Keywords CBV conditioning regimen - autologous stem cell transplant - Hodgkin lymphoma - non-Hodgkin
lymphoma
Introduction
High-dose chemotherapy (HDC) followed by autologous stem cell transplant (ASCT) is
the current standard of care for relapsed/refractory lymphoma.[1 ]
[2 ] Several HDC regimens with varying drug combinations, with or without total body
irradiation (TBI), have been in use as the conditioning protocol in autologous transplant
of lymphomas. Most have shown similar efficacy but different toxicity profiles. Compared
to chemotherapy-TBI regimens, chemotherapy-only regimens have demonstrated superiority
in terms of disease-free survival (DFS), overall survival (OS), and lesser toxicity.[3 ]
[4 ] Commonly used HDC regimens in ASCT for lymphoma include BEAM (BCNU, etoposide, cytarabine,
and melphalan), BEAC (BCNU, etoposide, cytarabine, and cyclophosphamide), CBV (cyclophosphamide,
BCNU, and etoposide), and LACE (lomustine, etoposide, cytarabine, and cyclophosphamide),[5 ]
[6 ]
[7 ]
[8 ]
[9 ] but no prospective randomized study has been done so far comparing these regimens.
Most of the retrospective studies comparing various HDC regimens have shown variability
in toxicity, and some have reported differences in disease outcomes.[3 ]
[10 ]
[11 ]
[12 ]
[13 ]
[14 ]
[15 ]
[16 ]
In our center, CBV has been the commonest conditioning regimen used for autologous
transplant in lymphomas. Unfortunately, data regarding the use of CBV are scant in
contemporary published literature, and there are no reports on the use of CBV conditioning
from India. This study has retrospectively analyzed the toxicity profile, engraftment
kinetics, and survival outcomes of lymphoma patients who have undergone ASCT using
a CBV conditioning regimen.
Methodology
Patient Population
From January 2013 to May 2019, all consecutive histology-proven relapsed or refractory
Hodgkin lymphoma (HL) and non-Hodgkin lymphoma (NHL) patients, who had a complete
or partial response to salvage chemotherapy and underwent ASCT at our center, with
CBV conditioning regimen were included in this retrospective study. Patients who received
other conditioning regimen were excluded from the study.
We collected the data for baseline characteristics, pre-transplant response, apheresis,
post-transplant toxicities, post-transplant response, and survival outcomes from medical
records maintained in the department. Endpoints were toxicity, post-transplant response,
event-free survival (EFS), and overall survival (OS).
Pre-Transplant Assessment
Relapsed or refractory lymphoma was treated with 3 to 4 cycles of first- or second-line
salvage chemotherapy depending on their primary diagnosis and previous treatment history.
Post salvage response assessment was done with either contrast-enhanced computed tomography
(CECT) scan or positron emission tomography and computed tomography (PET-CT) scan.
Pre-transplant chemosensitivity was defined as either complete or partial response
following salvage therapy. Evaluation was done for organ functions (renal, hepatic,
cardiac, and pulmonary) and general fitness as per the department protocol for all
patients prior to transplant.
Stem Cell Mobilization, Collection, and Cryopreservation
Peripheral blood (PB) stem cell mobilization was done with GCSF 5 µg/kg twice daily
for 4 days. One day prior to apheresis, on the fourth day of mobilization, PB CD34
enumeration was done. Plerixafor was used 12 hours before apheresis if the PB CD34
was <20 cells/mm3 or as per physician's discretion based on the baseline risk factors for poor mobilization.
All patients had undergone peripheral blood stem cell (PBSC) harvest by apheresis,
and stem cell enumeration was done at the end of harvest. PBSC collected were volume
depleted and cryopreserved using 10% of dimethyl sulfoxide (DMSO) and autologous plasma
at –80°C until day 0 (day of stem cell reinfusion).
