in June 2017, for patients who have received at least two prior therapies including lenalidomide or a proteasome inhibitor. This was based on clinical trial results from the phase 1 EQUULEUSstudy, which showed an overall response rate of 59.2 percent with the daratumumab triplet. We wait on approval in Canada.

This designation reinforces the versatility of daratumumab with a range of treatment regimens and provides an urgently needed option for this patient sub-group. Daratumumab is also being investigated as a front-line therapy for patients with multiple myeloma in Phase 3 clinical trials.

 

EHA 2017: News in Hematology

Chronic Lymphocytic Leukemia: Ibrutinib Monotherapy

EHA 2017. S769. Long-term Efficacy and Safety with Ibrutinib in Previously Treated CLL: Up to Four Years Follow-up of the RESONATE Study

Byrd, John C et al.

Results: A total of 391 patients were randomized to receive ibrutinib (n=195) or ofatumumab (n=196). The median age was 67 years, with 40% age ≥70 years, and Rai stage III/IV in 57% of patients. At a median follow-up of 44 months (maximum 53 months) for the ibrutinib arm, PFS was significantly longer for ibrutinib vs ofatumumab (median NR vs 8 months, [HR 0.133; P<0.0001]). The 3-year PFS was 59% for ibrutinib vs 3% for ofatumumab. A significant PFS benefit was observed across baseline subgroups. In the ibrutinib arm, PFS for the del11q subgroup trended to have the most favorable outcome; however, PFS outcomes were not statistically different for patients with del17p or del11q or patients without these FISH abnormalities. At time of analysis, with the majority of patients randomized to ofatumumab (68%) crossing over to receive ibrutinib therapy, OS was longer for ibrutinib vs ofatumumab (median OS NR for either arm). The 3-year OS rate for ibrutinib was 74%. The ORR for ibrutinib was 91% with a CR/CRi rate that increased over time (currently 9%). Baseline cytopenias improved with extended ibrutinib therapy for hemoglobin (85% of patients), platelet (95% of patients), and absolute neutrophil counts (95% of patients). The adverse event (AE) profile of ibrutinib was consistent with previous reports. During a follow-up of up to 4 years, major hemorrhage occurred in 6%, grade ≥3 atrial fibrillation occurred in 6%, and grade ≥3 hypertension occurred in 8% of patients. The incidence of most grade ≥3 AEs decreased from year 1 vs year 2-3: neutropenia: 18% vs 8%; pneumonia: 11% vs 4%; atrial fibrillation: 4% vs 2%, respectively. The most frequent reasons for treatment discontinuation were progressive disease (27%) and AEs (12%). At analysis, 90 patients randomized to ibrutinib (46%) continue to receive ibrutinib.

Conclusion: In this international phase 3 RESONATE study with median follow-up of up to 4 years, long-term treatment with ibrutinib showed a favorable tolerability profile with sustained PFS and OS benefit regardless of high-risk cytogenetics. The results in relapsed del17p and del11q patients compared favorably to those previously reported in phase 2 studies.

Clinical trial information: NCT01578707

CARE Faculty Perspective: Ibrutinib improves long-term survival outcomes, especially in patients with relapsed/refractory CLL who are not eligible for chemotherapy approaches.

This phase 3 RESONATE trial confirmed these positive survival effects in terms of PFS and OS, while maintaining a favourable tolerability profile.  Furthermore, at the recent International Workshop on Chronic Lymphocytic Leukemia, pooled data from the RESONATE, RESONATE-2, and HELIOS trials were presented. Ibrutinib achieved higher CR rates, ORR rates, PFS, and OS when compared with other agents. This pooled analysis confirms the data from the original studies and highlights the efficacy of ibrutinib as monotherapy or as part of a combination.

Access & Innovation Considerations - The main concerns with ibrutinib use relate to toxicities that may limit its use or lead to the introduction of alternative therapies. Ibrutinib resistance is another clinical challenge. A better understanding of the mechanisms of resistance to monotherapy and combination strategies as well more in depth understanding of the effects of ibrutinib on immune effectors will be of benefit for practicing clinicians.

CCH-QC Montréal 2017: Myélome multiple

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Myélome multiple

Richard Leblanc, MD

Le myélome multiple est une maladie morbide et incurable avec les modalités de traitement standard. Avec les nouveaux agents thérapeutiques, la survie et la qualité de vie des patients se sont toutefois grandement améliorées. Parmi ces nouvelles modalités thérapeutiques prometteuses se retrouve l’immunothérapie. Depuis 2 décennies, l’allogreffe de cellules souches hématopoïétiques est reconnue la seule thérapie pouvant éradiquer le myélome. Toutefois, en raison de ses risques de mortalité associés aux complications infectieuses et immunitaires, elle est toujours jugée comme un traitement expérimental pouvant être considérée chez les patients à mauvais risque ou les jeunes patients. Au courant des dernières années, plusieurs autres modalités thérapeutiques sont en développement dont d’autres types de thérapie cellulaire comme les CAR T-cells, la vaccination, mais surtout les anticorps monoclonaux dont les anti-CD38, anti-CS1 et anti-PD1/PD-L1. Ces agents sont particulièrement efficaces en combinaison, bien que les anticorps monoclonaux anti-CD38 démontrent également une activité en monothérapie.

