1 Introduction
Current management of relapsed/refractory non-Hodgkin lymphoma (NHL) remains an unmet medical need, due to a poor prognostic outlook and lack of treatment options [
1]. First-line therapy for aggressive B-cell NHL is an anthracycline-based regimen in combination with rituximab, such as R-CHOP (rituximab, cyclophosphamide, doxorubicin, vincristine and prednisolone) [
2‐
4]. Complete response rates with R-CHOP of around 80% have been reported, with a 5-year progression-free survival (PFS) of approximately 50% [
5]. However, up to 25% of patients inevitably relapse [
6].
Due to the risk of cardiotoxicity with increasing cumulative anthracycline dose, repeated use of anthracyclines is limited in patients with relapsed/refractory disease [
7,
8]. Newer agents are few, and include ibrutinib for relapsed/refractory mantle-cell lymphoma [
9] and idelalisib for refractory follicular lymphoma [
10]. Pixantrone, an agent that belongs to the aza-anthracenedione family [
1,
11], is a recommended option in multiply relapsed and refractory disease or heavily pretreated patients with NHL [
3,
12]. Pixantrone’s molecular structure is different from anthracyclines [
1,
13,
14]. The differences in its structure result in a unique mechanism of action, notably with a lesser potential for iron binding and therefore less cardiotoxicity compared with anthracyclines [
1,
11].
Pixantrone has conditional approval in Europe [
11], based on results from the open-label, randomized phase 3 PIX301 study [
15,
16], where significantly more patients who received pixantrone than comparator (physician’s choice of treatment) achieved a complete (CR) or an unconfirmed complete response (CRu) and a higher overall response rate (ORR) [
15]; median PFS was also significantly prolonged in the pixantrone arm. It is indicated as monotherapy for the treatment of adult patients with multiply relapsed or refractory aggressive B-cell NHL [
11]. To complete post-authorization measures, a confirmatory phase 3 study (PIX306) is underway [
15]. Study recruitment is complete and results from the primary efficacy endpoint analysis are expected in 2018.
There were several cases of long-term remission in the PIX301 study, including a case of a very durable partial response (PR) with pixantrone in a patient with relapsed diffuse large B-cell lymphoma (DLBCL) at study entry (see
Box 1), in addition to some patients with durable CRs. In the current post-hoc analysis of data from the PIX301 trial, we explored possible correlations between patient characteristics and clinical response in these cases.
4 Discussion
At the end of treatment in the main PIX301 study [
15], significantly more patients who received pixantrone achieved a CR/CRu (20.0 vs 5.7%;
p = 0.021) and an ORR (37.1 vs 14.3%;
p = 0.003) than did those who received a comparator drug. Median PFS was also significantly prolonged in the pixantrone treatment group [5.3 vs 2.6 months; hazard ratio (HR) 0.60; 95% CI 0.42, 0.86;
p = 0.005]. A post-hoc analysis of data from a subgroup of patients in the study with histologically confirmed relapsed or refractory aggressive B-cell NHL also demonstrated a significantly improved CR/CRu (23.1 vs 5.1%;
p = 0.047) and ORR (43.6 vs 12.8%;
p = 0.005) with third- or fourth-line pixantrone treatment compared with comparator agents [
16]. Clinical response was especially improved among those patients who had received previous rituximab treatment, with an improved CR (30.0 vs 5.6%;
p = 0.093), ORR (45.0 vs 11.1%;
p = 0.033), and median PFS (5.4 vs 2.8 months; HR 0.52; 95% CI 0.26, 1.04) with pixantrone versus comparator agents.
The results of the present analysis build on previous results and suggest that it is possible to obtain a long-lasting response with pixantrone. Also, the potential for a durable response to pixantrone appears to be independent of whether the best response to prior therapy was a CR, PR, stable disease, or progressive disease. Of note, our results indicate that it is possible to get a response with later lines of NHL treatment, even with monotherapy, which is important because monotherapy is typically associated with lower rates of toxicities than multi-agent regimens.
Our observations are in line with those in a phase 2 study of pixantrone monotherapy in patients with relapsed, aggressive NHL, in which several patients had very long CRs that lasted more than 1 year [
17]. In this study, two female patients with stage II DLBCL and stage IV mantle cell lymphoma experienced CRs lasting 17+ and 15.2 months, respectively. This study also included one patient (male; aged 66 years) with stage IV transformed follicular lymphoma who experienced a PR lasting 24+ months.
