This systematic review and meta-analysis evaluated the role of upfront autologous hematopoietic stem cell transplantation (auto-HCT) consolidation for patients with aggressive B-cell lymphomas in first remission in the rituximab era. The analysis included 4 randomized controlled trials comparing R-chemotherapy alone to R-chemotherapy plus auto-HCT. There were no differences in overall survival, progression-free survival, or response rates between the two treatment arms. Patients receiving auto-HCT had significantly higher rates of grade 3-4 infections and gastrointestinal toxicities. The review concludes that in the rituximab era, auto-HCT consolidation does not provide a benefit over chemotherapy alone, even for

1. Upfront Autologous Hematopoietic Stem Cell
Transplantation Consolidation for Patients With
Aggressive B-Cell Lymphomas in First
Remission in the Rituximab Era: A Systematic
Review and Meta-Analysis

2. • The combination of doxorubicin-based chemotherapy
regimens such as cyclophosphamide, doxorubicin, vincristine,
and prednisone (CHOP) and CHOP with rituximab (R-CHOP)
is the standard of care for patients with diffuse large B-cell
lymphoma (DLBCL)

4. IPI score - survivals

5. Age adjusted IPI Score

6. Role of Auto BMT-Pre Rituximab era
• Meta-analyses of these pre- rituximab era randomized trials
demonstrated no survival benefit for auto-HCT in this setting.

8. • A comprehensive search of 2 databases was conducted to
identify potentially eligible studies with no restrictions on
language or study years.
• The search was conducted on December 1, 2018, and included
the Cochrane Library and PubMed/MEDLINE.
• Studies were included if they reported patients aged 18 years
or older with DLBCL and used an RCT study design directly
comparing R-chemo with R-chemo and auto-HCT.

9. • Data collection:
 Study characteristics -- design, timing of study, and location.
 Patient characteristics -- age, sex, and disease characteristics.
 Treatment characteristics -- dose and cotherapies.
 Outcomes related to benefits -- overall survival [OS],
progression-free survival [PFS], and response rates.
 Harms - treatment-related mortality [TRM] and adverse events
• The risk of bias in individual studies was evaluated using the
Cochrane Risk of Bias assessment tool for RCTs.

10. Primary outcome is overall survival.
Secondary outcomes
• Our secondary outcomes are:
• Progression-free survival
• Response rate
• Treatment related mortality
• Grade 3 / 4 adverse events

12. • The studies were conducted across different continents (1 in
North America and 3 in Europe) and the duration of the studies
spanned over a decade (1999-2011).
• DLBCL constituted the predominant histology, there were
other aggressive B-cell NHLs (range, 2%-34%) and T-cell
NHL (12%) .
• The median ages of the patients ranged from 47 to 53 years,
with a male preponderance noted across all the studies (54% to
63%).
• The median duration of follow-up -- 42 to 76 months.

14. Schmitz 2012-

15. • After a median of 42 months
• Patients with age-adjusted IPI 2 had significantly better event-free
survival if treated with R-CHOEP-14 (75·5% [95% CI 66·5–84·5] in
the R-CHOEP-14 group vs 63·5% [53·5–73·5] in the R-
MegaCHOEP group; p=0·0509) and overall survival (91·0% [95% CI
85·1–96·9] vs 77·1% [68·3–85·9]; p=0·01 .
• No significant differences were seen if patients with age- adjusted IPI
3 only were assessed (event-free survival: 53·9% [95% CI 37·2–
70·6] vs 55·5% [38·6–72·4];
R-CHOEP R-MegaCHOEP
3yr EFS 69.5% 61.4% (p=0.14)
3yr PFS 73.7% 69.8% (P=0.48)
3yr OS 84.6% 77% (P=0.08)

16. • Further analysis was done restricting the comparison of R-
CHOEP-14 and R-MegaCHOEP to 125 patients who had
received all treatment per protocol.
• No significant differences were seen in event-free survival
(p=0·51), progression-free survival (p=0·41), or overall
survival (p=0·051) between treatment arms