 

CCH-QC Montréal 2017: Médecine régénératrice (yeux)

Médecine régénératrice (yeux)

Isabelle Brunette, MD, FRCSC

Il existe un intérêt grandissant pour des alternatives cliniques à la greffe de cornée traditionnelle, afin de dépasser les limites imposées par l’utilisation de cornées de banques. Les progrès récents dans les domaines des technologies des biomatériaux et du génie tissulaire apportent l’espoir de pouvoir un jour mieux contrôler les problèmes d’astigmatisme induit, de rejet, d’attrition endothéliale, de défaillance épithéliale et de lutte contre l’infection et la vascularisation qui assombrissent encore le pronostic de la greffe de cornée. Elles permettent aussi d’espérer pouvoir un jour alléger le fardeau de la pénurie en cornées greffables dans le monde.

Press Release: CARE Congress on Biosimilars

On January 13th, 2017 CARE faculty specialists representing the fields of gastroenterology, hematology, oncology, respirology and rheumatology met to consider the integration of Biosimilars into the Canadian healthcare system.

Biosimilars are drugs that may replace expensive biologic drugs that are going off patent.  With biosimilars being relatively new to the Canadian landscape, there are also a number of questions/considerations on extrapolating data, interchangeability, immunogenicity, and systemic challenges (tracking and monitoring) that require attention.

Recognizing both the potential impact on the Canadian healthcare system and the importance of involving stakeholders, CARE faculty invited 16 speakers representing Canadian researchers, clinicians, Health Canada, public and private funding agencies, health economists, hospital pharmacists, nurses, advocacy groups, ethicists and legal experts to share perspectives, concerns, wants and needs.

An audience of 100+, representing the above named stakeholders, along with various levels of government, pharmaceutical companies and industry associations, listened in while speakers and assembled faculty discussed biosimilars from multiple perspectives.

The aim of this Congress is to increase collective understanding, consider education needs for specialists and assembled stakeholders, and ultimately refine a CARE guidance/position on Biosimilars.

 

CARE Faculty believes: 

  • Developing clinical practice through optimization of current therapies
  • Improving patient outcomes by developing innovative therapeutics
  • Ensuring access to quality care for all Canadians by the responsible and evidence-based use of treatment
  • Competition is welcomed to improve efficiency and access

 

CARE™ funding sources:

CARE™ receives unrestricted funding from multi-industry sponsors, institutions and associations. Content reflects the opinions, presentations 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).

 

Background Steps that led up to this CARE™ Congress

  • CARE™ conducted needs assessments in oncology, hematology, rheumatology, and gastroenterology to understand current perceptions of biosimilars and their use in Canada
  • A multi-disciplinary group of CARE faculty members met October 27th, 2016 to discuss the various needs assessment data, and the impact biosimilars will have in Canada
  • There was consensus to host a larger meeting involving more stakeholders; CARE™ has worked to quickly assemble this Congress involving not only different specialties, but different stakeholder representatives.

For more information on the steering faculty, assembled CARE faculty, speaker list, or for questions/information needs regarding CARE, please contact Christina Lopes or Erica Duncan. 

 


References:

  1. Hirsch BR, Lyman GH. Biosimilars: are they ready for primetime in the United States? J Natl Compr Canc Netw. 2011;9: 934–943
  2. Based on 2013 sales of biologics with patents expiring before 2021 (Remicade, Eprex, Aranesp, Levemir, Humira, Avastin, Enbrel, Lucentis, Rituxan, Gonal-F). IMS Health Canada - Canadian Drug and Hospital (CDH) Sales, December 2013, page 11

Click here to view more highlights from the CARE Congress on Biosimilars.

ASH 2016 News in Hematology: Chronic Lymphocytic Leukemia

ASH 2016 Abstract 234. Updated Efficacy and Safety from the Phase 3 Resonate-2 Study: Ibrutinib As First-Line Treatment Option in Patients 65 Years and Older with Chronic Lymphocytic Leukemia/Small Lymphocytic Leukemia

Paul Barr et al.

