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ASH Highlights 2011 San Diego, California. Lymphoma. Lymphoma in Pregnancy: Excellent Foetal Outcomes and Maternal Survival in a Large Multicenter Analysis Advani et al, #94. Retrospective analysis of patients with Hodgkin Lymphoma (HL) or non-Hodgkin Lymphoma (NHL)

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ASH Highlights 2011 San Diego, California

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Ash highlights 2011 san diego california

ASH Highlights 2011

San Diego, California



Ash highlights 2011 san diego california

Lymphoma in Pregnancy: Excellent Foetal Outcomes and Maternal Survival in a Large Multicenter Analysis Advani et al, #94

  • Retrospective analysis of patients with Hodgkin Lymphoma (HL) or non-Hodgkin Lymphoma (NHL)

  • Standard chemotherapy for HL/NHL administered (minus antimetabolites)

    • Typical regimens – ABVD, CHOP+/- R,CODOX-M/IVAC

Summary of results

Summary of Results

  • 48 pts had chemo initiated at a median of 25 wks (13-37)

    • 79% in 2nd trimester

  • Chemo administered with minimal pre-term complications

    • 1 still birth following 1x R-CHOP

    • 1 case of microcephalus following 4x CHOP

    • No other malformations detected

  • Median birth weight of infants similar between patients who received chemo during pregnancy vs. those who deferred treatment until after birth

  • Median f/u: 41 months

    • Approach associated with expected lymphoma related outcomes PFS, OS

  • Uncommon extra nodal sites included vaginal and breast

Relevance to practice

Relevance to Practice

  • This retrospective analysis will provide some confidence that standard treatment may be administered to pregnant women with HL and NHL

  • Questions remain about long-term effects and patients who require anti-metabolite chemo, particularly in early stage pregnancy

Ash highlights 2011 san diego california

Phase 2 Trial of Alisertib (MLN8237), An Investigational, Potent Inhibitor of Aurora A Kinase (AAK), in Patients (pts) with Aggressive B- and T-Cell Non-Hodgkin Lymphoma (NHL),  Friedberg et al #95

  • 48 patients with relapsed/refractory aggressive B cell (MCL, DLBCL, BL, transformed FL)+ T-cell lymphoma

    • Alisertib 50mg BD x 7d (21d cycle)

    • 41 response evaluable

    • Median of 3 prior treatments

  • ORR 32%, CR 12%

    • ORR T-Cell: 57%, MCL: 23%, DLBCL: 20%

    • Response seen in all patients

  • Major AEs: neutropenia, thrombocytopenia, stomatitis

  • Generally well tolerated, AEs manageable with dose reduction however 50% of pts required dose reduction

Relevance to practice1

Relevance to Practice

  • Alisertib has activity in aggressive lymphoma in patients who are heavily pre-treated

  • No current impact to UK practice but one to watch, future trials include:

    • SWOG phase III study in relapsed/refractory T-cell lymphoma

    • Millennium sponsored phase III randomised relapsed/refractory T-cell trial

    • B-cell study planned

Ash highlights 2011 san diego california

Analysis of Patients with Common Peripheral T-Cell Lymphoma Subtypes From a Phase 2 Study of Romidepsin in Relapsed or Refractory Peripheral T-Cell Lymphoma, Coiffier et al #591

Phase 2, open label, single arm study

Romidepsin 14 mg/m² IV infusion over 4 hours on days 1, 8 and 15 of a 28 day cycle for 6 cycles

Primary endpoint: rate of CR

n = 130, median f/u: 21 months, median of 2 prior therapies

ORR: 28%

CR/CRu: 16%

PR: 12%

ORR + SD ≥90 days: 46%

Ash highlights 2011 san diego california

Results of E4402 (RESORT): A Randomized Phase III Study Comparing Two Different Rituximab Dosing Strategies for Low Tumour Burden Follicular Lymphoma, Kahl et al #LBA6


375mg/m² q3months



CR or PR


375mg/m² weekly (x4)







On progression


  • Previously untreated low tumour burden follicular lymphoma pts

  • Major definition of treatment failure:

    • Progression within 6 months of R or failure to achieve CR while on R

  • Re-treatment group received 4.5 doses R

  • Maintenance group received 15.8 doses R

Results and relevance to practice

Results and Relevance to Practice

  • Primary Endpoint: Time to Treatment Failure – no difference

  • Secondary Endpoints:

    • Time to first cytotoxic – longer in maintenance arm (p=0.03)

    • QoL – not fully analysed but not expected to differ

  • No evidence of superiority of maintenance and much more expensive

  • Current practice not expected to change until OS data available

  • Biomaker evaluation may help to select patients who are likely to respond to rituximab induction therapy

  • Note: this is only low tumour burden population

Ash highlights 2011 san diego california

A Phase 3 Randomized Intergroup Trial (SWOG S0016) of CHOP Chemotherapy Plus Rituximab Vs. CHOP Chemotherapy Plus Iodine-131-Tositumomab for the Treatment of Newly Diagnosed Follicular Non-Hodgkin’s Lymphoma (FL), Press et al #98

5 days at 3 week intervals

  • 554 patients with advanced stage (bulky stage II, III or IV) evaluable FL of any grade (1, 2, or 3), with no prior therapy

  • All patients received CHOP chemo

    • 750mg/m2 cyclophosphamide

    • 50mg/m2 doxorubicin

    • 1.4mg/m2 vincristine

    • 100mg predisolone

  • Arm 1 – CHOP-R (x 6 cycles)

    • + 6 doses of rituximab (375mg/m2) on days 1, 6, 48, 90, 134 and 141

    • Arm 2 – CHOP-RIT (x 6 cycles)

    • + dosimetric infusion of tositumomab/iodine I-131 tositumomab and then 1-2 weeks later a therapeutic infusion of I-131-tositumomab labelled with sufficient I-131 (median 85 mCi) to deliver a total body dose of 75 cGy (CHOP-RIT)

Summary of results1

Summary of Results

  • No statistically significant differences in PFS, OS, or serious toxicities

    • However, PFS and OS are outstanding with either of the two  regimens with median times to progression not yet reached for either treatment

  • Future studies needed to assess whether combining CHOP-R with RIT consolidation and with maintenance rituximab will confer additive benefit

    • Currently being evaluated in a follow-up trial (SWOG protocol S0801)

Relevance to practice2

Relevance to Practice

Trial recruited 2001-08: during this period, rituximab+chemo and then maintenance rituximab have been recommended as standard practice for first-line treatment of FL in the UK.

