Oral CHOP-like chemotherapy in 60-80 years-old patients with diffuse large B-cell lymphoma.

The cancer treatment paradigm is moving towards oral therapy. In this context, we developed a R‐CHOP (rituximab, cyclophosphamide, doxorubicin, vincristine, prednisolone)‐like regimen: R‐oroCIEP, an all‐oral chemotherapy, for patients with diffuse large B‐cell lymphoma (DLBCL). Preclinical studies have identified idarubicin, an oral anthracyclin, as one of the most potent anthracyclines (Kuffel et al, 1992). Although no clear superiority was identified in clinical studies for lymphoma (Hohloch et al, 2014), its oral bioavailability, cerebral diffusion (Boogerd et al, 1999) and (probably) less cardiac toxicity make idarubicin an important anthracycline for DLBCL study treatment.

We hypothesized that newly diagnosed DLBCL patients aged between 60 and 80 years old would particularly benefit from a more ambulatory all‐oral oroCIEP regimen, with a similar activity and safety profile. We performed an open label multi‐centre phase 1/2 trial evaluating escalating doses of oral idarubicin (3 + 3 design) to determine the maximum tolerated dose (MTD) of this drug given orally on day 1 every three weeks. The oroCIEP regimen combined idarubicin, at 4 planned dose levels (20, 30, 40 and 50 mg/m2), with cyclophosphamide, etoposide, prednisolone and rituximab. Cyclophosphamide and etoposide were given orally at a fixed dose of 150 mg/m2/day and 100 mg/m2/day respectively, days 1 to 3. Prednisolone was given orally at the fixed dose of 60 mg/m2/day, days 1 to 5. Rituximab was administrated intravenously (IV) on day 1 at the fixed dose of 375 mg/m2. Granulocyte colony‐stimulating factor was systematically used from day 6 to time of haematological reconstitution. Granisetron was given orally on day 1 to 4 for nausea. (Table SI). Eight courses were proposed, based on the historical study by Coiffier et al (2002). Dose limiting toxicity (DLT) was defined as grade 4 neutropenia lasting more than 4 days, grade 4 thrombocytopenia, grade 3 or 4 non‐haematological toxicity other than nausea and alopecia, at Cycle 1. If toxicity occurred during a cycle, the next cycle dose was adapted according to the neutrophil and platelet levels at day 21 and the nadir during the cycle (Table SII). The inclusion criteria were similar to those selected by Coiffier et al (2002). Response to treatment was evaluated after 4 courses and at the end of treatment, according to Cheson et al (1999). Statistical analysis is described in Data S1.

Twenty‐six patients were enrolled from five French centres across phase 1 (n = 12) and 2 of the study. The baseline characteristics are summarized in Table 1. No DLT was observed at dose level 1 (20 mg/m2), whereas 2 of 6 patients developed a DLT at dose level 2. At level 3, all of the first 3 patients developed a DLT. The recommended phase 2 dose of oral idarubicin was thus considered at the MTD of 30 mg/m2, and 14 patients were enrolled in the phase 2 part of the study. The idarubicin relative dose intensity (DI) in comparison with the planned DI, was 99·3%, 93·8% and 79·7% at dose level 1, 2 and 3, respectively. No toxic death was observed.

Table 1

Baseline characteristics.

Characteristic	N	Percentage
Gender
Male	11	42
Female	15	58
Age, years
60–69	10	39
70–80	16	61
ECOG performance status
0–1	11	42
>1	15	58
Disease stage
II	1	4
III	6	23
IV	19	73
B symptoms	5	19
Bulky tumour (>5 cm)	8	31
Aged‐adjusted IPI score
1	10	38
2	12	46
3	4	16

ECOG, Eastern Cooperative Oncology Group; IPI, International Prognostic Index.

A total of 180 cycles were administered and 176 were assessable for toxicity. Grade 3 and 4 neutropenia occurred in 21%, 26% and 100% of cycles for levels 1, 2 and 3 respectively. Grade 3 and 4 thrombocytopenias were observed in 4%, 3% and 50% for levels 1, 2 and 3 respectively. Across non‐haematological toxicities, grade 3 and 4 infections were reported in 5% at level 2, and 50% at level 3. Four patients experienced cardiac toxicity: atrial fibrillation (2 cases) ventricular extra systole (1 case) and diastolic heart failure (1 case). Second primary malignancies were reported in three patients: a fatal breast carcinoma observed 9 years post‐treatment, a surgically cured lung cancer observed 2 years post‐treatment and two skin cancers for the same patient: in situ melanoma and epidermal carcinoma, both surgically cured. The most common adverse events are listed in Table SIII.

The overall response (ORR) and complete response (CR) rates were 85% and 77%, respectively (Table SIV). With a median follow‐up of 8·8 years (6·1–11·0), 7 patients died from the disease and 2 from other causes. The median overall survival (OS) and median progression‐free survival (PFS) were not reached in our study (Fig 1) with a 3‐ and 5‐year OS rate of 74% (95% confidence interval [CI] 48–88%) and 65% (95%CI 41–81%), respectively.

Figure 1

Survival curves. (A) Overall survival; (B) Event‐free survival; (C) Cumulative incidence of disease‐related events.

Six phase 3 randomized clinical trials have documented the efficacy and safety of R‐ CHOP for the treatment of fit DLBCL patients aged 60–80 years (Coiffier et al, 2002; Habermann et al, 2006; Pfreundschuh et al, 2008; Merli et al, 2012; Cunningham et al, 2013; Delarue et al, 2013), with reported CR rates between 71% and 78% and 3‐year OS from 67% to 78%. Our results seem to be acceptable in term of disease control and safety profile. We did not observe any secondary leukaemia or myelodysplastic syndrome. No left ventricular cardiac failure was seen, in line with the known safe cardiac profile of idarubicin. The most important weakness of the study was a relatively large PFS and OS 95% CI. However, our phase 1/2 study suggests that R‐OroCIEP was safe and seemed to be as active as standard R‐CHOP in first‐line treatment for fit DLBCL patients aged 60–80 years. These data need to be confirmed in a larger cohort. A phase 3 randomised study with pharmaco‐economic and quality of life evaluations may ultimately demonstrate the novel aspect of this regimen.

Conflict of interests

The authors declare no potential conflicts of interest

Author contributions

Conception and design: VD, IP, MC, LLT, JG. Development of methodology: VD, LLT, BD, KD, GO, AC, JB, AM, EF, CT, CM, CDD. Acquisition of data: VD, CDD, SG, JG. Analysis and interpretation of data: VD, SG, XL, JG. Writing, review and/or revision of the manuscript: VD, SG, BD, KD, GO, AC, JB, AM, EF, CT, CM, IP, MC, CDD, XL, JG. Administrative, technical, or material support: VD, XL. Study supervision: VD, SG, XL, JG.

Table SI. Treatment schedule.

Table SII. Dose modification.

Table SIII. Adverse events.

Table SIV. Response rate assessment, N (%).

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Data S1. Statistical analysis.

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