Patients with chronic lymphocytic leukaemia (CLL) have a median of 2 comorbidities (Thurmes, et al 2008), which compromise overall and CLL-specific survival (Brenner, et al 2008, Cramer 2006). While chemotherapeutic agents remain an accepted standard of care therapy in CLL, efficacy data in patients with comorbidities have been limited. A Phase II study of the alkylating agent bendamustine (90 mg/m2) in combination with rituximab (BR) established an overall response rate (ORR) of 88% in patients with previously untreated CLL (Fischer, et al 2012). While BR demonstrated a favourable adverse event profile over fludarabine, cyclophosphamide and rituximab (FCR) in a randomized Phase III trial (CLL10) in "fit" patients with previously untreated CLL, 67.8% of patients who received BR experienced severe neutropenia and 25.4% suffered severe infections (Eichhorst, et al 2014). Several recent randomized trials deliberately focused on patients with comorbidities, using the Cumulative Illness Rating Scale (CIRS) as a semi-quantitative tool (Furman, et al 2014, Goede, et al 2014). CIRS determines the burden of medical illness while taking into account the severity of each condition. CIRS accurately predicts mortality in the geriatric population (Salvi, et al 2008) and treatment-related toxicity and overall survival (OS) in patients with CLL (Hallek, et al 2010).
We conducted a Phase I dose-ranging study of BR in patients with previously untreated or relapsed/refractory CLL who had comorbidities. Eligible patients had a CIRS score of ≥7 (Salvi, et al 2008), with at least one grade 3 comorbidity (“severe”) and met International Working Group CLL 2008 criteria for treatment requirement. Patients had preserved bone marrow function and creatinine clearance ≥30 ml/min. The study followed a standard 3+3 dose escalation design with 3 dose cohorts, with bendamustine administered at 45 mg/m2 on days 1, 2 of 28-day cycles for up to 6 cycles with rituximab (375 mg/m2 on cycle 1, 500 mg/m2 with cycles 2–6), with planned bendamustine dose escalation to 70 or de-escalation to 25 mg/m2 if dose-limiting toxicities (DLT) occurred.
The primary study endpoint was treatment-related toxicity and determination of the maximum tolerated dose (MTD), defined as the dose cohort above which ≥2/6 patients experienced DLTs. Secondary endpoints included efficacy (ORR and event-free survival [EFS]), bendamustine pharmacokinetic (PK) disposition and patient-related outcome measures. The following were considered DLTs if observed during cycle 1: (i) non-haematological - any grade ≥3 except for grade 3 nausea, vomiting or diarrhoea occurring without optimal treatment, infusion-related reactions, rash, fatigue; asymptomatic grade 3–4 laboratory abnormalities that are reversible to grade ≤2 within 7 days; (ii) haematological - febrile neutropenia or failure of adequate haematological recovery within 14 days of the scheduled start date of cycle 2. An expansion cohort was planned once the MTD was determined. All patients received pegfilgrastim with cycle 1 and prophylactic trimethoprim-sulfamethoxazole and acyclovir. Plasma bendamustine concentrations were measured using a modified validated high performance liquid chromatography/fluorescence assay (Rasschaert, et al 2007).
No inferential statistical tests of hypotheses were planned due to the small sample size. EFS (treatment start until disease recurrence, subsequent anti-leukaemic therapy, or death) was analysed using Kaplan–Meier estimates. Patient-related outcomes were assessed using the EuroQol five dimensions (EQ-5D) and Functional Assessment of Chronic Illness Therapy (FACIT)-Fatigue questionnaires on day 1 of cycles 1, 3, 5, and two and six months after therapy completion and comparisons were made using t-test statistics. Primary bendamustine PK parameters were estimated from the plasma concentration versus time data using non-compartmental analysis.