Tositumumab + CHOP is certainly as good as CHOP-R in first line treatment of FL.

However there would need to be further study to see if tositumumab + CHOP produces remission rates comparable to CHOP-chemo followed by maintenance rituximab.

Tositumumab has to be given in specialist facilities which are not widely available in the UK. Rituximab can be given in hospital and homecare settings: this probably gives the edge to rituximab for first-line treatment of FL.

Ash highlights 2011 san diego california

Fractionated 90y Ibritumomab Tiuxetan (ZevalinTM) Radioimmunotherapy As An Initial Therapy of Follicular Lymphoma (FL) – First Results From a Phase II Study in Patients Requiring Treatment According to GELF/BNLI Criteria, Illidge et al #102

  • 74 patients with untreated FL (grade 1, 2 or 3a) and at least 1 criterion of high tumour burden received:

    • 2 x doses of 90Y-ibritumomab tiuxetan (11.1 MBq/kg) given 8-12 weeks apart

    • Patients with > 20% bone marrow involvement (BM) with lymphoma received 4 weekly infusions rituximab (375 mg/m2) and proceeded to fractionated RIT, only if a repeat BM biopsy demonstrated clearing of lymphoma with ≤ 20% involvement

  • Primary endpoint: end of treatment response (EOR) of ITT population

    • Assessed 12 weeks after last 90Y-ibritumomab tiuxetan infusion (21 weeks after treatment start)

  • Secondary endpoints: Safety & PFS

Summary of results2

Summary of Results

  • 2/72 patients did not have recorded response data

    • EOR was 95.7% (67/70) with Cru of 57.1% (40/71)

    • 6 patients subsequently improved response:

      • ORR = 97.1% (68/70) (95% CI 90.0% - 99.7%)

      • Cr/Cru = 64.3% (45/70) (95% CI 51.9% - 75.4%)

  • PFS = 67%

    • Based on median follow up of 1.52 years (range 0.13 – 3.68 years)

  • Most common toxicities were haematological and occurred after the first 90Y-ibritumomab tiuxetan dose

    • Transient neutropenia 20.8%, 18 days median duration)

    • Thrombocytopenia (20.8%; 20 days median duration)

Relevance to practice3

Relevance to Practice

  • Zevalin appears to be effective and reasonably well tolerated in this group of patients

  • Further studies are required;

    • This is a relatively small trial size (n = 72)

    • Phase II data - The trial did not compare this drug against any other treatment

  • As with other radioimmunotherapies, specialist facilities are required to give Zevalin

    • This limits the usefulness of this drug in the UK.

Ash highlights 2011 san diego california

The Addition of Rituximab to Fludarabine and Cyclophosphamide (FC) Improves Overall Survival in Newly Diagnosed Mantle Cell Lymphoma (MCL): Results of the Randomised UK National Cancer Research Institute (NCRI) Trial Rule et al #440

  • 370 newly diagnosed, mantle cell lymphoma patients

  • Phase II trial initiated in 2002, extended to phase III in 2006

  • Up to 8 x cycles (28 days)

    • Fludarabine po 40mg/m2 D1 – D3

    • Cyclophosphamide po 250mg/m2 D1 – D3

    • Randomised to + / - rituximab iv 375mg/m2 D1

  • Median age was 66 years (range 36 – 88)

  • 76% male patients

  • 78% and 72% respectively received 4 or more cycles of FCR/FC

Summary of results3

Summary of Results

  • Patients in the FCR arm had a longer PFS and OS compared to FC

  • Median follow up 38.8 months

Adverse events

Adverse events

  • The major toxicities were haematological

    • Significantly more patients in the FCR arm experienced grade 3 or 4 Leucopoenia and Thrombocytopenia however the numbers of grade 4 were not significantly different

    • Combined grade III/IV toxicity showed 23.3% thrombocytopenia, 45.8% leucopoenia, 12.9% anaemia and 51.4% neutropenia

    • 11.8% of patients had significant infections

  • Renal toxicity was modest.

    • 1 patient experienced grade III but there was no grade IV toxicity

  • 29% FCR patients and 24% of FC patients died of other causes

    • Almost half were infection related

    • 11 patients died of a second malignancy (4/11 AML)

Relevance to practice4

Relevance to practice

  • The addition of rituximab resulted in a significant increase in overall survival

    • FC is not standard treatment across the UK in all MCL patients

    • Most UK centres are already using rituximab for MCL

    • Results may support applications to the CDF for centres currently unable to use

  • Acceptable toxicity in patients <70 years

  • Rituximab is not licensed in this setting

    • Unlikely to be considered by NICE

Ash highlights 2011 san diego california

Phase II Study of Ofatumumab in Combination with ICE or DHAP Chemotherapy in Relapsed or Refractory Aggressive B-Cell Lymphoma Prior to Autologous Stem Cell Transplantation (ASCT) Matasar et al #957

  • 61 pts with DLBCL, 36 pts with follicular or transformed follicular lymphoma randomised to receive ofatumumab with ICE or DHAP

    • Median age 54yrs

    • Must have previously received R+anthracycline 1st line

    • Chemotherapy regimen selected by investigator

    • Study not powered to look at the difference between regimens

  • Primary endpoint: ORR of ofatumumab + chemo

Results and relevance to practice1

Results and Relevance to Practice

  • ORR shows that combination is effective

  • However, a large randomised trial against R + chemo in relapsed patients is required with multiple arms to determine the most effective regimen for relapsed patients

