Abstract
INTRODUCTION
Disease relapse is the most common cause of therapy failure in non-Hodgkin lymphoma (NHL) patients undergoing reduced-intensity conditioning (RIC) allogeneic hematopoietic cell transplantation (alloHCT). It is not known whether or not increasing total body irradiation (TBI) dose from 2Gy to 4Gy in RIC-platform can provide improved disease control without increasing non-relapse mortality (NRM). Using the CIBMTR database we evaluated the outcomes of NHL patients receiving RIC alloHCT with either fludarabine (Flu)/2Gy TBI vs. Flu/4Gy TBI.
METHODS
In the CIBMTR registry, 413 adult NHL patients underwent a first alloHCT using either a matched related or unrelated donor between 2008–2017, utilizing a RIC regimen with either Flu/2Gy TBI (n=349) or Flu/4Gy TBI (n=64). The primary endpoint was overall survival (OS). Secondary endpoints included acute (a) and chronic (c) graft-versus-host disease (GVHD), NRM, relapse/progression and progression-free survival (PFS).
RESULTS
At baseline the Flu/2Gy TBI cohort had significantly fewer patients with KPS ≥90 and significantly more patients had a higher HCT-CI. On multivariate analysis the two conditioning cohorts were not significantly different in terms of risk of grade 3–4 aGVHD or cGVHD. Compared to Flu/2Gy TBI, the Flu/4Gy TBI conditioning was associated with a significantly higher risk of NRM (HR 1.79, 95%CI=1.11–2.89, p=0.02), and inferior OS (HR 1.51, 95%CI=1.03–2.23, p=0.03). No significant differences were seen in the risk of relapse/progression (HR 0.78, 95%CI=0.47–1.29, p=0.33) or PFS (HR 1.09, 95%CI=0.78–1.54, p=0.61) between the two regimens. Comparing Flu/2Gy TBI vs. Flu/4Gy TBI cohorts the 5-year adjusted outcomes were; NRM (28% vs. 47%; p=0.005), relapse/progression (35% vs. 29%; p=0.28), PFS (37% vs. 24%; p=0.03) and OS (51% vs. 31%; p=0.001), respectively. Relapse was the most common cause of death in both cohorts.
CONCLUSIONS
In NHL patients undergoing Flu/TBI-based conditioning, augmenting TBI dose from 2Gy to 4Gy is associated with higher NRM and inferior OS, without any significant benefit in terms of disease control. 2Gy is optimal dose in the RIC Flu/TBI platform for lymphomas.
Keywords: fludarabine, TBI, reduced-intensity conditioning, allogeneic hematopoietic cell transplant
INTRODUCTION
Reduced-intensity conditioning (RIC) or non-myeloablative conditioning (NMA) regimens currently account for ~45% of all allogeneic hematopoietic cell transplants (alloHCT) performed in the United States (U.S)1. Owing to their lower intensity, these regimens are generally associated with a reduced risk of non-relapse mortality (NRM) and can be offered to older patients and those with significant comorbid conditions. Considering the median age at diagnosis of non-Hodgkin lymphoma (NHL) patients is 67 years,2 it is not surprising that RIC/NMA regimens now account for the majority of alloHCT performed for this indication in the U.S3. Unfortunately, disease relapse remains the most common cause of treatment failure in NHL patients undergoing alloHCT with lower-intensity conditioning platforms.4–6
The RIC/NMA conditioning approach with the best risk/benefit profile (NRM vs. relapse rate) in NHL patients remains controversial. A Center for International Blood & Marrow Transplant Research (CIBMTR) analysis7 compared HCT outcomes among lymphoma patients undergoing alloHCT with either 2Gy total body irradiation (TBI)-based or non-TBI containing NMA conditioning alloHCT. The study found a higher risk of graft-versus-host disease (GVHD) with TBI-based approaches, but no difference in relapse risk or survival outcomes between the two approaches. Recent data for patients with non-malignant blood disorders undergoing alternative donor NMA alloHCT suggest that increasing the dose of TBI in transplant conditioning to 4Gy can substantially reduce the risk of graft failure, without negatively impacting NRM rates.8 However, it is not known whether increasing TBI dose from 2Gy to 4Gy in RIC/NMA-platforms can provide improved disease control without increasing NRM in lymphoma patients. Using the CIBMTR database we evaluated the outcomes of NHL patients receiving RIC alloHCT with either fludarabine (Flu)/2Gy TBI vs. Flu/4Gy TBI.
