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R-CPOP as first line treatment for patients with diffuse large B-cell lymphoma and significant reduced LVEF or high risk of anthracycline induced cardiotoxicity


R-CHOP chemotherapy remains the standard of care in treatment of fit patients without comorbidities suffering from diffuse large B-cell lymphoma ( DLBCL ), even in elderly patients up to 80 years.
Anthracyclines are essential in treatment however they are as well as liposomal anthracyclines contraindicated for patients with impaired cardiac function.
No standard treatment for cardiac frail patients exists.
Pixantrone is an aza-anthracenedione showing reduced cardiotoxicity in vitro compared to standard anthracyclines.
Data by Herbrecht et al ( Ann Oncol, 2013, 24:2618 ) comparing R-CHOP as first line treatment for DLBCL with R-CPOP ( substituting Doxorubicin with Pixantrone, 88 mg/m2 ) resulted in similar progression free survival ( PFS ) with reduced grade 3 congestive heart failure ( CHF ) rates.

Researchers have investigated efficacy and safety of first line R-CPOP in DLBCL patients with significant cardiac morbidity or high risk of anthracycline induced cardiotoxicity.

This trial was a mixed prospective and retrospective analysis.
The prospective non-randomized, multicenter phase 2 trial recruited patients in 5 investigational sites in Germany.
Patients were aged more than 18 years with untreated DLBCL and impaired cardiac function with a left ventricular ejection fraction ( LVEF ) more than 40% and less than or equal to 50%.

In addition, researchers have conducted a retrospective analysis from patients with untreated DLBCL and significant reduction in LVEF or high risk of anthracycline induced cardiotoxicity who were not eligible for the prospective trial.

Patients received up to six 21-day cycles of R-CPOP ( Rituximab 375 mg/m2 i.v. day 0 or day 1, Cyclophosphamide 750 mg/m2 i.v. day 1, Pixantrone 88 mg/m2 i.v. day 1 ( = 150 mg/m2 Pixantrone dimaleate ), Vincristine 1.4 mg/m2 ( maximum dose 2 mg ) i.v. day 1, Prednisone 100 mg orally day 1-5 ) followed by additional 2 cycles of Rituximab every 21 days.

The primary endpoint of the prospective trial was the rate of complete response ( CR ) after induction therapy as assessed by PET-CT at the end of treatment.
Secondary endpoints were overall survival ( OS ) and progression free survival ( PFS ).

A total of 28 patients were treated between 2016 and 2021 and included in the analysis ( 10 patients in the prospective multicenter trial, 18 patients were retrospectively analyzed from Department of Hematology and Oncology, Universitätsklinikum Freiburg [ Germany ] ).
Median age was 76 years ( range 51-85 ) with 75% male patients.
71% had an advanced Ann Arbor stage ( III/IV ), 71% had an IPI greater than or equal to 3.
The median LVEF was 45% ( range 25-63% ), 79% patients had a LVEF less than or equal to 50%.
Patients with LVEF less than 50% had echocardiographic signs of cardiac morbidity like severe heart valve disease, history of significant cardiac impairment or prior treatment with anthracyclines.
The median number of R-CPOP cycles delivered was 5 ( range 1-6 ).

Overall response rate was 82.1%, with 17 patients ( 60.7% ) achieving CR after induction.

With a median follow up of 24.7 months, estimated 2 years- PFS and OS both were 71.9%.

Concerning the cardiac parameter NT-ProBNP there was no significant change of the median NT-ProBNP from start of induction ( 685 pg/ml, range 103-1598 ) to end of treatment ( 655 pg/ml, range 96-2199 ) in 15 patients which received at least 4 cycles R-CPOP and achieved a complete response.

In conclusion, with this mixed prospective and retrospective analysis researchers have shown not only feasibility but also encouraging efficacy of R-CPOP in DLBCL patients with high risk of anthracycline induced cardiotoxicity.
Therefore, one could envision additional clinical trials to establish R-CPOP as standard first line treatment in this patient cohort. ( Xagena )

Lorenz K et al, HemaSphere 2022; 6: 1997-1998

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