Seven patients were treated at Dartmouth on the Phase I part of the study. The study completed the dose escalation phase and accrued one patient onto the expansion cohort, at which point it was closed due to slow accrual. Results of the dose escalation phase are reported here. 6/7 patients were male, median age was 71 (range, 65–77) years. Median time since diagnosis was 2 and 8 years for patients with previously untreated (N=5) and relapsed CLL (N=2), respectively. Median CIRS score was 9 (Table I). The most common grade 3–4 (severe) comorbidities were hypertension (n=4; required ≥2 drugs), diabetes (n=4; HbA1c>7% or complications) and renal (n=2).
Table I.
Clinical characteristics, toxicities and response in a Phase I study of patients with CLL and comorbidities.
| Patient | Dose of bendamustine (mg/m2) |
FISH | Prior treatment | WBC count (× 109/l) |
Hb (g/l) |
Platelet count (× 109/l) |
CIRS score |
Toxicities, grade | Cycles (n) |
Cumulative dose of bendamustine (mg/m2) |
Response |
|---|---|---|---|---|---|---|---|---|---|---|---|
| 1 | 45 | Normal | None | 15.6 | 136 | 70 | 8 | Headache, 1 Constipation, 1 Thrombocytopenia, 1 |
6 | 500 | CR |
| 2 | 45 | 12, 13q | Cyclophosphamide, vincristine, prednisone |
46.1 | 97 | 67 | 11 | Infusion reaction, 3 Anaemia, 3 Thrombocytopenia, 4 Fall, 2 Erythema, 2 DVT, 2 |
6 | 460 | nPR |
| 3 | 45 | 13q, 11q | FCR; ofatumumab; lenalidomide |
213 | 133 | 81 | 9 | None | 6 | 540 | SD |
| 4 | 70 | Trisomy 12 | None | 191.9 | 114 | 83 | 10 | Infusion reaction, 4 Infection, 4 Thrombocytopenia, 4 Febrile neutropenia Anaemia, 3 Atrial fibrillation, 3 |
<1 | 45 | Not evaluable |
| 5 | 70 | 13q | None | 295 | 102 | 171 | 8 | Chest wall pain, 3 Rash and pruritus, 3 |
2 | 325 | PR |
| 6 | 70 | 13q | None | 20.8 | 104 | 83 | 8 | Fever, 2 Thrombocytopenia, 3 Febrile neutropenia, 4 AKI, 2 Atrial fibrillation, 3 Rash, 3 |
2 | 280 | PR |
| 7 | 70 | 13q | None | 33.2 | 124 | 69 | 13 | Fatigue, 3 Neutropenia, 3 Anaemia, 1 |
6 | 590 | CRi |
FISH, fluorescence in situ hybridization; WBC, white blood cell; Hb, haemoglobin; CIRS, Cumulative Illness Rating Scale; FCR, fludarabine, cyclophosphamide, rituximab; DVT, deep vein thrombosis; AKI, acute kidney injury; CR, complete response; PR, partial response; nPR, nodular partial response; SD, stable disease; CRi, complete response with incomplete marrow recovery.
All three patients who received bendamustine 45 mg/m2 (Cohort 1) completed six cycles of therapy with minimal toxicities and 2/3 did not require dose reductions. The third patient sustained grade 3 neutropenia in cycle 3 requiring a dose reduction to 35 mg/m2. 2/4 patients enrolled on dose cohort 2 (70 mg/m2) experienced DLTs: grade 4 infection and persistent grade 3 neutropenia. Patient 7 completed six cycles of BR (following a dose reduction to bendamustine 45 mg/m2), while three patients discontinued therapy early due to toxicities (Patients 4–6). No change in health status or fatigue was reported during and after 6 cycles of therapy per the EQ-5D and FACIT-Fatigue questionnaires, indicating that treatment was well tolerated. Therefore, BR at 45 mg/m2 was the MTD in this study.
