Outcomes of first line chemotherapy in patients with chronic lymphocytic leukemia.

OBJECTIVE: Chronic lymphocytic leukemia (CLL) is a heterogeneous disease in terms of survival with and without treatment. Many chemo and immunotherapeutic agents are available to treat this indolent disease. Aim of this study was to determine the outcomes of patients with chronic lymphocytic leukemia treated with different available chemotherapeutic regimens.
METHODS: All patients with diagnosis of CLL from 2008 to 2013 were included. Data were collected from hospital information system. Objective response rate (ORR) in terms of complete or partial response (CR, PR), stable or progressive disease (SD, PD), overall survival (OS), and progression free survival (PFS) were calculated.
RESULTS: Fifty seven patients were included; 42 (74%) male and 15 (26%) were female. Patients with Binet stage A 10 (18%); B 20 (35%) and C were 27(47%). Median age was 50.9 years. Forty six (80%) were treated and 11(20%) remained on watch and wait. Treatment indications were B symptoms 14 (30%), symptomatic nodal disease 18(39%), thrombocytopenia 4(9%), anemia 7(15%) and doubling of lymphocyte count 3 (7%). Chemotherapy regimens used were FC in 38 (83%), FCR 5(11%), chlorambucil 2(4%) and CVP in 1(2%) patient. Twenty two (56%) patients had CR, 13(33%) PR, 3(7.6 %) SD, and 1(2.5%) had PD. ORR was 89%. Median PFS was 23.1 months and median 3 years OS was 55%.
CONCLUSION: Majority of patients was in a relatively younger age group and presented with advanced stage disease requiring treatment. Small number of patients received rituximab due to cost. PFS and OS are comparable with published literature.

INTRODUCTION

CLL is a disease of elderly, with male predominance and a median age of more than 70 years. Median age is 58 years in familial cases.1 CLL is an incurable disease with a remitting and relapsing course and life-long observation and follow-up is recommended. There are two staging systems, Binet and Rai, separating patients with different prognoses.2,3 Overall survival (OS) of patients with advanced disease has improved with the new treatment options.4 Previous studies have shown that treatment with chemotherapeutic agents does not translate into a survival advantage in patients without symptoms and an early-stage disease.5 The standard treatment of asymptomatic is a watch-and-wait strategy. Treatment should only be initiated in patients with active disease that includes B symptoms, cytopaenias, symptoms or complications from lymphadenopathy, splenomegaly or hepatomegaly, lymphocyte doubling time of <6 months, autoimmune anaemia and/or thrombocytopenia non responsive to steroids.6

In physically fit patients FCR (Fludarabine, Cyclophosphamide, Rituximab) is the standard first-line therapy.7 Combinations based on other purine analogues such as cladribine8 or pentostatin9 have shown similar activity, but it is uncertain whether they can replace fludarabine in FCR regimen. In elderly, FCR is associated with a higher rate of severe infections than bendamustine plus rituximab (BR). However, BR produces fewer complete remissions than FCR.10 In patients with comorbidities and older age, combination of chlorambucil plus an anti-CD20 antibody (rituximab, ofatumumab or obinutuzumab) is considered as standard approach.11,12

In this study, we analyzed objective response rate, progression free survival and overall survival in patients with chronic lymphocytic leukemia treated with different available chemotherapeutic regimens.

METHODS

This is a retrospective study. All patients of CLL from October 2008 to September 2013 were studied. Diagnosis was made according to standard guidelines.13 Patient characteristics such as age, gender, hemoglobin (Hb), lymphocyte count, white blood cells, platelet count, bone marrow biopsy and CT scan results (before and after treatment) were analyzed. Binet system was used for staging. Indications for treatment6 and type of chemotherapy regimens were noted.

Complete and partial response (CR, PR), stable disease (SD), progressive disease (PD) and relapse were defined according to National Cancer Institute–Working Group 1996 guidelines.14 PFS defined as time from start of the treatment to disease progression or death. OS defined as time from enrollment of patient in hospital to death from any cause or last follow up.

Statistical analysis

Distributions were determined as frequencies and percentages for categorical variables. For continuous variables mean, median, standard deviation and range were computed. Progression free interval survival, interval between dates of treatment ended and relapse in months, was conducted using the Kaplan Meier method and the end point of interest was relapse. The log rank test was applied and considered to be significant at an alpha level of 0.05. The analysis was conducted using SPSS, version 19.

RESULTS

Fifty seven patients were included. Forty two (74%) patients were male and 15(26%) were female. Median age was 50.9+8.2 years (range 25-72). Patients of Binet stage A, B and C; were 10(18%), 20 (35%) and 27(47%), respectively. Forty six (80%) patients were treated and 11(20%) remained on watch and wait policy. Treatment indications were B symptoms in 14(30%), bulky disease 18(39%), thrombocytopenia 4(9%), anemia 7(15%) and doubling of lymphocyte count in 3 (7%) patients. Chemotherapy regimens used were FC in 38 (83%), FCR 5(11%), CVP 1(2%) and chlorambucil in 2(4%) patients (Table-I). Two patients developed acute kidney injury (AKI), one patient died before any intervention and one patient lost to follow up. These four patients were excluded. Three patients treated with chlorambucil (2) or CVP (1) were also excluded. Twenty two patients (56%) achieved CR, 13(33%) PR, 3(7.6 %) SD, and 1(2.5%) had PD (Table-II). Overall response rate (ORR) was 89%. There were 9 (23.9 %) patients who had disease relapse. More relapses were seen in FC group 8(23.5%) compared to FCR 1 (20%). Median PFS for whole group was 23.1 months and median three years OS was 55%. However, PFS was significantly higher for stage A (35.7 months) compared to B (14.4 months) and C (22.2 months), p=0.05 (Table-III, Fig.1). In addition, PFS was better in FCR group than FC, p=0.04 (Table-III, Fig.2). Due to small number of patients, both regimens were not compared for survival analysis.