Conditioning Regimen
CBV conditioning regimen was given over a period of 6 days in the following schedule:
BCNU (carmustine) 300 mg/m2 intravenous (iv) over 2 hours on D-6, cyclophosphamide 1.5 g/m2 /day i.v. over 2 hours on D-6 to D-3, mesna 120% of cyclophosphamide dose as i.v.
infusion over 24 hours on D-6 to D-3, and 40% of cyclophosphamide dose as i.v. infusion
over 12 hours on D-2, etoposide 125 mg/m2 /dose i.v. over 1 hour 12th hourly on D-6 to D-4. The above CBV schedule is considered
as CBV (low) compared to the older regimen CBV (high), which used carmustine at 600 mg/m2 .[10 ]
[11 ]
Supportive Care
All patients received G-CSF 5 µg/kg/day subcutaneous (s.c.) starting on day +1 after
stem cell infusion until the absolute neutrophil count (ANC) was greater than 0.5 × 109 /L for least 3 days.[17 ]
[18 ] Irradiated packed red cell concentrates and platelet concentrates were given to
keep hemoglobin >8.0 g/dL and platelet count >20 × 109 /L, respectively. Oral fluconazole and acyclovir were started from day 1 as antifungal
and antiviral prophylaxis, respectively. Routine antibacterial prophylaxis was not
given. Total parenteral nutrition (TPN) was administered in patients who developed
grade 3–4 mucositis and in any grade mucositis with decreased food intake. Febrile
neutropenia was managed as per the department antibiotic policy.
Study Definitions
Time to neutrophil engraftment was defined as the first of three consecutive days
with an absolute neutrophil count of ≥ 0.5 × 109 /L.[19 ]
[20 ] Time to platelet engraftment was defined as the first of three consecutive days
when the platelet count was maintained ≥ 20 × 109 /L without platelet transfusion.[19 ] Engraftment syndrome was defined by the presence of noninfectious fever and one
other symptom (i.e., skin involvement, diarrhea, or pulmonary manifestations) during
the peri-engraftment period.[21 ] Regimen-related organ toxicities, evaluated in the first 100 days, were graded using
the Seattle criteria, whereas mucositis and chemotherapy-induced nausea and vomiting
(CINV) were graded using the National Cancer Institute Common Terminology Criteria
For Adverse Events (NCI CTCAE) v4.0.[22 ]
[23 ] The length of hospital stay (LOS) was defined as the time from the day of infusion
of stem cell product (Day 0) to the day of hospital discharge. Transplant-related
mortality (TRM) was defined as any death not related to relapse or disease progression
during the first 100 days after the transplant. EFS (event-free survival) was defined
as the time interval from the date of the transplant to disease progression, relapse,
or death due to any cause. Overall survival (OS) was defined as the time from transplant
to death due to any cause or date of the last follow-up.
Statistical Analysis
Descriptive statistics were used to summarize baseline disease features, pre-transplant
disease status, patient characteristics, and post-transplant outcomes. Estimation
of EFS and OS was done using the Kaplan–Meier method and compared using log rank test.
Data were censored on 31 March 2020 for survival analysis. IBM SPSS Statistics for
Windows, Version 19.0. Armonk, NY: IBM was used for analysis.
Ethics
The procedures followed were in accordance with the ethical standards of the responsible
committee on human experimentation and with the Helsinki Declaration of 1964, as revised
in 2013. The study was approved by the Institute Ethics committee (no. JIP/IEC/2016/30/979,
dated 23.10.2016), and waiver of informed patient consent was granted.
Results
Baseline Characteristics and Pre-Transplant Data
During the study period, 45 patients (28 males and 17 females) underwent autologous
transplant with a CBV conditioning regimen for refractory/relapsed lymphoma. The median
age was 30 years (range: 6–64). Diagnosis was HL in 26 patients (58%) and NHL in 19
patients (42%). Of the 45 patients, 28 (62%) had relapsed after their primary treatment,
and 15 (35%) had refractory disease. The median time from diagnosis to transplant
was 19 months, and median lines of previous therapy were two. As a part of pretransplant
response assessment, PET CT and CECT was done in 22 (49%) and 23 (51%) patients, respectively.
Among the 45 patients, 43 (96%) had chemosensitive disease (either complete response
[CR] or partial response [PR]). All patients had ECOG (Eastern Cooperative Oncology
Group) performance status of 1 before transplant baseline clinical characteristics,
and pre-transplant disease status is shown in [Table 1 ].
