Bendamustine-Rituximab in Young CLL: Relevance in the Era of Small Molecule Inhibitors

Abstract

Purpose

Chemo-immunotherapies like Fludarabine-Cyclophosphamide-Rituximab (FCR) are used for treatment of chronic lymphocytic leukemia (CLL) in young and fit patients while Bendamustine-Rituximab (BR) is used in older patients. In a resource constrained setting, managing toxicities of FCR chemotherapy is challenging and this study explores the use of upfront BR treatment in young CLL patients (age < 65).

Methods

Data of 61 CLL patients treated with the BR regimen between 2016 and 2020 was analysed. Overall-survival and progression-free-survival (OS and PFS) were compared between the two age groups (< / > 65 years) and correlated with the fluorescent-in-situ-hybridization (FISH) data, duration of illness and time to initiation of chemotherapy.

Results

Out of 61 patients, 34 (85%) were below 65 years. Five patients had del 17p and were excluded from the analysis. Forty patients had indications for treatment. Twenty-four (70.5%) of the forty patients achieved overall response; 10 developed progressive disease. The median OS and PFS was 1874 days (95% CI 1617–2130 days) and 1226 days (95% CI 1021–1432 days) respectively and were non inferior between the 2 age-groups. There were no correlations with clinical, laboratory or FISH parameters. The OS and PFS were better for patients with longer time to initiation of chemotherapy as compared to those with short duration of illness and short wait-and-watch periods (p < 0.000).

Conclusions

Our results show that BR chemotherapy can safely and effectively be used in upfront treatment of young CLL patients and provide durable responses.

Targeted therapy with small molecule inhibitors has now taken center stage in the treatment of chronic lymphocytic leukemia (CLL). Randomized trials with ibrutinib, acalabrutinib, venetoclax have shown almost 75% lower risk of progression than that with chemoimmunotherapy [1–4]. However, their use in a developing country is difficult due to inaccessibility and considering that these agents must be used indefinitely, the patients often cannot afford such treatments. In these settings, chemoimmunotherapy is still the only treatment available for CLL.

In India, the incidence of CLL is lower (0.41 per 1,00,000 population) as compared to the West but with a younger age at presentation, aggressive clinical course, and shorter time to treatment [5, 6]. Indian data on treatment outcomes with different therapies is also sparse [6].

CLL is treated according to International workshop on Chronic Lymphocytic Leukemia (iwCLL) guidelines [7, 8]. Fludarabine-cyclophosphamide-rituximab (FCR) (for fit patients aged < 65 years) has a more severe toxicity profile compared to Bendamustine-Rituximab (BR) with higher incidence of grade ¾ neutropenia, infections, and increased risk of death from treatment related toxicity [9, 10]. Management of these complications in resource poor settings is challenging and BR presents a feasible therapy option.

We report a 5 year retrospective data from a resource constrained center in India where we used BR as upfront chemotherapy in all CLL patients requiring treatment and compared the outcomes in young patients (aged < 65 years) versus those aged more than 65 years. Ethical clearance was obtained from institutional ethical committee (MC/KOL/IEC/NON-SPON/963/03/2021). Sixty-one CLL patients were diagnosed at our institute between 2016 and 2020, of which 5 were 17p deleted and received rituximab-methylprednisolone therapy and were excluded from this analysis. Out of the 56 remaining patients, 40 required treatment. Indications for treatment were mainly cytopenias (27/40), compressive symptoms (6/40), excessive fatigue (3/40), B symptoms (14/40) and organ compromise due to lymphadenopathy (4/40) with some patients having more than one indication. Median age of the cohort was 58.5 years (age range 36–78 years). 85% (34/40) patients requiring therapy were < 65 years of age. 67.9% were males and the rest females. B symptoms were present in 25% (14/56) patients and bulky disease in 17.9% (10/56) patients. FISH positivity for deletion 11q, 13q or trisomy of 12p were present in 10.7% (6/56), 17.9% (10/56) and 3.6% (2/56) of the patients respectively. [Table 1] Patients needing treatment were given 6 cycles of BR. Rituximab was given on Day 1 of each cycle [375 mg/m2 in cycle 1 and 500 mg/m2 from cycle 2–6 respectively] while bendamustine was dosed at 90 mg/m2 on Day 1 and Day 2 of each cycle. Supportive therapy in the form of packed red blood cell (PRBC) transfusion, platelet transfusions, growth factor support (filgrastim and peg-filgrastim) was used when clinically indicated to maintain dose intensity and schedule of chemotherapy. Patients received prophylaxis with acyclovir and sulfamethoxazole-trimethoprim and vaccines as per institutional practice.

Table 1.