17. Stiff 2013

20. Three initial courses of doxorubicin-containing chemotherapy -vincristine 1.4 mg/m2 and oral
prednisone , then
1. HD cyclophosphamide 7 g/m2 IV (day 1) and rituximab 375 mg/m IV (days 3 and 11),
followed by the harvest of peripheral blood progenitor cells (PBPCs);
2. HD-Ara-C 2 g/m2 IV (twice a day for 6 days), followed on day 7 by the infusion of 1.5 to 2
3 106 autologous CD34+ cells/kg and rituximab 375 mg/m2 IV (day 8 and day 16); a second
PBPC harvest was scheduled after HD-Ara-C if in- adequate harvesting was obtained after
HD-cyclophosphamide or in the case of initial bone marrow involvement;
3. HD etoposide 2.4 g/m2 IV (day61), cisplatin 100 mg/m2 IV (day 2); a small amount of
PBPC (2 3 10 CD34+ cells/kg) were reinfused following etoposide/cisplatin.
Cortelazzo 2016

21. • Clinical response (complete response, 78% v 76%; partial
response, 5% v 9%) and failures (no response, 15% v 11%; and
early treatment-related mortality, 2% v 3%) were similar after R-
CHOP versus R-HDS, respectively.
• After a median follow-up of 5 years, the 3-year event-free
survival was 62% versus 65% (P = .83).
• At 3 years, compared with the R-CHOP arm, the R-HDS arm had
better disease-free survival (79% v 91%, respectively; P = .034),
but this subsequently vanished because of late-occurring
treatment-related deaths.
• No difference was detected in terms of progression-free survival
(65% v 75%, respectively; P = .12), or overall survival (74% v
77%, respectively; P = .64).

22. • Significantly higher hematologic toxicity (P <.001) and
more infectious complications (P <.001) were observed in
the R-HDS arm.

23. Chiappella 2017
• 203 patients were assigned to receive R-CHOP-14 and
196 were assigned to receive R-MegaCHOP-14.
• Median follow-up of 72 months (IQR 57–88)

25. • 2-year failure-free survival was 71% (95% CI 64–77) in the
transplantation group versus 62% (95% CI 55–68) in the no
transplantation group (hazard ratio [HR] 0·65 [95% CI 0·47–
0·91]; stratified log-rank test p=0·012).
• No difference in 5-year overall survival was observed between
these groups (78% [95% CI 71–83] versus 77% [71–83]; HR
0·98 [0·65–1·48]; stratified log-rank test p=0·91).

26. • No difference in 2-year failure-free survival was observed
between patients receiving R-CHOP-14 and those receiving R-
MegaCHOP-14

27. • Grade 3 or worse haematological adverse events were reported
in 183 (92%) of 199 patients in the transplantation group
versus 135 (68%) of 200 patients in the no transplantation
group.
• Grade 3 or worse non-haematological adverse events were
reported in 90 (45%) versus 31 (16%)
• The most common grade 3 or worse non-haematological
adverse event was gastrointestinal (49 [25%] vs 19 [10%]).
• Treatment-related deaths occurred in 13 (3%) patients; eight in
the transplantation group and five in the no transplantation
group.

28. META- ANALYSIS

29. Survival Outcomes
• There was no difference in OS noted for patients who received
R-chemo and auto- HCT compared with those who received
R-chemo alone (HR, 1.01; 95% CI, 0.74-1.37 [P = .96]) .