There are several advantages of long-term responses in this setting, where treatment options are limited. Treatment is usually of palliative intent, and patients are often unable to tolerate combination regimens because of factors including comorbidities, age, poor performance status and cardiotoxicity from previous anthracycline therapy [
1]. Therefore, monotherapies with good tolerability and long-term efficacy are sorely needed [
1]. Pixantrone was designed to maintain efficacy while reducing the risk of cardiotoxicity. It is non-cross-resistant with anthracyclines and generally well tolerated with a manageable toxicity profile, making it a useful treatment option [
13,
18].
Case studies have also indicated that pixantrone may be useful in the routine clinic setting, as a bridge to autologous SCT, or to induce a CR following relapse after allogenic SCT [
19,
20]. One patient with DLBCL achieved a CR with third-line pixantrone monotherapy plus a single dose of rituximab and benefited from long-term remission after consolidation with high-dose chemotherapy and autologous SCT [
19]. Another patient with DLBCL who relapsed after allogeneic SCT achieved a CR with pixantrone without any considerable side effects [
20].
Patients with long-term responses clearly have a tumor that is chemosensitive to pixantrone. Intercalation of pixantrone into DNA results in successive rounds of aberrant mitosis, ultimately leading to cell death [
13]. In contrast to anthracyclines, pixantrone is only a weak inhibitor of topoisomerase II, and while it directly alkylates DNA, forming stable DNA adducts and cross-strand breaks [
1,
11], the main way pixantrone causes cell death is to impair the fidelity of mitosis without triggering the DNA damage response or mitotic checkpoint activation. While it is clear that pixantrone has a mechanism of action that is unique from anthracyclines, the specific mechanisms involved in the long-term responses seen among patients receiving pixantrone in PIX301 are unknown.
Our study has several limitations. First, the descriptive nature of the analysis is an obvious limitation, as is the small sample size, which prevents firm conclusions from being drawn. Additionally, there was no biopsy or positron emission tomography (PET) scan performed at the time of relapse and study entry for the clinical case presented in
Box 1, which is because PET scans and imaging were not standard practice at the time of study entry. The clinical case received etoposide and corticosteroids in the second line, which could be regarded as an inadequate second-line treatment, but this did not appear to negatively affect the outcome.
6 Boxed Case Report
Box 1 Clinical case of long-term remission with pixantrone
A 55-year-old male patient presented with enlarged inguinal, para-iliac, and bronchopulmonary lymph nodes, sweating and weight loss in November 2006. In December 2006, an inguinal lymph node biopsy was performed, and histological and immunohistochemical findings showed diffuse large B-cell lymphoma (DLBCL), stage IIIB. By June 2007, the patient had achieved a partial response (PR) after six cycles of CHOP as first-line treatment. In December 2007, the patient presented with enlarged inguinal and para-iliac lymph nodes, indicating disease progression. The patient then received second-line therapy with etoposide and corticosteroids. There was further disease progression in January 2008. In February 2008, the patient signed an informed consent to participate in PIX301. Computed tomography (CT) assessment revealed Ann Arbor stage III with enlarged bronchopulmonary and para-iliac lymph nodes. The diagnosis was confirmed by blinded central histological review, as per protocol. The bone marrow biopsy revealed no bone marrow involvement; the patient had an Eastern Cooperative Oncology Group performance status of 1 and an International Prognostic Index of 1, and no history of previous or concomitant diseases. He was randomly allocated to pixantrone in March 2008 and started therapy with 85 mg/m2 pixantrone dimaleate (which corresponds to 50 mg/m2 in pixantrone’s base form), given on days 1, 8 and 15 of each 28-day cycle for six cycles. Treatment was completed in August 2008 without any missed or reduced doses. Response to therapy was monitored using CT every 8 weeks, as well as 28 days after the end of treatment. The patient achieved a PR at the end of treatment. Electrocardiographic measurements, troponin T, multigated acquisition scan and echocardiogram were used to assess possible cardiotoxicity; all were within normal limits. No adverse events were observed during treatment, except for relatively long-lasting skin discoloration (over 6 months after the end of the therapy). After the end of treatment (August 2008), CT monitoring was performed regularly (4, 6, 8, 10, 12, 14 and 18 months) until June 2010 and annually thereafter. No disease progression was observed. The patient’s last visit was in January 2017; he was asymptomatic, with no evidence of recurrent disease.
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