METHODS
Data sources
The CIBMTR is a working group of more than 500 transplantation centers worldwide that contribute detailed data on HCT to a statistical center at the Medical College of Wisconsin (MCW). Participating centers are required to report all transplantations consecutively and compliance is monitored by on-site audits. Computerized checks for discrepancies, physicians’ review of submitted data, and on-site audits of participating centers ensure data quality. Observational studies conducted by the CIBMTR are performed in compliance with all applicable federal regulations pertaining to the protection of human research participants. The MCW and National Marrow Donor Program, Institutional Review Boards approved this study.
The CIBMTR collects data at two levels: Transplant Essential Data (TED) and Comprehensive Report Form (CRF) data. TED-data includes disease type, age, gender, pre-HCT disease stage and chemotherapy-responsiveness, date of diagnosis, graft type, conditioning regimen, post-transplant disease progression and survival, development of a new malignancy, and cause of death. All CIBMTR centers contribute TED-data. More detailed disease and pre- and post-transplant clinical information is collected on a subset of registered patients selected for CRF data by a weighted randomization scheme. TED- and CRF-level data are collected pre-transplant, 100-days, and six months post-HCT and annually thereafter or until death. Data for the current analysis were retrieved from CIBMTR (TED and CRF) report forms.
Patients
Included in this analysis are adult (≥18 years) patients with NHL, undergoing their first Flu/TBI-based RIC/ NMA alloHCT between 2008 and 2017. Eligible donors included either HLA-identical sibling donors or adult unrelated donors (URD) matched at the allele-level at HLA-A, -B, -C and -DRB1. All the patients received peripheral blood as the graft-source and GVHD prophylaxis was limited to calcineurin inhibitor (CNI)-based approaches.
Definitions and Study Endpoints
Response to the last line of therapy before alloHCT was determined using the International Working Group criteria in use during the era of this analysis9. The primary endpoint was overall survival (OS); death from any cause was considered an event and surviving patients were censored at last contact. Secondary endpoints included NRM, progression/relapse, progression-free survival (PFS), acute and chronic GVHD. NRM was defined as death without evidence of lymphoma progression/relapse; relapse was considered a competing risk. Progression/relapse was defined as progressive lymphoma after HCT or lymphoma recurrence after a complete response (CR); NRM was considered a competing risk. For PFS, a patient was considered a treatment failure at the time of progression/relapse or death from any cause. Patients alive without evidence of disease relapse or progression were censored at last follow-up. Neutrophil recovery was defined as the first of 3 successive days with absolute neutrophil count (ANC) ≥500/μL after post-transplantation nadir. Platelet recovery was considered to have occurred on the first of three consecutive days with platelet count 20,000/μL or higher, in the absence of platelet transfusion for 7 consecutive days. For neutrophil and platelet recovery, death without the event was considered a competing risk. Acute GVHD10 and chronic GVHD11 were graded using standard criteria. Primary and secondary graft failures were considered as a single outcome. Primary graft failure was defined as failure to achieve an ANC of ≥500/μL for 3 consecutive days or donor chimerism < 5% (peripheral blood CD3+ or bone marrow). Secondary graft failure was defined as initial donor engraftment followed by graft loss, evidenced by a persistent decline in the ANC (≥500/μL) or loss of donor chimerism < 5% or a second transplantation in patients with documented clinical remission12.