Table 1
Baseline clinical, treatment characteristics and pre-transplant disease status in
HL and NHL
Features
Entire Cohort (N = 45)
HL (N = 26)
NHL (N = 19)
Age (at transplant) in years
30 (6–64 years)
26 (6–47)
38 (19–64)
Gender
Male
Female
28 (62.2%)
17 (37.8%)
17 (65%)
9 (35%)
11 (58%)
8 (42%)
Diagnosis (lymphoma)
26 (58%)
19 (42%)
Relapsed
28 (62%)
14 (54%)
14 (74%)
Refractory
15 (34%)
12 (46%)
3 (16%)
Upfront (in CR1 for HR)
2 (4%)
–
2 (10%)
NHL
Relapsed/refractory DLBCL
–
–
12 (63%)
ALCL (ALK negative) (upfront)
2 (11%)
Relapsed FL
2 (11%)
Relapsed PTCL
1 (5%)
Relapsed AITL
1 (5%)
Relapsed ALCL
1 (5%)
Time from diagnosis to transplant in months (median, range)
19 (5-102)
21 (8–84)
16 (5–102)
Number of lines of treatment (median, range)
2 (1–4)
2 (1–4)
2 (1–3)
ECOG PS (median, range)
1 (0–1)
1 (0–1)
1 (0–1)
Chemosensitivity
Yes
43 (95.6%)
24 (92%)
19 (100%)
No
2 (4.4%)
2 (8%)
0
Pre-transplant imaging for disease status
PET CT-22 (49%)
CECT–23 (51%)
PET CT response (N = 22)
CR (complete response)
15 (68%)
10 (77%)
5 (55%)
PR (partial response)
7 (32%)
3 (23%)
4 (45%)
SD (stable disease)
0
0
0
PD (progressive disease)
0
0
0
CECT response (N = 23)
CR (complete response)
8 (35%)
5 (39%)
3 (30%)
PR (partial response)
13 (56%)
6 (46%)
7 (70%)
SD (stable disease)
1 (4.5)
1 (7.5%)
0
PD (progressive disease)
1 (4.5%)
1 (7.5%)
0
Abbreviations: AITL, angioimmunoblastic T cell lymphoma; ALCL, anaplastic large cell
lymphoma; CECT, contrast-enhanced computed tomography; DLBCL, diffuse large B cell
lymphoma; ECOG PS, Eastern Cooperative Oncology Group-Performance status; FL, follicular
lymphoma; HL, Hodgkin lymphoma; NHL, non-Hodgkin lymphoma; PET CT, positron emission
tomography and computed tomography; PTCL, peripheral T cell lymphoma.
Apheresis
For 45 patients, a total of 70 apheresis procedures were done. The median number of
apheresis done was 2 (range: 1–3); for HL was 2 (range: 1–3), and for NHL was 1 (range:
1–3). The median CD34 cells/kg for entire cohort was 2.95 × 106 /kg (range: 0.9–9.56), for HL 2.99 × 106 (range: 0.90–7.3), and for NHL 2.90 × 106 (range: 1.77–9.56). The median total MNC/kg for the entire cohort was 6.04 × 108 (range: 2–27), for HL 6.03 × 108 (range: 2–27), and for NHL 6.35 × 108 (range: 4–20). All PBSC apheresis products were cryopreserved and stored at –80°C
until the day of infusion.
Conditioning Regimen and Post-Transplant Outcomes
All 45 patients received a CBV conditioning regimen without any modifications. The
median day to neutrophil engraftment and platelet engraftment was 11 days (range:
9–23) and 13 days (range: 8–36), respectively. Five patients had engraftment syndrome,
and all responded to low-dose steroids. All patients had febrile neutropenia, of which
11 (24%) had an FUO (fever of unknown origin) while others had either a CDI (clinically
documented infection), MDI (microbiologically documented infection), or both CDI and
MDI. The median day to the onset of fever was 2 days (range: 0–11). The median number
of antibiotics used was 4 (range: 1–8), and median days of antibiotic usage was 14
(range: 6–29) days. Empirical antifungal, amphotericin B was used in 15 patients (33%).