Table-I

Characteristics, stage and treatment.

Age (years)	Median 50.9±8.2 (range 25-72)
Gender	n=
Males	42(74%)
Females	15(26%)
Binet’s stage	n=
A	10(18%)
B	20 (35%)
C	27(47%)
Lymphocyte count (103/microlitre)	Mean 107.56 (range 4-466)
Presentation	n=
B symptoms	14(30%)
Bulky disease	18(39%)
Thrombocytopenia	4(9%)
Anemia	7(15%)
Doubling lymphocyte count	3 (7%)
Management	n=
Treated	46(80%)
Watch and wait	11(20%)
Chemotherapy	n=
FC	38 (83%)
FCR	5(11%)
Chlorumbucil	2(4%)
CVP	1(2%)

Table-II

Responses according to stage and regimen.

Response	Regimen	Binet’s Stage			Total treated
		A	B	C	Patients n=39
CR	FC	1(2.5%)	6(15.3%)	12(30.7%)	19(48.7%)
	FCR	-	-	3(7.6%)	3(7.6%)
	Total	1(2.5%)	6(15.3%)	15(38.4%)	22 (56.4%)
PR	FC	3(7.6%)	5(12.8%)	3(7.6%)	11(2.8%)
	FCR	-	-	2(5.1%)	2(5.1%)
	Total	3(7.6%)	5(12.8%)	5(12.8%)	13 (33.3%)
SD	FC	-	1(2.5%)	2(5.1%)	3(7.6%)
	FCR	-	-	-
	Total	-	1(2.5%)	2(5.1%)	3 (7.6%)
PD	FC	-	-	1(2.5%)	1(2.5%)
	FCR	-	-	-	-
	Total	-	-	1(2.5%)	1 (2.5%)

Table-III

Follow up of CLL patients according to stage and chemotherapy regimen.

Relapse	Binet stage	N	Median (months)	p value
Yes	A	1	35.7	0.05
	B	3	14.4
	C	5	22.2
	Total	9	18.2
No (On follow up)	A	3	3.5	0.31
	B	10	18.8
	C	17	24.2
	Total	30	21.8
Relapse	Regimens	N	Median (months)	P value
Yes	FC	8	17.0	0.04
	FCR	1	35.7
	Total	9	18.5
No (On follow up)	FC	26	22.2	0.59
	FCR	4	198
	Total	30	21.8

Fig.1

Kaplan-Meier survival curve for progression free survival according to stage.

Fig.2

Kaplan-Meier survival curve for progression free survival according to regimens.

DISCUSSION

Outcomes of CLL are variable, some patients have very indolent course while other may have aggressive disease behaviour from the start.15 A significant number of patients may not need treatment at the time of presentation and they could be put on observation.16 Treatment is started when patients develops symptoms or cytopenias, which are disease related. The treatment paradigm for CLL has changed significantly over the last few years.17

There is a strong evidence that FCR is better than FC, however, former is associated with more side effects.7,18 A systematic review with meta-analysis of clinical trials between 2000 and 2012 compared FC and FCR in patients with CLL. PFS and OS showed significant difference between two regimens, with CR more frequent with FCR but significantly higher neutropenia and serious adverse reactions.19

Our results showed that the onset of CLL is in a relatively younger age group compared to western data.1 One explanation may be due to shorter life span in our region. CLL was common in males as expected. The vast majority of patients needed treatment at the time of diagnosis and this is consistent with published literature that younger patients have aggressive disease behaviour and shorter time to first treatment.20 The majority of patients presented with advanced stage disease (Binet stage B&C). That may be another reason to start early treatment. One reason for this could be delay in making proper diagnosis and referring patients to appropriate cancer centre. Only few patients received rituximab. Major factor behind the underutilization of rituximab was high cost of the drug. Response rate was high with more than half patients achieving CR. Interestingly; more CRs were seen in Binet stage C. Although, there was no significant difference in the response rate with FC or FCR regimen but PFS was better with the later. PFS with both regimens including FC and FCR were comparable with published data. Patients treated with chlorambucil or CVP were not included in survival analysis due to small number of patients in this group. Due to the same reason, FC and FCR were not compared for survival out comes.

CONCLUSIONS

Based on our results, onset of CLL is in a relatively younger age group. Majority of the patients present with advanced stage disease and require treatment at the time of diagnosis. Fludarabine based regimens are affective. Addition of rituximab should be considered where available as it will lead to improved outcomes in CLL.