Ash highlights 2011 san diego california

Frontline Therapy with Brentuximab Vedotin Combined with ABVD or AVD in Patients with Newly Diagnosed Advanced Stage Hodgkin Lymphoma, Younes et al #955

  • Study aimed to assess safety of brentuximab vedotin (B) in combination with ABVD or AVD and determine MTD in combination

  • 44 pts, 18-60 yrs, treatment naive with stage IIa bulky or IIb-IV hodgkin lymphoma

    • ABVD/AVD administered for 6 x 28d cycles

    • B dose escalation 0.6mg/kg to 1.2mg/kg

  • MTD not reached therefore 1.2mg/kg every 2 weeks is escalation phase dose

  • Pulmonary toxicity of ABVD was increased when combined with B but not with AVD

  • 1.2mg/kg B + AVD is the combination that will be used in future trials

  • Watch this space!

Ash highlights 2011 san diego california

Brentuximab Vedotin (SGN-35) Enables Successful Reduced Intensity Allogeneic Hematopoietic Cell Transplantation (RIC allo-HCT) in Relapsed/Refractory Hodgkin Lymphoma Chen et al #664

  • Retrospective analysis of 46 relapsed/refractory HL pts treated with the antibody-drug conjugate, brentuximab-vedotin

  • 16/46 (34.8%) patients subsequently underwent RIC allo-HSCT

    • 14/16 had received prior autologous HSCT

    • Pre-treated population (2-6 prior lines of therapy)

  • 1 yr OS: 100%

  • Brentuximab did not delay engraftment times post HSCT and the procedure was well tolerated

  • Disease status at time of transplant:

    • 7 x CR, 6 x PR, 2 x PD (no bulky disease), 1x SD

Relevance to practice5

Relevance to Practice

  • Strengths and Weaknesses

    • Demonstrates that previously reported efficacy (75% RR) can be translated into a chance of cure by allowing allo-HSCT

    • Not compared to standard UK relapse treatment (ChlVPP or GemP)

    • Unclear what happened to 30 patients who did not receive allo-HSCT

  • Treatment with brentuximab could secure sufficient disease control to allow HSCT in the small cohort of patients with HL refractory to current standard therapies

  • Likely to be extremely expensive – could this be a CDF therapy?



Ash highlights 2011 san diego california

Initial Findings From the PACE Trial: A Pivotal Phase 2 Study of Ponatinib in Patients with CML and Ph+ ALL Resistant or Intolerant to Dasatinib or Nilotinib, or with the T315I Mutation, Cortes et al #109

Single arm study of ponatinib, a multikinase inhibitor that accommodates T315I mutations (n=449)

This is only a phase II study with no control arm, the wide patient mix could be a strength or weakness

Very early follow up therefore low response rates

Relevance to practice6

Relevance to Practice

Current data is very early however clinicians will want rapid access to ponatinib for their resistant/T315I mutated patients

Should we expect phase III data or will phase II be enough?

A treatment for 2nd generation resistant and T351I mutated patients is needed – could this be it?

Expect ponatinib to be coming to a pharmacy near you within 18 months!

Ash highlights 2011 san diego california

Imatinib Dose Interruption in Responding CML Patients Is Associated with Characteristic BCR-ABL Kinetics, Which Could Help to Differentiate Non-Adherence From Drug Resistance, Branford et al #111

Study aimed to distinguish if loss of response can be related to biological resistance or adherence using BCR-ABL doubling time (DT)

n=539 achieving MCyR

DT: 62d for 10-20% of no dose days

Relevance to practice7

Relevance to Practice

Doubling time of 9 days suggests non-adherence if patient is still in CP

Calculating doubling time may indicate a non-adherent patient at no extra expense to the NHS

There is a role for pharmacists to identify non-adherent patients although poorly adherent patients may be harder to identify

Ash highlights 2011 san diego california

Multiple Low Level Mutations Identifies Imatinib Resistant CML Patients At Risk of Poor Response to Second-Line Inhibitor Therapy, Irrespective of the Resistance Profile of the Mutations, Parker et al #111

  • Mass spectrometry BCR-ABL mutation assay

    • Detecting 90% of all mutations (31)

    • Detection limit <0.5% compared to 10-20% in direct sequencing methods

  • Could sensitive mutational analysis before 2° TKI therapy predict response?

  • 132 low level mutations not detected by direct sequencing

    • Up to 10% of mutations per patient

    • Previously demonstrated (JCO 2011) that use of resistant TKI can select for these mutations

  • Number of mutations is important even if not conferring resistance to TKI

Results and relevance to practice2

Results and Relevance to Practice

  • n=175 - no nilotinib/dasatinib mutation

    • 19% detected with mass spectrometry

    • 9% by direct sequencing

  • 0/1 mutations: 50% CCyR, 31% MMR

  • ≥2 mutations: 21% CCyR, 6% MMR

    • 56% developed new mutations

  • Study provides evidence that prediction of patient response to 2° TKIs can be achieved

  • Allows provision of alternative treatments to those who will not respond

    • Preventing wasted money on therapies that will not work in patients with mutations

Ash highlights 2011 san diego california

Lenalidomide and Rituximab for the Initial Treatment of Patients with Chronic Lymphocytic Leukaemia (CLL) ­ A Multicenter Study of the CLL Research Consortium James et al #291

*Day 8



R 50mg/m2






Len 2.5mg/d

Len 5mg/d








Len 10mg/d


Cycle 2

28 days

Cycles 3 - 7

28 days

Cycle 1

35 days

  • Standard pre-meds given and GCSF as per guidance

  • The study has closed to accrual with 69 treatment naive pts enrolled

    • 40 pts enrolled into arm A (< 65 yrs)

    • 27 in arm B (≥ 65 yrs)

    • 57 now have final response data

  • Primary Endpoint: Complete Response

Phase II, 2 stage study

* Increased lenalidomide dose to 5mg at day 8 or cycle 2

Summary of results4

Summary of results

  • 27/39 pts in arm A achieved a median L dose of 10 mg while only 13/27 pts in arm B tolerated the 10 mg L dose

    • Neutropenia was frequently Gr 3/4 in severity.