Grade 3–4 mucositis was seen in four patients, and all received total parenteral nutrition.
Grade 3/4 diarrhea and CINV (chemotherapy-induced nausea and vomiting) were observed
in four and two patients, respectively. Hypokalemia and hypomagnesemia were seen in
18 (40%) and 11 (25%) patients, respectively. None of the patients had hemorrhagic
cystitis, and no grade 3/4 toxicity was observed in other organs viz. renal, liver,
pulmonary, or cardiac. The median duration of stay in the transplant unit was 18 days
(range: 10–37). Transplant-related mortality (TRM) at 100 days was 6.6% (n = 3; HL, 1 and NHL, 2), the cause of death being severe sepsis for all patients.
One patient died before engraftment on d + 20, and two patients died after engraftment
on d + 26 and d + 78. [Table 2 ] presents the data on engraftment kinetics, pattern of infection, and toxicity post-transplant.
Table 2
Post-transplant engraftment kinetics, pattern of infection, toxicity, and supportive
care in HL and NHL
Entire cohort
(N = 45)
HL
(N = 26)
NHL
(N = 19)
Day of engraftment
Neutrophils
11 (9–23)
11 (9–17)
10.5 (9–23)
Platelets
13 (8–36)
12.50 (8–36)
14.5 (11–30)
Febrile neutropenia
FUO
11 (24%)
8 (31%)
3 (16%)
CDI
18 (40%)
9 (35%)
9 (47%)
MDI
10 (22%)
5 (19%)
5 (26%)
CDI and MDI
6 (14%)
4 (15%)
2 (11%)
No of antibiotics
4 (1–8)
4 (2–8)
4 (1–7)
Organism
Sterile
26 (58%)
15 (58%)
11 (58%)
Gram negative
13 (30%)
6 (23%)
7 (37%)
Gram positive
0
0
0
Polymicrobial
5 (10%)
5 (19%)
0
Fungal
1 (2%)
0
1 (5%)
Mucositis
Grade 0
10 (22%)
3 (10%)
7 (37%)
Grade1–2
31 (69%)
19 (76%)
12 (63%)
Grade 3–4
4 (9%)
4 (14%)
0
CINV
Grade 0
9 (20%)
4 (16%)
5 (26%)
Grade 1–2
34 (66%)
20 (77%)
14 (74%)
Grade 3–4
2 (4%)
2 (7%)
0
Diarrhea
Grade 0
21 (47%)
13 (50%)
8 (42%)
Grade 1–2
20 (43%)
10 (38%)
10 (53%)
Grade 3–4
4 (10%)
3 (12%)
1 (5%)
TPN
Yes
4 (9%)
4 (15%)
–
No
41 (91%)
22 (85%)
19 (100%)
Blood products
PRBC
3 (0–8)
3 (0–8)
3 (0–7)
SDP
4 (2–13)
4 (2–12)
4 (2–13)
Length of stay in days (median, range)
18 (10–37)
25 (10–37)
18 (10–30)
Abbreviations: CDI, clinically documented infection; CINV, chemotherapy-induced nausea
and vomiting; FUO, fever of unknown origin; HL, Hodgkin lymphoma; MDI, microbiologically
documented infection; NHL, non-Hodgkin lymphoma; PRBC, packed red blood cells; SDP,
single donor platelets; TPN, total parenteral nutrition.
Post-Transplant Response
The post-transplant response was available for 40 (89%) patients. Post-transplant
response assessment was not done in five patients as three died before d + 90, and
two were lost to follow-up post-ASCT. In the entire cohort, post-transplant CR was
observed in 25 (62.5%) patients, PR in 8 (20%) patients, and progressive disease (PD)
in 7 (17.5%) patients. Change in the disease status from pre-transplant period to
post-transplant is shown in the bar diagram in [Fig. 1 ].