30. • There was no difference in OS noted between the 2 groups, even when
the analysis was limited to the high-risk aaIPI group (HR, 0.75; 95%
CI, 0.47-1.19 [P = .22]).
• One study that demonstrated significantly improved OS in the R-
chemo and auto- HCT treatment arm compared with the R-chemo
alone arm among the patients with high-risk aaIPI (HR, 0.35; 95% CI,
0.16-0.78) was based on the ad hoc analysis.(Stiff 2013)

31. Progression Free Survival
• There was no difference in PFS noted for patients who received R-
chemo and auto-HCT compared with those who received R-chemo
alone (HR, 0.77; 95% CI, 0.58- 1.04 [P = .09])

32. • PFS stratified by aaIPI was provided in only 2 studies.
• There was no difference in PFS observed between the 2 groups
when the analysis was limited to the group of patients with
high-risk aaIPI (HR, 0.51; 95% CI, 0.23- 1.10 [P = .09])

33. Response Rates
• Response rates (ORR and CR) were reported in 3 studies.
• There was no difference in the ORR observed for patients who
received R-chemo compared with those treated with R-chemo
and auto-HCT (RR, 0.98; 95% CI, 0.92-1.04 [P = .46])

34. • There was no difference in the CR rate noted between
the 2 groups (RR, 0.99; 95% CI, 0.91-1.07 [P = .78])

35. Treatment-Related Mortality
• There was no difference in the risk of TRM noted between
patients who received R-chemo and auto-HCT and those who
received R-chemo alone (RR, 1.57; 95% CI, 0.92- 2.69 [P =
.10]) .

36. Adverse Events
• All 4 studies reported grade 3 or 4 infections.
• Patients who received R-chemo and auto-HCT had a
significantly higher risk of grade 3 or 4 infections (RR, 4.20;
95% CI, 2.32-7.59 [P < .00001])
• Patients in the R-chemo and auto- HCT arm were found to
have significantly higher rates of grade 3 or 4 hematologic
toxicities compared with patients in the R-chemo alone group

37. • Nonhematologic toxicities were reported in 3 studies.
• Patients in the R-chemo and auto- HCT arm were found to
have significantly higher rates of grade 3 or 4 gastrointestinal
AEs compared with patients in the R-chemo alone group (RR,
3.15; 95% CI, 2.14-4.64 [P < .00001])
• However, there was no difference in the rates of grade 3 or 4
cardiac (RR, 1.50; 95% CI, 0.48-4.63 [P = .49]) or neurologic
(RR, 0.57; 95% CI, 0.10-3.16 [P = .52]) AEs noted between
the 2 groups.

38. DISCUSSION
• Despite the application of modern chemoimmunotherapies, the
outcomes of subgroups of patients with high- risk features
(high aaIPI) are suboptimal.
• Auto-HCT consolidation in first remission after induction
therapy has been offered with the intent of improving the out-
comes of high-risk patients, with to our knowledge no clear
data establishing the superiority or lack thereof of this
approach in the rituximab era.

39. Current meta analysis –Rituximab
era
1. There was no superiority of auto-HCT consolidation in first
remission noted compared with standard chemotherapy alone
in the rituximab era.
2. The benefit was not observed in recipients of auto-HCT
consolidation compared with chemotherapy alone in first
remission, even among patients in high-risk clinical groups
as defined by aaIPI in the rituximab era.
3. Increased toxicity was noted among patients who underwent
R-chemo and auto-HCT compared with those who received
R-chemo alone.

40. Prerituximab era
• Several randomized studies have evaluated the role of auto-
HCT consolidation in patients in first remission and reported
conflicting results.
• However, a meta-analysis pooling data from these studies did
not demonstrate the superiority of auto-HCT consolidation
compared with standard chemotherapy alone.

41. • In the rituximab era, the SWOG S97049 study demonstrated a
possible OS benefit in an unplanned/post hoc analysis for the
high-risk IPI sub- group, reigniting the discussion concerning
the role of upfront consolidative auto-HCT.
• However, other randomized studies did not demonstrate any
benefit of upfront auto-HCT consolidation in patients in the
high-risk aaIPI group.
• The current study, which pooled the data from all 4 RCTs, not
only indicated a lack of benefit but demonstrated significantly
higher toxicity with the use of upfront auto-HCT consolidation
in patients with high-risk DLBCL in first remission compared
with chemotherapy alone, as defined by clinical prognostic
markers (aaIPI).