    • Gr3/4 AEs were reported in 72% of arm A pts and 82% of pts on arm B (p = 0.55)

    • Non-haem Gr3/4 toxicities reported in 37% of arm A and 52% of arm B (p = 0.31)

  • Older patients less likely to complete 7 cycles

  • Tumour flare more likely in younger patients

Relevance to practice8

Relevance to Practice

  • Strengths and Weaknesses

    • Open label, physician choice study with small numbers however a wide age range was used

    • No control: against single agent lenalidomide

  • Access to lenalidomide in this setting is currently via trials in the UK

  • Ideally recruitment to those trials should be encouraged rather than IFR requests for this regimen

  • There is a need to reinforce increased value of combination treatment vs single agent in CLL

Ash highlights 2011 san diego california

Lenalidomide and Rituximab for the Initial Treatment of Patients with Chronic Lymphocytic Leukaemia (CLL) James et al #291

Escalation of lenalidomide ONLY when no major toxicity seen

40% of pts <65 achieved 10mg dose escalation

  • n=69

  • Cycle 1:

    • Lenalidomide (L): d1-7: 2.5mg, d8-21: 5mg, d22-35: no L

    • Rituximab (R): d29: 50mg/m² d31: 325mg/m² d33: 375mg/m²

  • Cycle 2:

    • L: d1-21: 5mg, d22-28: no L

    • R: d1, 8, 15, 22: 375mg/m²

  • Cycle 3: (28 days) Cycle 7 (28 days)

    • L: d1-21: 10mg, d22-28: no L

    • R: d1 375mg/m²

  • Allopurinol 300mg, aspirin 8mg

Results and relevance to practice3

Results and Relevance to Practice

  • Primary Endpoint: Complete Remission Rate: 16%

  • Secondary Endpoints:

    • Overall Response Rate: 88%

    • Progression Free Survival: 19-20 months

  • Active regime but lenalidomide is very toxic and requires intra patient dose increase

  • This is one to watch and could demonstrate better results as currently only 16% CR

Ash highlights 2011 san diego california

A Combination of Fludarabine/Rituximab with Escalating Doses of Lenalidomide in Previously Untreated Chronic Lymphocytic Leukaemia (CLL): The REVLIRIT CLL5 AGMT Phase I/II Study,  Egle et al #292

  • n=45

  • Cycle 1:

    • Fludarabine (F): d1-3: 40mg/m² oral

    • Lenalidomide (L): d1-6: 0mg, d7-21: 2.5mg, d22-28 0mg

    • Rituximab (R): d4 375mg/m²

  • Cycle 2:

    • F: d1-3: 40mg/m² oral

    • L: d1-21: 5mg, d22-28 no L

    • R: d1: 500mg/m²

  • Cycle 3: (28 days) Cycle 6 (28 days)

    • F: d1-3: 40mg/m² oral

    • L: d1-21: 10mg (then escalated by 5mg each cycle), d22-28:no L

    • R: d1 500mg/m²

Results and relevance to practice4

Results and Relevance to Practice

  • Primary Endpoint: MTD, not reached

    • 34% pts escalated to 25mg, 27% pts didn’t reach 10mg

  • Secondary Endpoint:

    • Complete Response: 49%

    • Partial Response: 38%

  • Another promising combination with good activity, (CR rate) again requiring intra patient dose escalation

    • Therefore risk of errors will be high

  • If this enters clinical practice, pharmacy can expect to be busy!

Ash highlights 2011 san diego california

Fractionated Doses of Gemtuzumab Ozogamicin (GO) Combined to Standard Chemotherapy (CT) Improve Event-Free and Overall Survival in Newly-Diagnosed De Novo AML Patients Aged 50-70 Years Old, Castaigne et al #6

  • Prospective randomized phase 3 trial from the Acute Leukaemia French Association (ALFA)

  • 278 pts (50-70 yrs) with de novo AML:

    • Received DA with or without GO (3mg/m² on days 1, 4 and 7) (DA vs DAGO)

    • Primary endpoint: EFS

    • Secondary endpoint: RR, DFS, Safety and OS

  • Main additional toxicities in DAGO arm were prolonged G≥3 thrombocytopenia (n=19) and veno-occlusive disease (n=3)

Relevance to practice9

Relevance to Practice

  • The addition of GO to standard chemotherapy improved EFS and OS in elderly patients with AML and is well tolerated

    • Historically a difficult patient group to treat

    • Investigators used a different dosing schedule compared to that used in MRC trials

  • The drug has been recently, voluntarily withdrawn from the market – hopefully this will prompt reconsideration by Pfizer

Ash highlights 2011 san diego california

High Dose (HD-AraC) Vs Standard Dose Cytosine Arabinoside (SD-AraC) During Induction and IL-2 Vs Observation After Consolidation/Autologous Stem Cell Transplantation in Patients with Acute Myelogenous Leukaemia (AML), Willemze et al #257

Daunorubicin 50mg/m² for 3/7

Etoposide 50mg/m² for 5/7

HD AraC 3 g/m²/12hrsfor 4/7


Daunorubicin + AraC(500 mg/m²/12hrs for 6/7)

All CR pts


Daunorubicin 50mg/m² for 3/7

Etoposide 50mg/m² for 5/7

SD AraC 100 mg/m²for 10/7


  • Final report of the AML-12 trial of EORTC and GIMEMA Leukaemia Groups

  • Randomised phase III trial of 2005 newly diagnosed AML patients from 68 centres

    • Median age 45yrs (15 – 50 yrs)

    • >30% blasts

    • Excluded APL, pts converting from MDS/MPD and CML to AML

Summary of results5

Summary of Results

  • Median F/U: 6yrs

  • At 6yrs 1114 pts had died

  • Primary Endpoint:

    • OS at 6yrs: 42.5% (HD AraC) vs 38.7% (SD AraC) non sig

    • OS in pts <45yrs: 51.9% vs 43.4% (p=0.009)

  • Secondary Endpoints:

    • CR: 78.7% (HD AraC) vs 71.9% (SD AraC) (p=0.002)

    • PFS at 6yrs in pts <45yrs: 52.8% vs 46.6% non sig

    • Toxicity: no significant difference in rates of death

  • Good sample size that met statistical requirements

  • However the standard comparator is not equivalent to UK practice

Relevance to practice10

Relevance to Practice

High Dose AraC has significant benefit compared to Standard Dose AraC for AML induction, but only in patients under 45 years

This is relevant for the UK, however we may need to put this into context with UK gold standard therapy

UK trial portfolio is looking at development/integration of newer agents in consolidation

Ash highlights 2011 san diego california

Activity of Bosutinib by Baseline and Emergent Mutation Status in Philadelphia Chromosome–Positive Leukaemia Patients with Resistance or Intolerance to Other Tyrosine Kinase Inhibitors, Khoury et al #110

Phase I/II trial in Ph+ leukaemias following intolerance to imatinib plus a second generation TKI (dasatinib/nilotinib)

CHR rates were generally similar across the arms however lower response rates were seen in dasatinib resistant mutations

Emergent mutations on treatment were mostly T315I or dasatinib predictable mutations

Bosutinib shows poor activity in T315I patients

Another TKI, good or bad thing?



Ash highlights 2011 san diego california

Maintenance Therapy with Bortezomib Plus Thalidomide (VT) or Bortezomib Plus Prednisone (VP) In Elderly Myeloma Patients Included In the GEM2005MAS65 Spanish Randomized Trial Mateos et al #477

  • 2 stage, randomised trial including 260 elderly untreated myeloma patients.

Maintenance regimen

  • Stage 1: VMP and VTP as induction yielded similar Overall Response Rates of 80% and 81% respectively (Mateos et al Lancet Oncology 2010)

  • Bortezomib 1.3mg/m2 iv on days 1, 4, 8 and 11 at 3 month intervals


  • Prednisone 50mg po alt day


  • Thalidomide 50mg po OD

Summary of results6

Summary of results

  • 178 pts analysed – remaining relapsed before maintenance

  • Median follow-up after second randomization 34 months (8-54)

  • Overall, maintenance therapy resulted in an increased IF-CR rate, from 24% after induction up to 42% with maintenance

    • Better depth of response

  • For all patients receiving maintenance therapy,

    • Median PFS from initiation of treatment was 35 months (95% CI 29-39)

    • Median OS 60 months (95% CI 51-69)

  • From the randomization to maintenance therapy,

    • Median PFS 30 months (95% CI 21–39) vs. 24 months (95% CI 15–33; p=0·1) for VT vs. VP respectively

  • No significant difference in overall survival from this time point for VT and VP arms were observed (HR 1·4, 95% CI 0·8–2·4)

Adverse event profile

Adverse event profile

  • Only 6% discontinued due to toxicity

  • ≥Grade 3 haematological toxicity:

    • neutropenia in one patient in each arm

  • Most non-haematological toxicity was grade 1-2 in both arms

    • Incidence was greater for VT as compared with VP arm (p=0·0001).

    • Seven patients in VT arm developed cardiac events vs. one patient in the VP arm

    • Gastrointestinal toxicity, as constipation or paralitic ileus, was reported in 11 patients in VT and 3 patients in VP arm.

  • Grade 3-4 peripheral neuropathy was observed in 9 patients in VT (1 new, 8 worsened) and 3 in VP arm.

Relevance to practice11

Relevance to Practice

  • Strengths and Weaknesses

    • 1/3rd of patients didn’t reach maintenance

    • Interesting that there is no difference between induction regimens or maintenance

  • This could be an option instead of maintenance lenalidomide

    • Velcade only every 3 months

    • Can avoid ImID use (use at relapse)

    • Much cheaper than lenalidomide (1 yr Tx = 4 mo lenalidomide)

    • Reduced clinic appointments

  • Needs a phase 3 study to support clinical use

Ash highlights 2011 san diego california

Smoldering Multiple Myeloma (SMM) At High-Risk of Progression to Symptomatic Disease: A Phase III, Randomized, Multicenter Trial Based On Lenalidomide-Dexamethasone (Len-Dex) As Induction Therapy Followed by Maintenance Therapy with Len Alone Vs No Treatment, Mateos et al #991

No induction treatment

No maintenance




Smouldering myeloma pts

Lenalidomide 10mg (21/28) until progression

Lenalidomide + dexamethasone x4 (induction)


  • Primary Endpoint: Time To Progression

    • HR 6.0, 23mo vs not reached (<45mo)

  • Secondary Endpoints:

    • OS – median not reached, significant differences (p=0.04)

    • OS from Δ HR 5.01

Relevance to practice12

Relevance to Practice

  • Weaknesses

    • 4 early deaths in no treatment arm, due to progression – 1 disease, 3 treatment related toxicities!

    • Given small patient numbers, does this show results? Would not expect treatment related deaths in first line myeloma therapy

  • First study to show benefit in smouldering myeloma – are the results robust?

  • Unsure about treating smouldering myeloma with lenalidomide while still using CTD2 in some MM patients

  • Don’t do this without more evidence!

Ash highlights 2011 san diego california

Second Primary Malignancies in Newly Diagnosed Multiple Myeloma Patients Treated with Lenalidomide, Palumbo et al #996

  • Pooled data analysed 2253 pts with MM treated 1st line with lenalidomide with at least 1 yr F/U

    • Lenalidomide in combination with Melphalan or Cyclophosphamide and Corticosteroids (n=534), Melphalan autograft followed by Lenalidomide maintenance (n=336), MP/MPT/MPV/VMPT (n=898).

