ASH Clinical News September 2016 | Page 41

CLINICAL NEWS ment in 51 patients ( median age = 71 years ; range = 62-84 years ) with MCL .

Patients were enrolled from 19 centers in Sweden , Norway , Denmark , and Finland between October 12 , 2009 , and May 22 , 2013 . All patients who had a confirmed stage II-IV MCL diagnosis were eligible for inclusion if they could not tolerate high-dose chemotherapy , had a World Health Organization performance status of 0-3 , and had not received any previous treatment other than one cycle of chemotherapy and / or radiotherapy .

The multicenter , non-randomized , open-label study consisted of two phases : phase I was a doseescalation stage to identify the maximum tolerated dose ( MTD ); phase II was an expansion cohort to measure survival outcomes .

In phase I , patients received L + BR induction therapy in six 28- day cycles :

• Lenalidomide administered orally twice-daily on days 1-14 ( following a 3 + 3 doseescalation design with an initial dose of 5 mg in cycles 1-6 , escalating 5 mg in each step , followed by 25 mg in cycles 7-13 )

• 90 mg / m 2 of bendamustine administered intravenously ( IV ) on days 1-2

• 375 mg / m 2 of rituximab IV on day 1

This was followed by a 28-day maintenance cycle with singleagent lenalidomide administered orally twice daily on days one through 21 for a maximum of seven cycles ( 52 weeks ).

The researchers determined the MTD to be lenalidomide 10 mg during cycles two through six , followed by 10 mg in cycles seven and eight and 15 mg in cycles nine through 13 . Notably , a high number of adverse events ( AEs ) were observed in the first stages of phase I , prompting the researchers to amend the treatment protocol in the following ways :

• Omitting lenalidomide during the first treatment cycle

• Administering corticosteroids prior to every rituximab infusion and in cycle two

• Administering antibiotic prophylaxis to all patients

Of the 50 patients included in the analysis ( one patient was removed because of screen failure ), 37 patients ( 73 %) completed the induction phase ( cycles 1-6 ), and 12 ( 24 %) completed the maintenance phase ( cycles 1-13 ). Most patients ( n = 36 ; 68 %) received the MTD dose of L + BR .

After a median follow-up of 31 months ( range = 13-59 months ), the median PFS ( primary endpoint of phase II ) was 42 months ( 95 % CI 31-53 ). “[ This ] is longer than the reported PFS of 35 months in the BR arm of MCL patients in the German STiL study ,” the authors noted .

The median overall survival ( OS ) was 53 months , with a 73 percent three-year OS rate , and the overall response rate ( ORR ) was 80 percent based on intention to treat ( TABLE 2 ).

In addition , compared with lymphocyte levels at baseline , lymphocyte levels after three months of L + BR treatment were

TABLE 2 . Response Rates per CT Scan and Bone Marrow Results

CT = computed tomography ; ORR = overall response rate ; CR = complete remission ; CRU = complete remission undetermined ; PR = partial remission ; PD = progressive disease

*

Not evaluated included death of any cause , consent withdrawn , end of study due to anything other than PD , end of treatment due to any cause and not evaluated at this time point , not done due to other cause / missing data

significantly decreased ( p < 0.001 ). The researchers also found that 36 percent of evaluable patients had MRD-negativity in bone marrow after induction with L + BR , “ suggesting that molecular remission can be achieved with this regimen ,” the authors wrote .

However , these benefits seemed to come at the expense of an “ unexpected high degree of severe adverse events ” starting in phase I , most of which were allergic or cutaneous reactions . “ By omitting lenalidomide from cycle one and by adding corticosteroids in cycle two , the allergic reactions observed in the first cohorts could be prevented and the risk of severe cutaneous reactions was diminished , although not completely eradicated ,” Dr . Albertsson-Lindblad and colleagues wrote .

The incidence of grade 3-5 infections was high ( 42 %), they added , and led to treatment discontinuation in 10 percent of patients ( n = 5 ). Treatment discontinuation was related to :

• Toxicity ( n = 28 ; 74 %, 15 of which occurred during induction phase )

• Progressive disease ( PD ; n = 6 ; 16 %, 5 of which occurred during the induction phase )

• SPM ( n = 3 ; 8 %)

• Withdrawal of consent ( n = 1 )

Twelve deaths were reported , six due to PD , three due to infection during induction phase , and two due to SPM ( including lung cancer and chronic myelomonocytic leukemia ).

“ It is likely that the increased toxicity associated with lenalidomide addition outweighs a possible benefit in efficacy ,” the authors concluded .

The study is limited by its nonrandomized design and its use of data from previously reported clinical trials , rather than a comparator arm . The authors recommend long-term follow-up and analysis of additional treatment combinations to improve outcomes for this patient population .

REFERENCE

Albertsson-Lindblad A , Kolstad A , Laurell A , et al . Lenalidomide-bendamustine-rituximab in untreated mantle cell lymphoma > 65 years , the Nordic Lymphoma Group phase I + II trial NLG-MCL4 . Blood . 2016 June 27 . [ Epub ahead of print ]

In a multicenter , retrospective , cohort study , Matthieu Mahévas , MD , PhD , of the National Reference Center for Adult Auto-Immune Cytopenias at Hôpital Henri Mondor , in Créteil , France , and authors defined a new set of patients with “ multirefractory ” immune thrombocytopenia ( ITP ) who , compared with control patients with ITP , were at a greater risk for developing secondary ITP and monoclonal gammopathy of undetermined significance ( MGUS ).

“ Refractory ITP was previously defined as lack of a minimum response to splenectomy and the requirement for long-term treatment to reduce the significant bleeding events ,” Dr . Mahévas and colleagues wrote . However , in the current study , “ the characteristics and outcome of [ multirefractory ITP ] clearly differed from those of controls with ‘ typical ’ ITP .”

The trial compared 37 patients with multirefractory ITP with 183 matched controls enrolled at tertiary-care university hospitals specializing in adult ITP between 1990 and 2014 to determine the characteristics and outcomes of multirefractory , defined as severe chronic ITP that does not respond to rituximab ( used off-label for ITP ), splenectomy ( or if splenectomy was contraindicated ), and the two thrombopoietin-receptor agonists ( Tp-RAs ) approved in France ( romiplostim and eltrombopag ). Patients could have achieved a transient response to corticosteroids and / or intravenous immunoglobulin ( IVIg ), as these are considered first-line and / or rescue therapies .

To analyze baseline data , researchers gathered clinical data from medical charts for each patient ; to gather information about outcomes , they conducted telephone interviews with patients and physicians using a standardized questionnaire .

Among the 37 patients with multirefractory ITP , most were women ( n = 25 ; 67.5 %), with a median age at ITP diagnosis of 47.2 years ( range = 12-79 years ). Many patients ( n = 28 ; 75.7 %) presented with some bleeding symptoms at the time of ITP diagnosis – 30 percent of whom ( n = 11 ) had severe bleeding .

One-third of patients ( n = 13 ; 35 %) presented with secondary ITP :

• 5 patients had definite autoimmune disease ( including , antiphospholipid syndrome [ n = 1 ], lupus erythematosus [ n = 1 ], and Evans syndrome [ n = 3 ])

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