Fig. 1 Comparison of disease status pre and post-transplant in the entire cohort; CR, complete
response, PR, partial response, PD, progressive disease. X axis indicates disease
status pre-transplant and Y axis indicates disease status post-transplant. Among 21
patients who had CR pre transplant, 16 maintained CR, and 5 had progressive disease
post-transplant. Among the 18 patients who had PR before transplant, 9 achieved CR,
7 maintained PR, and 2 had progressive disease. One patient who had progressive disease
pre transplant achieved PR post-transplant.
Survival
The median follow-up for the entire cohort was 44.8 months (95% CI: 33.8–55.8). The
median EFS for the entire cohort was 23.8 months (95%CI: 0.00–63.68); for HL, the
median EFS was not reached, and for NHL, it was 7.97 months (95%CI: 1.57–14.37). Estimated
3-year EFS was 48% for the entire cohort; for HL and NHL, it was 57.4% and 33.7%,
respectively. The median OS for the entire cohort and for HL was not reached; for
NHL, it was 24.3 months (95%CI: 0.56–48.11). The estimated OS at 3 years was 61.6%
for the entire cohort and 74.6% and 43.4% for HL and NHL, respectively.
An association of survival outcomes with respect to baseline features viz. relapsed
vs. refractory disease, number of lines of salvage therapy, and pre-transplant disease
status, complete response vs. partial response is shown in [Supplementary Tables S1 ] and [S2 ]. A comparison of survival outcomes based on the pre-transplant disease status of
CR vs. PR in subgroups of HL and NHL, respectively, is shown in [Fig. 2 ].
Fig. 2 Kaplan–Meier survival estimate for (A ) event-free survival, (B ) overall survival for Hodgkin lymphoma, and (C ) event-free survival (D ) overall survival for non-Hodgkin lymphoma, comparing outcomes with respect to pre-transplant
disease status.
Discussion
The present standard of care for relapsed/refractory lymphoma is HDC followed by ASCT.[2 ]
[5 ] Several HDC regimens have been in use as conditioning protocol in the autologous
transplant of lymphomas, and most have shown similar efficacy but with different toxicity
profiles. CBV is one of the older conditioning regimens for lymphoma with a relatively
safer toxicity profile, especially with low-dose CBV. Sparse data are available on
the contemporary use of CBV, especially from India. Our study found CBV practicable,
less toxic, and had efficacy comparable to that reported in the literature for other
regimens used in lymphoma conditioning.
We report the results of 45 transplants for HL and NHL with CBV conditioning. The
majority of the patients (95%) had chemosensitive disease at transplant. Grade 3 or
4 toxicities were observed in only 10% of our patients, common toxicities being mucositis,
diarrhea, and CINV. No grade 3/4 toxicity was observed in other organs viz. renal,
liver, pulmonary, or cardiac. Toxicity in our study was comparable to that reported
for low-dose CBV.[10 ]
[11 ]
[16 ] Studies with the original CBV (high dose) regimen with BCNU dose of 600 mg/m2 have reported higher pulmonary toxicity (5–10%). However, subsequent reports with
the use of BCNU at 450 mg/m2 or 300 mg/m2 (CBV low) have shown less pulmonary toxicity (<1%) without any loss of efficacy.[10 ]
[11 ]
[12 ]
[16 ] Also, Chen et al proved that carmustine dose higher than 300 mg/m2 resulted only in increased toxicity without any survival benefit.[10 ] Other grade 3 or 4 toxicities with CBV (low) included mucositis in about 8 to 25%,
diarrhea 10 to 25%, CINV 4 to 8% from various studies in the literature.[10 ]
[14 ]
[16 ] As summarized in [Table 3 ], grade 3/4 regimen-related toxicities were relatively less with CBV (low) compared
to other commonly used conditioning regimens such as BEAM, BEAC, or LACE (10–25% in
CBV low vs. 30–55% in other regimens) although with comparable survival outcomes.