  • 48 secondary malignancies in total (2.1%)

    • ~ 1.9% in normal population

  • Risk of progression with MM is 10x higher than development of a 2° malignancy

  • This data may be relevant to patients with concerns regarding secondary malignancies

  • Risk of death from treatment toxicity or myeloma is higher than development of a 2° malignancy

Ash highlights 2011 san diego california

Efficacy and Safety of Three Bortezomib-Based Combinations in Elderly, Newly Diagnosed Multiple Myeloma (MM) Patients: Results From All Randomized Patients in the Community-Based, Phase 3b UPFRONT Study, Niesvizky et al #478

49 weeks maintenance

24 Weeks induction (8 x 21-day cycles)

Pts with symptomatic, measurable MM randomised 1:1:1

  • VcTD (n=167)

  • Induction with VELCADE –thalidomide - dexamethasone

  • Vc as per VcD

  • T 100mg

  • D as per VcD

  • Concomitant prophylaxis with aspirin, full-dose warfarin, or low‑molecular weight heparin unless medically contraindicated

  • VcMP (n=167)

  • Induction with VELCADE –melphalan - prednisolone

  • Vc as per VcD

  • M 9 mg/m2 and P 60 mg/m2 days 1–4, every other cycle

  • VcD (n=168)

  • Induction with VELCADE-dexamethasone

  • Vc 1.3 mg/m2 days 1, 4, 8 and 11

  • D 20 mg days 1, 2, 4, 5, 8, 9, 11, 12 [cycles 1–4]), days 1, 2, 4, 5 [cycles 5–8]

25 weeks of maintenance with weekly Vc 1.6 mg/m2 days 1, 8, 15, 22

Summary of results7

Summary of Results

Best confirmed response rates during the treatment period

*nCR includes patients IF+ as well as patients IF- but in whom confirmatory BM biopsy was not performed

PFS (Primary endpoint) & OS

Adverse event profile1

Adverse Event Profile

Safety profile during induction (I; cycles 1–8) and during maintenance (M; cycles 9–13)*

  • Most common grade ≥3 AEs across all three arms:

    • Peripheral neuropathy (23%)

    • Fatigue (10%)

    • Diarrhoea (9%)

* The M column represents first onset of an AE during maintenance



Not compared to UK standard treatment

VcD, VcTD, and VcMP induction followed by weekly Vc maintenance produced similar activity in elderly, newly diagnosed, transplant-ineligible MM patients

Patients in the VcD doublet arm appear to have similar long-term outcomes to patients in the VcTD and VcMP triplet arms

Relevance to practice13

Relevance to Practice

  • Strengths and Weaknesses

    • Good study in ‘real world’ patient group

    • Not compared to standard practice – difficult to identify benefits

    • Problematic toxicity

    • EORTC QoL data included – decrease in QoL across all 3 arms

    • Early data, not yet complete

  • VMP approved but will be helpful to see data cf. VD

  • Consider practicalities of weekly maintenance injections for elderly patients

  • Generally, VD and VMP demonstrated similar efficacy and V maintenance was well tolerated (cf. Induction)

Ash highlights 2011 san diego california

  • Placebo

  • Placebo

  • Lenalidomide

A Phase 3 Study Evaluating the Efficacy and Safety of Lenalidomide (Len) Combined with Melphalan and Prednisone Followed by Continuous Lenalidomide Maintenance (MPR-R) in Patients (Pts) ≥ 65 Years (Yrs) with Newly Diagnosed Multiple Myeloma (NDMM): Updated Results for Pts Aged 65-75 Yrs Enrolled in MM-015 Palumbo et al #475

  • 116/152, 116/153 and 116/154 of MPR-R, MPR, and MP pts, respectively were aged 65-75 yrs.

  • Median follow up 30 months

MM-015, Phase III randomised, placebo controlled trial, compared MPR-R with with fixed-duration MPR and MP induction in transplant-ineligible NDMM pts

Interim results showed unprecedented reduction in disease progression risk with MPR-R (Palumbo et al, IMW 2011)

This analysis focuses on pts aged 65-75 yrs in whom the greatest benefit was observed

Induction x 9 cycles


Summary of results8

Summary of results

Median PFS 31 months vs. 12 months for MPR-R vs. MP respectively; HR 0.30 [95% CI, 0.20-0.45]; p < .001

Median PFS 31 months vs. 15 months for MPR-R vs. MPR respectively; HR: 0.44 [95% CI, 0.30-0.66]; P < .001

Adverse event profile2

Adverse event profile

  • During induction, discontinuation due to AEs occurred in 13% of MPR and 4% of MP pts.

    • The most common induction Gr 4 hematologic AEs for MPR-R, MPR, and MP were neutropenia (39%, 29%, and 7%) and thrombocytopenia (33%, 12%, and 4%).

    • The most frequent Gr 3/4 non-haematologic AE was bone pain (3%, 3%, and 4%).

  • Lenalidomide maintenance was generally well tolerated

    • The most frequent Gr 4 hematologic AEs were thrombocytopenia (5%), neutropenia (4%), and anemia (3%);

    • Gr 3/4 non-hematologic AEs included bone pain (5%) and diarrhea (5%).

  • Hematologic second primary malignancies during induction and maintenance were 3 (2 AML, 1 ALL), 1 (MDS), and 0 in the MPR-R, MPR, and MP arms, respectively.

  • Solid tumor SPMs occurred in 2 pts per arm, were heterogeneous and balanced across arms

Relevance to practice14

Relevance to Practice

  • Well-conducted study: has 30 months’ median follow up and is well-powered.

    • MP is no longer an appropriate comparator arm – Thalidomide

  • There is a significant improvement in PFS with the MPR-R regimen (maintenance lenalidomide) vs MPR.

    • Predictably, both regimens are much better than MP.

  • The MPR regimen is not used in the UK as lenalidomide isn’t funded in this situation.

    • MPR-R involves long-term administration of lenalidomide and it’s highly unlikely that NICE would agree to fund this, even at a 10mg dose.