42. • The results of the current meta-analysis demonstrated that the
clinical prognostic markers (incorporated into aaIPI) are
unlikely to identify a high-risk DLBCL cohort in whom the
application of auto-HCT may improve outcomes.
• In recent years, various immunohistochemistry-based assays
(eg, Hans algorithm to identify cell of origin, double expressor
lymphoma based on c-MYC and BCL2
immunohistochemistry) or genomic assays (gene expression
profiling or fluorescence in situ hybridization [FISH] assays to
identify subsets of patients with DLBCL with c-MYC, BCL2,
and/or BCL6 rearrangements) have helped to identify
biologically high-risk subgroups of patients with DLBCL.

44. • It is not known if the outcomes in patients with high-risk
DLBCL as defined by biologic markers such as the presence of
c-MYC (rearrangement or copy number gains/amplification by
FISH or increased expression by immunohistochemistry) can
be improved with upfront auto-HCT consolidation.
• One study that used patient samples from the German High
Grade NHL Study Group confirmed the negative prognostic
impact of c-MYC rearrangement and demonstrated the
independent prognostic relevance of BCL2-only
rearrangement, it did not demonstrate the impact of these
molecular aberrancies on the survival outcomes of those
patients who underwent upfront auto-HCT consolidation.

45. • It now is known that the outcomes of patients with double-hit
lymphoma (DHL) are poor when they are treated with R-
CHOP or R-CHOP–like regimens.
• However, those patients who achieve a CR with more
intensive frontline therapies may experience durable disease
control with or without auto-HCT consolidation.
• Aggressive options currently are being considered in high-risk
populations (such as patients with DHL), especially in those
receiving R-CHOP as first-line treatment or those not
achieving CR with more intensive induction therapies

46. Strengths
• The study population was homogeneous
• The extracted data were available for the majority of the
studies.
• All of the studies included were RCTs and had a low risk of
bias.

47. Limitations
• Heterogeneity in the auto-HCT arm noted across the 4 studies
(different high-dose therapies administered prior to autologous
stem cell rescue).
• The absence of individual patient data did not allow for
evaluation of effect of treatment intensification in various
disease risk groups based on the molecular characteristics of
the disease as well as for the removal of patients with
aggressive B-cell or T-cell NHLs other than DLBCL, which
ranged from 2% to 45% across all studies.

48. • The current study did not address the role of consolidative
auto-HCT in patients with DLBCL according to cell of origin.
• However, previous studies have shown the lack of prognostic
impact of cell of origin on OS.
• The outcomes of patients with genomically defined high-risk
DLBCL (c-MYC/BCL2 and/ or BCL6 rearrangement by FISH
and increased c-MYC/ BCL2 expression status by
immunohistochemistry) can be affected by auto-HCT.
• Although one study (a secondary analysis of the SWOG S9704
study) attempted to address the role of consolidative auto-HCT
in patients with genomically defined high-risk DLBCL, it was
limited by small numbers.

49. • Last, the remission status of patients at the end of induction
therapy was not assessed by positron emission tomography
scan, which now is the standard of care.
• Whether auto-HCT consolidation could improve the outcomes
of patients with DLBCL with chemosensitive disease after
treatment with R-CHOP with residual positron emission
tomography activity cannot be examined using the trials
included in the current meta-analysis.

50. Conclusion
• Even in rituximab era,there is no beneficial effect of upfront
auto-HCT consolidation in patients with aggressive B-cell
NHL, including those patients in the high-risk clinical groups
(high aaIPI).
• Larger studies urgently are needed to further define the role of
upfront auto-HCT in patients with biologically defined, poor-
risk DLBCL, such as those with DHL.