Statistical analysis
The Flu/2Gy TBI cohort was compared against the Flu/4Gy TBI cohort. Probabilities of PFS and OS were calculated as described previously13. Cumulative incidence of NRM and lymphoma progression/relapse were calculated to accommodate for competing risks14. Associations among patient-, disease-, and transplantation-related variables and outcomes of interest were evaluated using multivariable Cox proportional hazards regression. A forward stepwise selection was used to identify covariates that influenced outcomes. Covariates with a p<0.05 were considered statistically significant. The proportional hazards assumption for Cox regression was tested by adding a time-dependent covariate for each risk factor and each outcome. Interactions between the main effect and significant covariates (e.g. remission status, lymphoma subtype) were examined and none were found. Results are expressed as hazard ratio (HR). The center effect was examined using the random effect score test15 for OS, PFS, relapse, and NRM. There was no center effect noted for any of the outcomes. The variables considered in multivariable regression analysis include conditioning regimen (main effect), patient age, Karnofsky performance status (KPS), HCT-comorbidity index (HCT-CI), race, lymphoma histology, remission status at HCT, history of prior autologous HCT, interval between diagnosis and HCT, donor type, GVHD prophylaxis, use of in vivo T-cell depletion, donor-recipient cytomegalovirus serostatus and year of HCT. All statistical analyses were performed using SAS version 9.4 (SAS Institute Inc., Cary, NC).
RESULTS
Baseline Characteristics
A total of 413 NHL patients were included in the analysis, of whom 349 patients received RIC with Flu/2Gy TBI and 64 received Flu/4Gy TBI. The baseline patient-, disease- and transplantation-related characteristics are shown in Table 1. The two groups had no significant differences in terms of patient age, gender, race, lymphoma subtypes, median interval between diagnosis and allogeneic HCT, remission status at HCT, history of prior autologous HCT, in vivo T-cell depletion use with conditioning, donor type, and donor-recipient CMV serostatus. The proportion of patients with KPS ≥90% was higher in Flu/4Gy TBI cohort compared to Flu/2Gy TBI group (79.7% vs. 60.5%; p=0.01). A greater proportion of patients in Flu/2Gy TBI group had an HCT-comorbidity index (HCT-CI), ≥3 (43.3% vs 21.9%; p=0.003) and CNI/mycophenolate mofetil-based GVHD prophylaxis (96% vs 85.9%; p=0.004) compared to the Flu/4Gy TBI cohort. Median follow-up of survivors was 59.4months in the Flu/2Gy TBI group and 48.5months in the Flu/4Gy TBI group.
Table 1.
Baseline characteristics for NHL patients receiving first alloHCT and Flu/2Gy vs. Flu/4Gy TBI in conditioning during 2008–2017
| Flu/2Gy TBI N=349 | Flu/4Gy TBI N=64 | P-value | |
|---|---|---|---|
| Number of centers | 55 | 8 | |
| Median Patient age (range) | 57.7 (20.4–77.1) | 55.3 (22.7–72.9) | 0.67 |
| Male gender (%) | 231 (66.2) | 50 (78.1) | 0.06 |
| Patient race (%) | 0.15 | ||
| Caucasian | 313 (89.7) | 55 (85.9) | |
| Other1 | 14 (4) | 1 (1.6) | |
| Not reported | 22 (6.3) | 8 (12.5) | |
| Karnofsky performance score ≥90 (%) | 211 (60.5) | 51 (79.7) | 0.01 |
| Lymphoma subtypes (%) | 0.09 | ||
| Follicular lymphoma | 87 (24.9) | 13 (20.3) | |
| Diffuse large B-cell lymphoma | 107 (30.7) | 11 (17.2) | |
| Mantle cell lymphoma | 74 (21.2) | 20 (31.3) | |
| Other B-cell | 23 (6.6) | 7 (10.9) | |
| T-cell NHL | 58 (16.6) | 13 (20.3) | |
| HCT-CI (%) | 0.003 | ||
| 0 | 90 (25.8) | 26 (40.6) | |
| 1–2 | 89 (25.5) | 23 (35.9) | |
| ≥ 3 | 151 (43.3) | 14 (21.9) | |
