In a study of previously treated patients with systemic light chain amyloidosis (AL), nearly half of patients treated with intravenous (IV) daratumumab experienced at least a very good partial response (VGPR), according to a study published in Blood. The authors, led by Murielle Roussel, MD, of IUCT Oncopole in Toulouse, France, noted that these responses occurred rapidly, which may be particularly important for improving survival in patients with severe amyloidotic organ compromise.
This open-label, phase II study enrolled 40 patients with biopsy-proven AL and measurable disease from 15 sites in France and Italy. Participants had AL that was either in relapse or had not reached VGPR with a difference between serum involved and uninvolved free light chain (dFLC) <40 mg/L after their last therapy.
The first 2 treatment cycles consisted of IV daratumumab 16 mg/kg on days 1, 8, 15, and 22. The four remaining 4-week treatment cycles consisted of IV daratumumab 16 mg/kg every other week.
All patients received premedication with paracetamol, antihistamines, and either IV methylprednisolone 100 mg or dexamethasone 20 mg to reduce the risk of daratumumab-related infusion reactions. In addition, patients received antiviral therapy to prevent herpes zoster and antibiotics to prevent bacterial infections, unless contraindicated.
The primary and secondary endpoints were as follows:
- Primary endpoint: VGPR or better at the end of the 6 treatment cycles
- Secondary endpoints: time to hematologic response, best hematologic response, cardiac and renal response, safety and tolerability, progression-free survival (PFS), and overall survival (OS)
A complete response (CR) was defined as negative serum and urine immunofixations plus normalized free light chain ratio; partial response was defined as a >50% reduction of the dFLC.
In the intention-to-treat population, all 40 patients received at least 4 daratumumab injections during the study period. The median age at baseline was 69 years (range = 45-83). Overall, 65% of patients presented with AL involvement in two or more organs; the most commonly involved organs were the heart and kidneys (observed in 60% and 65% of participants, respectively). The median baseline dFLC level was 164 mg/L (interquartile range [IQR] = 112-334), and 16 patients had a dFLC >180 mg/L.
The median time from diagnosis to treatment was 23 months (IQR=14-40), and the median time from last line of therapy was 5 months (IQR=1-14). More than half of patients (n=21) had received more than 3 lines of prior therapy. Seventeen patients had refractory disease and, overall, 22 patients had disease that was considered refractory or poorly responsive to therapy because VGPR or better was not reached prior to enrollment.
Among the 33 patients who completed the study, the median treatment duration was 6 months (IQR=5.5-6.2). Seven patients discontinued the study due to organ progression, absence of a hematologic response, or development of a malignancy. “No one stopped study treatment or died because of drug toxicity,” the authors reported.
The proportion of patients who achieved the primary endpoint of VGPR or better after the planned 6 therapy cycles was 478%. The responses were rapid, occurring within a median of 8.5 days, and deep, with 3 patients (7.5%) achieving CR and 16 (40%) achieving VGPR.
The overall response rate was 70%. The researchers observed that these responses occurred rapidly, with a median time to initial response of 1 week, and that just 1 dose of daratumumab resulted in a median dFLC reduction of 49%.
The investigators found that pretreatment dFLC level and percent of reduction after 1 daratumumab injection both held predictive value for hematologic response. For example, the 22 responders had a median dFLC of 38 mg/L and a 63% reduction, while the 15 non-responders had a median dFLC of 137 mg/L and a 24% reduction (both p<0.001).
Over a median follow-up of 26.4 months (IQR=19.3-30.1), 11 patients died. Two deaths on therapy were attributable to disease progression (n=2) or lung cancer (n=1), whereas 8 deaths during follow-up were related to disease progression (n=7) or colon cancer (n=1). The most common adverse events (AEs) included grade 1/2 infusion-related reactions (n=17; 43%) and no grade 4 or 5 daratumumab-related AEs were observed.
Twenty-four patients began a new therapy because of either unsatisfactory response or hematologic progression or organ progression after treatment with daratumumab. No relapses or rates of disease progression were observed in the responders before the end of the planned 6-month treatment.
Although the median OS was not reached, the median PFS estimate was 24.8 months. The investigators estimated a 2-year OS rate of 74% and a 2-year PFS rate of 51%. They also reported that patients who achieved a VGPR or better were significantly less likely to receive another treatment line after daratumumab (p=0.039).
Limitations of this trial include its single-arm design and small sample size. The study authors also suggest the analyses of response predictors lacked statistical power, which ex-plained the use of only univariate analyses in this study.
Study authors report relationships with Janssen, which sponsored this trial.
Roussel M, Merlini G, Chevret S, et al. A prospective phase II of daratumumab in previously treated systemic light chain amyloidosis (AL) patients. Blood. 2020 February 27. [Epub ahead of print]