Results: Median age of the 269 pts was 73 y (70% ≥70 y). Baseline characteristics were balanced between arms; 45% had advanced Rai stage, 20% had del11q, and 69% had comorbidities at baseline, including CIRS score >6, reduced creatinine clearance, or ECOG performance status of 2. With a median follow-up of 28.6 mo, prolongation of PFS for ibr vs clb was sustained (89% vs 34% at 24-mo; HR, 0.121; 95% CI 0.074-0.198; P<0.0001; Figure). PFS was significantly improved for ibr across high-risk subgroups, including del11q and unmutated IGHV gene (Figure). Overall, 4 of 135 pts discontinued ibr due to PD. 1 case of Richter’s transformation was observed in each arm. With 41% of pts switching from clb to ibr, the OS analysis in the ITT population resulted in 2-yr survival rate estimates of 95% and 84% in the ibr and chlorambucil arms, respectively. The investigator-assessed ORR was 92% with ibr vs 36% with clb (P<0.0001). CR/CRi within the ibr arm improved from 11% at 18.4 mo to 18% with longer follow-up of 28.6-mo. Sustained hematological improvements were higher for ibr vs clb for those with anemia (90% vs 45%; P<0.0001) or thrombocytopenia (80% vs 46%; P=0.0055) at baseline. The most frequent adverse events in ibrutinib treated pts (AEs; ≥20%) are presented in the Table. Grade [Gr] ≥3 AEs in ≥5% of pts included neutropenia (12%), pneumonia (7%), anemia (7%), and hypertension (5%); AEs (any Gr) leading to dose reductions occurred in 13%. The most common reason for discontinuation was AEs (12%), with most occurring during the first yr of ibr therapy. The incidence of the common Gr ≥3 AEs in these ibr-treated pts typically decreased over time. Major hemorrhage occurred in 7% (1 Gr 2, 7 Gr 3, 1 Gr 4; 5 in first 12 mo and 4 between 1-2 y) and atrial fibrillation occurred in 10% (1 Gr 1, 7 Gr 2, 6 Gr 3) of ibr-treated pts. With a median treatment duration of 28.5 mo (range, 1-36), 79% of pts remain on first-line ibr.

Conclusions: With a median time on study of 28.6 mo, ibr continued to have substantial efficacy, with 88% reduction in risk of progression or death. Furthermore, the quality of responses has improved over time, with 18% of CLL/SLL pts achieving a CR/CRi with single agent ibr. Treatment limiting AEs decreased in frequency with longer follow-up, with 79% of this elderly pt population continues daily ibr. Lastly, even with a high rate of cross-over in the clb arm, OS remains significantly improved for pts randomized to ibr.

CARE Faculty Perspective:  Results from the RESONATE-2 trial were first published in 2015 (Byrd et al.) and showed a significant improvement in survival and safety with the use of ibrutinib in the front-line CLL setting. Longer follow-up for this study was presented during this year’s ASH conference and further confirmed ibrutinib’s efficacy and safety across risk groups. Interestingly, results also showed that quality of response actually improved over time with durable PFS and OS

While these results validate and build on previous findings, there are still limitations to knowing the full impact that this will have in Canadian practice given the use of chlorambucil as the comparator (not the current standard of care chlorambucil with obinutuzumab). Clinical trials with more relevant comparators are awaited, however it is clear that novel oral agents like ibrutinib are challenging the current R-Chemo standard.  

ASH 2016 News in Hematology: Relapsed & Refractory CLL

ASH 2016 Abstract 637. Venetoclax (VEN) Monotherapy for Patients with Chronic Lymphocytic Leukemia (CLL) Who Relapsed after or Were Refractory to
Ibrutinib or Idelalisib

Jeffrey Jones et al.

Results: 

 

Conclusions: Venetoclax is the first agent to demonstrate robust activity, with good tolerability in pts with CLL progressing during or after treatment with ibrutinib or idelalisib, including a subset who were refractory to these therapies. Low rates of complete response have been thus far observed at an early time point; however, pts will be monitored to determine whether deeper responses are seen, as has been reported in prior VEN trials in CLL. Extended follow up will also be required to assess the durability of responses with venetoclax in this population.

CARE Faculty Perspective: This abstract provides longer follow-up data for a trial previously presented- in this case during the EHA Congress (June 2016).

Many CLL patients in Canada are now receiving newer TKIs (i.e. ibrutinib and/or idelalisib) as part of standard treatment. Managing these patients after TKI discontinuation has since become a new area of unmet need and is associated with poor outcomes. The positive results from this and other studies investigating the oral, small molecule BCL2 inhibitor venetoclax in this setting have positioned it as the preferred  option for these difficult-to-treat patients. More data to confirm activity and to establish durability of response are highly anticipated.