| Missing | 19 (5.4) | 1 (1.6) | |
| Prior autoHCT (%) | 186 (53.3) | 33 (51.6) | 0.80 |
| Median time from diagnosis to HCT, mons (range) | 40.9 (1.4–250.8) | 32.9 (4.4–165.6) | 0.60 |
| Donor type (%) | 0.38 | ||
| Matched related donor | 157 (45) | 25 (39.1) | |
| Matched unrelated donor | 192 (55) | 39 (60.9) | |
| Remission at HCT (%) | 0.92 | ||
| Complete remission | 174 (49.9) | 35 (54.7) | |
| Partial remission | 117 (33.5) | 21 (32.8) | |
| Resistant | 46 (13.2) | 6 (9.4) | |
| Untreated/Unknown | 12 (3.4) | 2 (3.1) | |
| ATG/alemtuzumab in conditioning (%) | 10 (2.9) | 3 (4.7) | 0.44 |
| Rituximab with conditioning (%) | 38 (10.9) | 0 | 0.005 |
| GVHD prophylaxis (%) | 0.004 | ||
| CNI + MMF +- other(s) | 335 (96) | 55 (85.9) | |
| CNI + MTX +- other(s) | 9 (2.6) | 7 (10.9) | |
| CNI + other(s) (except MMF, MTX) | 5 (1.4) | 2 (3.1) | |
| CMV donor negative/recipient positive (%) | 100 (28.7) | 18 (28.1) | 0.99 |
| Follow-up - median (min-max) | 59.4 (3.22–122.2) | 48.55 (3.78–96.88) |
Abbreviations: HCT-hematopoietic cell transplantation; HCT-CI- HCT comorbidity index; ATG-anti-thymocyte globulin; CMV-cytomegalovirus; CNI-calcineurin inhibitors; GVHD; graft-versus-host disease; MTX-methotrexate; MMF-mycophenolate mofetil
Patient race - other: Flu/2GyTBI: 14: 5 African American; 5 Asian; 2 Bi-racial; 1 Native American; 1 Native Pacific Islander. Flu/4Gy TBI: 1 African American.
Hematopoietic recovery and GVHD
The day 28 cumulative incidence of neutrophil recovery for the Flu/2Gy TBI group was 97.4% (95%CI=95.4–98.8) compared 95.3% (95%CI=88.1–99.3) for the Flu/4Gy TBI group (p=0.48; Table 2). The day 100 cumulative incidence of platelet recovery in the same order was 97.4% (95%CI=95.4–98.8) and 100% (95%CI=0–100) (p=0.15; Table 2), respectively. There was no difference in the risk of graft failure between the two cohorts.
Table 2:
Engraftment, graft-versus-host disease and adjusted HCT outcomes.
| Flu/2Gy TBI (N = 349) | Flu/4Gy TBI (N = 64) | ||||
|---|---|---|---|---|---|
| Outcomes | N | Probability (95% CI) | N | Probability (95% CI) | P Value |
| Neutrophil recovery | 348 | 64 | |||
| 28 days | 97.4 (95.4–98.8)% | 95.3 (88.1–99.3)% | 0.48 | ||
| Platelet recovery | 346 | 63 | |||
| 100-day | 97.4 (95.4–98.8)% | 100 (0–100)% | 0.15 | ||
| Acute grade II-IV GVHD | 342 | 61 | |||
| 6 months | 46.6 (41.4–51.9)% | 50 (37.4–62.6)% | 0.63 | ||
| Acute grade III-IV GVHD | 342 | 61 | |||
| 6 months | 14.7 (11.1–18.6)% | 18.3 (9.6–29.1)% | 0.50 | ||
| Chronic GVHD | 342 | 62 | |||
| 1-year | 53.3 (47.9–58.7)% | 64.7 (51.8–76.7)% | 0.10 | ||
| 2-year | 66 (60.7–71.1)% | 68.4 (55.6–79.9)% | 0.73 | ||
| Graft failure | 348 | 64 | |||
| 100-day | 0.6 (0.1–1.6)% | 1.6 (0–6.2)% | 0.54 | ||
| 1-year | 1.8 (0.6–3.5)% | 3.2 (0.3–8.9)% | 0.55 | ||
| Adjusted Non-relapse mortality | 345 | 63 | |||
| 1-year | 13 (9–16)% | 20 (12–28)% | 0.10 | ||
| 3-year | 22 (18–27)% | 30 (21–40)% | 0.12 | ||
| 5-year | 28 (23–33)% | 47 (35–59)% | 0.005 | ||
| Adjusted Relapse/progression | 345 | 63 | |||
| 1-year | 32 (28–37)% | 25 (14–35)% | 0.22 | ||
| 3-year | 35 (30–40)% | 29 (18–40)% | 0.31 | ||
| 5-year | 35 (30–40)% | 29 (18–40)% | 0.28 | ||
| Adjusted Progression-free survival | 345 | 63 | |||
| 1-year | 55 (50–60)% | 52 (42–62)% | 0.55 | ||
| 3-year | 42 (37–47)% | 39 (29–49)% | 0.56 | ||
| 5-year | 37 (31–42)% | 24 (14–34)% | 0.03 | ||
| Adjusted overall survival | 349 | 64 | |||
| 1-year | 74 (70–79)% | 64 (54–73)% | 0.04 | ||
| 3-year | 59 (53–64)% | 51 (41–61)% | 0.18 | ||
| 5-year | 51 (46–57)% | 31 (20–41)% | 0.001 |
Abbreviations: GVHD=graft-versus-host disease; CI = confidence interval; N = number.