Patient characteristics: clinical and laboratory parameters at diagnosis/first presentation to the hospital

Parameter		Mean	Min	Max	SD
Age (years)		58.5 (median)	36	78	11.056
Hb (g/dl)		10.087500	3.0000	15.7000	2.1297941
TLC (× 109/cumm)		99.527	12.0	349.0	71.6929
PLT (× 109/cumm)		114.48	23	260	43.798
Largest lymph node (cm)		4.191	1.0	11.0	2.0509
Palpable Spleen (cm)		3.39	0	15	3.478
Palpable Liver (cm)		0.89	0	6	1.603
ECOG status n (%)	0	22 (39.3)	–	–	–
	1	25 (44.6)
	2	8 (14.3)
	3	1 (1.8)
FISH N (%)	11q deletion	6/56 (10.7)	–	–	–
	13q deletion	10/56 (17.9)
	Trisomy 12	2/56 (3.6)
Stage	Binet A	11/56 (19.6)	–	–	–
	Binet B	6/56 (10.7)
	Binet C	39/56 (69.6

Of the 34 young CLL patients treated with BR, 24 (70.5%) patients achieved overall response (OR); 10 patients had progressive disease. OR was assessed as patients achieving a Complete response (CR), CR with incomplete bone marrow recovery (CRi) and partial response (PR) at last follow up, according to iwCLL criteria [8] The median overall survival (OS) for patients treated with BR was 1874 days (95%CI 1617–2130 days) i.e. 61.56 months while the median progression free survival (PFS) was 1226 days (95% CI 1021–1432 days) i.e. 39.12 months. (Fig. 1). The median OS for patients aged less than 65 years and more than 65 years was 1874 days (95% CI 1442–2305 days) and 1704 days (95% CI 903–2504 days) respectively. There was no statistically significant difference in the above two groups. Neither were there any correlations with clinical, laboratory or FISH parameters. The OS and PFS were better for patients with longer time to initiation of chemotherapy as compared to those with short duration of illness and short wait-and-watch periods (p < 0.000). Grade ¾ anemia (5/34), thrombocytopenia (2/34), neutropenia (9/34) were observed in 16/34 (47.05%) of the patients post BR chemotherapy leading to cycle delay and requiring PRBC and platelet transfusion support. None of the patients required admission for the neutropenic episodes and were managed on outpatient basis with filgrastim when absolute neutrophil count was below 500/cumm as per institutional policy. No febrile neutropenia was documented in the study cohort. There were no discontinuations of therapy due to toxicity. We observed an overall response rate of 70% in our young CLL cohort using BR chemotherapy.

Fig. 1.

A: Overall survival of the entire cohort treated with BR regimen. B: OS stratified by age group (1: < 65 years, 2: > 65 years). C: Progression Free Survival (PFS) of the entire patient cohort. D: PFS stratified by age groups (1: < 65 years, 2: > 65 years)

Indian data from 409 CLL patients, where chlorambucil and BR were used as regimens in upfront treatment showed overall response rates of 74.4 and 91.2%, respectively. The median duration of follow up was 32 months. The median age of the cohort was 61 years and 31.8% of the study population was less than 55 years of age. The time to next treatment (TTNT) was 33 months and not reached, respectively (P = 0.001). Grade 3/4 neutropenia and infections were seen in 52.6 and 38.5% of patients receiving BR. The median OS was not reached in both regimens (P = 0.25). FCR was used only in 3.3% patients of the study cohort and therefore was dropped from the analysis [10]. Other studies have shown that the Chlorambucil-Rituximab regimen has good overall responses in all age groups. However, bendamustine is associated with better quality of life as compared to chlorambucil in previously untreated CLL patients and has been recommended for use in first line therapy for CLL patients not eligible for FCR chemotherapy.11 The CLL10 trial, which compared BR and FCR regimens, showed a median PFS of 41·7 months (95% CI 34·9–45·3) with BR and 55·2 months (95% CI not evaluable) with FCR (HR 1·643, 90·4% CI 1·308–2·064). BR did not pass noninferiority analysis compared to FCR but was associated with fewer toxic effects.9 Our study gave similar results with the BR regimen.

There are only few studies on the use of small molecule inhibitors in CLL in India with their widespread use restricted by availability and financial issues [12–14]. The cost of the newer therapies proves prohibitive in India with Venetoclax costing around 15 lakhs/month and Ibrutinib around US $2000 compared to USD $900 per cycle of BR [13, 15]. The choice of therapy, however, should be guided by the FISH (del 17p), molecular (TP53 mutation) and Immunoglobulin heavy chain gene rearrangement (IgHV mutated/unmutated) status, and BTK inhibitors or BCL2 antagonists are recommended in such patients for upfront treatment. The availability of generic Venetoclax and Ibrutinib in India, at a low cost will benefit such patients. But in the present day, in a resource constrained setting like ours, where there is dearth of access to small molecule inhibitors as well as limited resources to deal with regimen related toxicities, the data summarised herein support the use of BR therapy for upfront treatment of CLL irrespective of age.

Author Contributions

S Bhattacharjee: Concept, data collection, manuscript drafting. S Ghosh: Concept, clinical data curation, statistics, manuscript editing and analysis. M Bhattacharyya: Concept, manuscript editing, analysis, overall supervision.

Funding

None.

Data Availability

Available for publication/review.

Declarations

Conflicts of interest

None.

Consent for Publication

Yes.

Ethics Approval

Retrospective study, IEC number: (MC/KOL/IEC/NON-SPON/963/03/2021).