Table 3
Summary of comparative studies of conditioning regimens for toxicity and survival
outcomes in lymphoma
Study
Regimen
Toxicity
TRM (d100-150)
PFS
OS
Arranz et al
1997, Spain[11 ]
HL (n = 49)
Retrospective study
CBVhigh vs. CBVlow
Not reported
9% vs. 8%
47% vs. 29%
(p = 0.57)
Not reported
Salar et al, 2001,
Spain[3 ]
NHL (n = 395)
Retrospective study
CBV vs. BEAM vs. CyTBI
Not reported
Not reported
CBV vs. BEAM
Relative risk
1.26 (0.77–2.05) (p = 0.34)
CBV vs. BEAM
Relative risk
1.30 (0.74–2.28)
(p = 0.36)
Puig et al, 2005, Spain[12 ] (n = 113)
NHL(n = 69)
HL (n = 44)
Retrospective study
CBVhigh vs. BEAM
Mucositis (grade 1–2)
6% vs. 34%
Pulmonary (grade 3)
4% vs. 0%
SOS: 5% vs. 0%
24% vs. 5%
Not reported
Not reported
Harris et al,
COG A5962, 2011, USA[16 ]
HL (n = 28)
NHL (n = 10)
Prospective study
CBV single arm study
CBVhigh :450mg/m2
CBVlow :300mg/m2
CBVhigh vs. CBVlow
Pulmonary toxicity (grade 3/4)
100% vs. 0%
Not reported
3year EFS
HL:45%
NHL:30%
3year OS
HL:63%
NHL:34%
Sharma et al, 2013
, India[15 ] (n = 51)
NHL (n = 26)
HL (n = 25)
Retrospective study
BEAM vs. LEAM
Mucositis (grade 3/4)
68% vs. 65%
Diarrhea (grade 3/4)
47% vs. 41%
18% vs. 12%
2 year EFS
(HL + NHL)
44.6% vs. 41.1% (p = 0.510)
2 year OS
(HL + NHL)
61.7% vs. 62.7%
(p = 0.928)
Chen et al, 2015,
Multicenter study[10 ] (n = 4,917)
NHL (n = 3,905)
HL (n = 1,012)
Retrospective study
CBVhigh vs. CBVlow vs.
BEAM vs. BuCy vs. TBI
CBVhigh vs. CBVlow vs. BEAM
Overall toxicity (grade 3–4)
6% vs. 3% vs. 3%
Not reported
CBVhigh vs. CBVlow vs. BEAM
3 year PFS
HL
57% vs. 60% vs. 62%
DLBCL
39% vs. 47% vs. 47%
CBVhigh vs. CBVlow vs. BEAM
3 year OS
HL
68% vs. 73% vs. 78%
DLBCL
43% vs. 55% vs. 58%
Khattry et al
2016, India[13 ]
(N = 139)
NHL = 92
HL = 47
Retrospective study
LACE vs. BEAM
Mucositis (grade 3–4)
8% vs. 38%
9% vs. 13%
5-year PFS
HL:
39% vs. 48%
(p = 0.747)
NHL:
34% vs. 46%
(p = 0.709)
5-year OS
HL:
49% vs. 48%
p = 0.279
NHL
37% vs. 46%
(p = 0.709)
SHI et al
2016, China[14 ]
NHL (n = 129)
Retrospective study
CBV vs. BEAM vs. BEAC
CBV vs. BEAM
Diarrhea(≥ grade 2)
18.8% vs. 63.9%
Mucositis (≥grade 2)
25% vs. 47.2%
0%
CBV vs. BEAM vs. BEAC
5-year EFS
43.8% vs. 66.7% vs. 67.5%
(p = 0.40)
CBV vs. BEAM vs.
BEAC
5-year OS
68.8% vs. 77.8% vs. 81.8%
(p = 0.584).
Our study (N = 45)
HL = 26
NHL = 19
Retrospective study
CBV–single arm
Diarrhea (grade 3/4)
10%
Mucositis (grade 3/4)
9%
6.6%
3-year EFS
HL 57.4%
NHL 33.7%
3-year OS
HL 74.6%
NHL 43.4%
Abbreviations: BEAC, BCNU, etoposide, cytarabine and cyclophosphamide; BEAM, BCNU,
etoposide, cytarabine, and melphalan; CBV, cyclophosphamide, BCNU and etoposide; DLBCL,
diffuse large B cell lymphoma; HL, Hodgkin lymphoma; LACE, lomustine, etoposide, cytarabine,
and cyclophosphamide; NHL, non-Hodgkin lymphoma; OS, overall survival; PFS, progression-free
survival; SOS, sinusoidal obstruction syndrome; TBI, total body irradiation; TRM,
treatment-related mortality.