The plasma bendamustine PK data concentrations versus time profiles were available in four patients (Table II). Because the mean bendamustine dose administered in our study was ~30% of that studied in patients with solid tumours (Rasschaert, et al 2007), we observed lower drug exposures. However, despite this, two patients achieved a complete response (CR; both had previously untreated CLL), one had a nodular partial response (nPR), and two had PRs. One heavily pre-treated patient (Patient 3) had a haematological improvement (clearance of peripheral CLL cells) and one patient was not evaluable. Thus, ORR was 83.3% (5/6) among the evaluable patients and 71.4% among all patients. Of note, patients who achieved CR/nPR received a median cumulative dose of 500 mg/m2 bendamustine (~42 mg/m2 per dose), while the remaining patients received 280 mg/m2 (p=0.19). With median follow-up of 30 months (range, 20–34 months) 6/7 study patients are alive. One patient developed progressive disease but was successfully treated with ibrutinib, and one patient died, yielding an estimated EFS of 71.4% at 2 years (95% confidence interval, 25.8 to 92.0%).
Table II.
Non-compartmental primary pharmacokinetic parameters for Bendamustine in chronic lymphocytic leukaemia patients with comorbidities
| Patient | Dose** (mg) |
Tmax (min) |
Cmax (ng/ml) |
T1/2 (min) |
AUC(0-infinity) | Vz (l/m2) | CL (ml/min/m2) | MRT (min) |
|---|---|---|---|---|---|---|---|---|
| 1 | 72 | 37 | 7527 | 22.1 | 344435.0 | 4.2 | 130.6 | 33.0 |
| 2 | 100 | 36 | 2318 | 16.1 | 101113.9 | 10.4 | 445.1 | 20.4 |
| 3 | 98 | 36 | 3892 | 17.7 | 175934.6 | 6.5 | 255.8 | 22.4 |
| Mean | 90 | 36.3 | 4597 | 18.6 | 207161.2 | 7.0 | 271.2 | 25.3 |
| (range) | (72–100) | (36–37) | (2318–7527) | (16.1–22.1) | (101113.9–344435.0) | (4.2–10.4) | (130.6–445.1) | (20.4–33.0) |
| 4 | 140 | 35 | 14884 | 38.8 | 1063729.5 | 3.7 | 65.8 | 49.7 |
| Rasschaert et al (2007) | ||||||||
|
Mean (SD) N=6 |
120–160 mg/m2 |
35.0 (8.4) | 49.1 (12.1) | 18.3 (6.4) | 265.0 (103.6) | |||
Patients 1–3 received 45 mg/m2 and Patient 4 received 70 mg/m2 of bendamustine. Blood samples were collected at the following times after the start of the bendamustine infusion on cycle 1 day 1: time zero (pre-bendamustine dose), 0.25, 0.5 (end of infusion), 0.75, 1, 1.5, 2, 3, 4, 6, 8 and 24 h
AUC(0-Infinity)=Area under the curve extrapolated to infinity; CL=clearance; Cmax, = peak (maximum) concentration; T1/2=half life; Tmax, time to reach peak concentration; Vz=volume of distribution; MRT = Mean residence time; SD = standard deviation.
Thus, in this Phase I study, BR at 45 mg/m2 was the MTD in CLL patients with significant comorbidities. Efficacy was demonstrated in the majority of evaluable patients despite a markedly reduced bendamustine exposure. While larger studies are needed to confirm our findings in CLL patients with comorbidities, our results suggest a dose reduction for BR in this patient population. Finally, CIRS could potentially serve as a valuable tool to guide the choice or dose of therapy in patients with CLL.
Acknowledgments
We would also like to thank all faculty and participants at 2012 ASH Clinical Research Training Institute for their help in study design.
Financial support: AVD is supported by the Lymphoma Research Foundation Clinical Investigator Career Development Award. JRB is supported by an American Cancer Society Research Scholar grant, Leukemia and Lymphoma Society Translational Research Program, National Comprehensive Cancer Network, and the Melton Family Fund for CLL Research. This study and AVD, SYJ, BH, BBB and LDL were supported in part by NCI P30 CA023108.
Footnotes
AVD and JRB designed the study. AVD, JRB, LDL and LR wrote the protocol. AV, FL, SYJ and BH enrolled patients. LDL and BBB performed pharmacokinetic analysis. AVD, JRB and LDL wrote the paper.
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