  • Interestingly, the authors point out that the PFS for MPR-R (31months), while much better than MPR, is not obviously better than the PFS for some other comparable regimens. This includes a PFS of 28 months obtained with MPT, a regimen that is widely adopted in the UK.

Ash highlights 2011 san diego california

A Phase 2 Study of Elotuzumab in Combination with Lenalidomide and Low-Dose Dexamethasone in Patients with Relapsed/Refractory Multiple Myeloma, Sagar et al #303

  • Elotuzumab is a humanised 1gG1 monoclonal antibody targeting human CS1 (cell surface glycoprotein)

    • Pre-clinical work showed potential for synergy with lenalidomide

  • 63 pts received:

    • Elotuzumab10mg/kg vs 20mg/kg weekly for 2 cycles

    • Followed by q14d lenalidomide standard schedule

    • Dexamethasone 40mg weekly

      • Median age 63

      • 55% had ≥2 prior therapies

      • Patients with no prior lenalidomide were excluded

Summary of results9

Summary of Results

  • Median F/U 14 months – PFS not reached therefore durable response achieved

  • Adverse Events included:

    • Muscle spasm, diarrhoea, lymphophenia (likely due to elotuzumab), fatigue

    • No G4 peri infusion reactions

  • *No statistical significance between ORR in 10mg/kg and 20mg/kg

Relevance to practice15

Relevance to Practice

  • Strengths and Weaknesses

    • Well designed study but not powered to see difference between 2 groups

  • Elotuzumab requires pre-medication

  • Eloquent 1 and 2 studies are ongoing and therefore these results are awaited however raise a number of questions regarding combination of agents

  • Elotuzumab + lenalidomide + dexamethasone:

    • Offers a high ORR in relapsed/refractory patients

    • Is well tolerated with limited additional toxicity and durable responses

Ash highlights 2011 san diego california

Continued Overall Survival Benefit After 5 Years’ Follow-up with Bortezomib-Melphalan-Prednisone (VMP) Versus Melphalan-Prednisone (MP) in Patients with Previously Untreated Multiple Myeloma (MM), and No Increased Risk of Second Primary Malignancies, San Miguel et al #476

  • VMP has previously demonstrated superiority to MP across all efficacy points

  • This study presents final results of the phase 3 VISTA trial at 60 months

  • 682 transplant ineligible MM patients

    • Median age: 71yrs

    • 30% age 75+

    • 34% ISS stage 3

  • 1:1 randomisation to:

    • Nine 6 week cycles of VMP (n=344)

    • Or MP alone (n=338)

  • At data cut off, 95% of patient data collected

Summary of results10

Summary of Results

Time to next treatment (27 vs 19.2 months) was significantly superior with VMP vs MP

Median overall survival for patients who were initially treated with VMP was 28.2 months vs 23 months in patients who initially received MP and then went on to receive Bortezomib at relapse

Relevance to practice suggests that receiving Bortezomib upfront in this group of patients is more beneficial

Relevance to practice16

Relevance to Practice

  • VMP provides an OS advantage compares to MP

    • These are final results – OS advantage is demonstrated, not just predicted

    • Persistant and significant

    • No emergency safety signed for secondary malignancies

  • VMP is now a possible option for 1st line therapy but only in a small number of patients

  • VMP vs MPR phase III is required however VMP vs MPT is a more relevant trial for UK practice, as this or CTDa would be first line UK treatment

Pomalidomide in relapsed and refractory multiple myeloma

Pomalidomide in relapsed and refractory Multiple Myeloma

Review of 2 studies:

Pomalidomide (POM) Alone or in Combination with Low-Dose Dexamethasone (LoDex) in Patients (Pts) with Relapsed and Refractory Multiple Myeloma Who Have Received Prior Treatment That Includes Lenalidomide (LEN) and Bortezomib (BORT): Phase 2 Results, Richardson et al# 634

High Response Rates to Pomalidomide and Dexamethasone in Patients with Refractory Myeloma, Final Analysis of IFM 2009-02, Leleu et al #812

Study design 634 812

Study Design (#634 & #812)

POMALIDOMIDE 4mg + 40mg Dexamethasone (LoDex) weekly

  • Both included patients relapsed and refractory to bortezomib and lenalidomide

  • 70% pts double refractory in both studies

  • Approx 1/3rd previous carfilzomib Tx

  • Median 5 prior lines Tx (3-13)



Study #634

POMALIDOMIDE 4mg with addition of LoDex on progression


POMALIDOMIDE 4mg + Dex 21 days of 28



Study #812

POMALIDOMIDE 4mg + Dex 28 days of 28


Both randomised phase II studies

Summary of results11

Summary of Results

  • Strengths and Weaknesses

  • Very precisely defines refractory and relapsed patient population

  • Too much sub set analysis

* ORR ≥ PR



  • These studies help to clarify the optimal schedule for pomalidomide, with patients similar to likely UK patients

    • Bortezomib and lenalidomide refractory/relapsed patients

  • Study #632 confirms that dexamethasone is required for pomalidomide to be effective, while study #812 suggests that a 21/28d cycle length is optimal

    • Similar response rates but decreased toxicity in 21/28d arm

Relevance to practice17

Relevance to Practice

Phase III studies planned in EU and US

Response rates are not huge but if this enters clinical practice, careful control of double refractory patients may be most appropriate rationing method

Addition of clarithromycin (#635) may increase activity further (ORR 60%)

More work is required in poor cytogenetic patients

Ash highlights 2011 san diego california

MRC Myeloma IX, 6 Year Median Follow-up (FU) Highlights the Importance of Long-Term FU in Myeloma Clinical Trials and Differential Effects of Thalidomide in High- and Low-Risk Disease Morgan et al #993

Then randomised to low dose thalidomide vs no maintenance until progression

  • Medical Research Council (MRC) Myeloma IX study evaluated the role of the addition of thalidomide to induction and maintenance therapy (n = 1,970)