The median time to engraftment was 11 days (range: 9–23) and 13 days (range: 8–36)
for neutrophils and platelets, respectively. Engraftment time was comparable to results
reported with CBV conditioning and other conditioning regimens.[12 ]
[13 ]
[15 ]
[24 ] Post day 0 (stem cell infusion) hospitalization was for 18 days (range: 10–37) in
our study, while it ranged from 17 to 25 days in reports of CBV and other regimens
from different transplant settings.[10 ]
[11 ]
[13 ]
[15 ] During the first 30 days of transplant, PRBC (packed red blood cell) and single
donor platelet (SDP) were required for a median of 3 and 4 units, respectively. TPN
was used in 7% of our patients, mostly for moderate to severe mucositis, comparable
to published data on TPN use for moderate to severe mucositis during lymphoma ASCT.[10 ]
[13 ]
[14 ]
[15 ] TRM at 100 days was 6.6% in our cohort comparable to that reported for CBV (7–10%)
in other settings.[10 ]
[11 ] A relatively higher TRM (13–18%) has been reported for other conditioning regimens
as BEAM.[13 ]
[15 ] Overall, from different studies in the literature, as summarized in [Table 3 ], including ours, CBV has shown a lower incidence of mucositis and other toxicities,
lesser requirement for parenteral nutrition, shorter hospital stay, and lower TRM
compared to other conventional regimens.
In our study, post-transplant evaluation of response had shown a CR of 62% and a PR
of 20% compared to 49% and 47%, respectively, during the pre-transplant assessment.
Thus, about 18% of patients had a progression within 3 months of transplant, indicating
a high-risk subset who had progressed despite having a chemosensitive disease. There
is scant literature on the evaluation of disease response in the immediate post-transplant
period as the majority of the studies on autologous transplant in lymphoma describe
efficacy outcomes in terms of DFS and OS. Nevertheless, besides chemosensitivity of
the disease pre-transplant, other risk factors for progression need further evaluation
in a larger cohort.
The median EFS in our cohort was 23.8 months, and the median OS was not reached. As
shown in [Table 3 ], our outcomes were comparable to those reported in the literature for CBV and other
regimens for HL and NHL transplants. We observed that patients who had received more
than two lines of salvage treatment and patients in PR before transplant had inferior
EFS and OS although statistically not significant. In the subset of HL, patients having
CR pre-transplant had higher 3-year EFS and OS (73% and 86%, respectively) than patients
in PR (43% EFS and 71% OS) although statistically not significant. In the NHL subset,
no statistically significant difference was seen in 3-year EFS or OS for patients
having CR (37% and 37.5%, respectively) or PR (30% and 48.5%, respectively) pre-transplant.
In several studies in the literature, CR pre-transplant has been shown to be a predictor
for better EFS, DFS, and OS in both HL and NHL.[25 ]
[26 ] We did not find any significant difference between patients in CR or PR, possibly
due to the small sample size and short follow-up.
Our results and a review of the literature suggest that CBV (low) is generally a safe
conditioning regimen with lower toxicities and similar efficacy compared to other
conventional regimens, viz. BEAM, BEAC, LACE, or LEAM, especially for patients with
HL. However, prospective randomized studies are needed with a larger cohort of patients
to know the difference in toxicities and outcomes with various conditioning regimens
for lymphoma. Our analysis had limitations inherent to a retrospective study. We had
a small number of patients and short follow-up, which precluded any meaningful interpretation
of the factors affecting the outcome. Nevertheless, this is the first study from India
to report the toxicity profile and efficacy of CBV conditioning.
Conclusion
CBV (low) is relatively safe, with common toxicities being mucositis, diarrhea, CINV,
and overall grade 3/4 toxicities experienced by less than 10% of patients. Thus, CBV
can be a preferred regimen in resource-limited settings. Event-free survival and overall
survival with CBV were comparable to that reported in the literature, especially for
patients with Hodgkin lymphoma.