  • May 2003 – November 2007

  • 2 arms

    • Intensive = CTD vs CVAD

    • Non-intensive = MP vs CTDa

    • All patients recieved zoledronic acid or clodronate

  • Previously presented data (median FU of 3.7 years) demonstrated an emergent survival benefit for thalidomide induction, though not reaching significance

Summary of results and relevance

Summary of results and relevance

  • Results of the extended follow up confirmed those of earlier analyses

  • Extended follow-up (5.8 years)

  • Non-intensive pathway

    • PFS 13 months versus 12 months (CTDa vs MP respectively)

    • No benefit in terms of overall survival

  • Intensive pathway

    • No statistically significant difference in PFS or OS (CTD vs CVAD)

  • Thalidomide maintenance therapy

    • Significantly improved PFS compared to no maintenance therapy (22 vs 16 months). Benefit seen mainly in patients with favourable chromosomal abnormalities

    • No impact on OS observed

Multiple myeloma other agents to look out for

Multiple Myeloma: Other agents to look out for...

  • Carfilzomib #633

  • From phase 1 studies:

    • MLN9708 – orally active proteasome inhibitor #301

    • marizomib – novel proteasome inhibitor #302

    • AZD6244 – oral MEK 1/2 inhibitor #306

    • BT062 - antiCD138 chimerised monoclonal IgG4, covalently linked to the cytotoxic agent maytansimoid (DM4)



5 adeno associated viral vector mediated gene transfer for hemophilia b nathwani et al 5

5 Adeno-Associated Viral Vector Mediated Gene Transfer for Hemophilia B, Nathwani et al #5

  • Gene therapy in haemophilia B patients using peripheral vein infusion of a single dose of adeno-associated virus (AAV) vector

  • 6 severe HB patients (FIX< or equal to 1%)

    • Vector administered without immunosupression

    • F/U of 6-16 months

  • AAV-mediated expression of FIX at 2-11% in all patients (most maintained without factor 9 infusions)

  • £400k saving to the NHS on infusions for these 6 patients

  • A novel approach showing promise for gene therapy of HB



Ash highlights 2011 san diego california

Consistent Benefit of Ruxolitinib Over Placebo in Spleen Volume Reduction and Symptom Improvement Across Subgroups and Overall Survival Advantage: Results From COMFORT-I Verstovsek et al #278

  • Pts with MF were randomized to start placebo or ruxolitinib at a dose of 15 mg or 20 mg PO BID depending on baseline platelet count (100–200 x109/L or >200 x109/L, respectively).

  • N = 309 (155 ruxolitinib, 154 placebo)

  • SV change was measured by MRI

  • MF symptoms were assessed using a daily diary (modified Myelofibrosis Symptom Assessment Form [MFSAF] v2.0) over 1 wk prior to dosing and throughout the 24 wks of dosing

  • The % changes from baseline to wk 24 in SV and MFSAF Total Symptom Score (TSS) were compared for ruxolitinib and placebo

Summary of results12

Summary of results

  • Ruxolitinib demonstrated consistent benefits in SV an and TSS across all subgroups compated with placebo

Summary of results13

Summary of results

  • After therapy interruption symptoms returned to baseline within 7 – 10 days

  • 13 ruxolitinib and 24 placebo pts died during the study or during extended follow-up (median follow-up of 52 and 51 wks respectively)

    • HR 0.499 (95 % CI 0.254 - 0.98) (p=0.0395)

  • Probability of surviving >48 weeks:

Relevance to practice18

Relevance to practice

  • Ruxolitinib may confer a survival advantage

    • Doesn’t appear to affect underlying disease

    • Primary endpoint was improvement in spleen volume by at least 35%. Was the trial powered to show survival benefit?

  • More studies are required to see whether JAK2 inhibitors improve marrow fibrosis and change natural history of disease or whether benefit is due to reduction in spleen size

  • Available in the UK through a compassionate use programme

  • Draft scope for NICE appraisal has been published

  • Alternatives that improve symptoms in patients with MF are limited

Ash highlights 2011 san diego california

Ruxolitinib Provides Reductions in Splenomegaly Across Subgroups: An Analysis of Spleen Response in the COMFORT-II Study Harrison et al #279

  • Background

    • COMFORT-II is a randomized, open-label, phase 3

    • Evaluated the safety and efficacy of ruxolitinib, in patients with primary myelofibrosis (PMF), post-polycythemia vera-MF (PPV-MF), or post-essential thrombocythemia-MF (PET-MF).

    • N =219 patients randomized (2:1) to receive:

      • Ruxolitinib (15 or 20 mg bd based on the baseline platelet count [100– 200 x 109/L or >200 x 109/L, respectively])

      • Best available therapy (BAT) of the investigator's choice.

    • The primary and key secondary endpoints of the study were both met: the proportion of patients achieving 35% reduction in spleen volume at week 48 (28.5%, ruxolitinib; 0%, BAT; P <.0001) and week 24 (31.9%, ruxolitinib; 0%, BAT; P <.0001), respectively.

  • Subgroup analysis was performed on both the 48- and 24-week endpoints

Summary of results14

Summary of results

Proportion of Patients in Each Subgroup with 35% Reduction in Spleen Volume from Baseline at Week 48

HU hydroxyurea

BL baseline

Ruxolitinib was shown to be more effective than BAT at reducing spleen volume in all patient subgroups regardless of gender, age, mutation status, IPSS risk category, baseline spleen size, MF subtype, or ruxolitinib starting dose.

No patients in the BAT group reached a 35% reduction in spleen volume at week 48

No significant difference in response rates was observed between patients with the JAK2V617F mutation compared with those without the mutation

Relevance to practice19

Relevance to practice

  • This was a large study but was not powered to assess overall survival

  • Included a population of patients with very large spleen size

    • Normal spleen volume150 – 200cm3

    • Ruxolitinib spleen volume 2408cm3

    • BAT spleen volume 2318cm3

  • There may be a weak suggestion that patients with primary MF do not achieve as a good a response as other MF types

    • But this was not shown in Comfort 1

  • Further follow up is required

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