On univariate analysis, the cumulative incidence of grade II-IV acute GVHD at day 180 (Table 2) in the Flu/2Gy TBI cohort was 46.6% (95%CI=41.4–51.9), compared to 50% (95%CI=37.4–62.6) in the Flu/4Gy TBI (p=0.63). The corresponding rates of grades III-IV acute GVHD were 14.7% (95%CI=11.1–18.6) vs. 18.3% (95%CI=9.6–29.1), respectively (p=0.50). On multivariable regression analysis (Table 3), the two cohorts were not significantly different in terms of risk of grade III-IV acute GVHD (odds ratio=1.29, 95%CI=0.63–2.64, p=0.49). On univariate analysis, the cumulative incidence of chronic GVHD at 1-year (Table 3) in Flu/2Gy TBI cohort was 53.3% (95%CI=47.9–58.7) compared to 64.7% (95%CI=51.8–76.7) in the Flu/4Gy TBI (p=0.10). On multivariable regression analysis (Table 3), the two cohorts were not significantly different in terms of risk of chronic GVHD (HR=1.35, 95%CI=0.97–1.88, p=0.08).
Table 3:
Multivariable Analysis Results
| N | OR | OR Lower CI | OR Upper CI | p-value | |
|---|---|---|---|---|---|
| Grade 3–4 acute GVHD** | |||||
| Main effect | |||||
| Flu/2GY TBI | 342 | 1 | 0.49 | ||
| Flu/4GY TBI | 61 | 1.29 | 0.63 | 2.64 | 0.49 |
| Chronic GVHD | |||||
| Main effect | |||||
| Flu/2GY TBI | 344 | 1 | 0.08 | ||
| Flu/4GY TBI | 63 | 1.35 | 0.97 | 1.88 | 0.08 |
| Non-relapse mortality | |||||
| Main effect | |||||
| Flu/2GY TBI | 344 | 1 | 0.02 | ||
| Flu/4GY TBI | 63 | 1.79 | 1.11 | 2.89 | 0.02 |
| HCT-CI | |||||
| 0 | 114 | 1 | 0.01 | ||
| 1 to 2 | 109 | 1.48 | 0.84 | 2.60 | 0.17 |
| 3+ | 165 | 2.25 | 1.36 | 3.73 | 0.0003 |
| missing | 19 | 1.52 | 0.57 | 4.01 | 0.40 |
| Progression/relapse | |||||
| Main effect | |||||
| Flu/2GY TBI | 349 | 1 | 0.33 | ||
| Flu/4GY TBI | 64 | 0.78 | 0.47 | 1.29 | 0.33 |
| Remission at HCT | |||||
| Complete remission | 209 | 1 | <0.0001 | ||
| Partial remission | 138 | 2.30 | 1.56 | 3.38 | <.0001 |
| Resistant | 52 | 2.49 | 1.52 | 4.08 | 0.0003 |
| Untreated/Unknown | 14 | 2.26 | 0.96 | 5.29 | 0.06 |
| Donor type | |||||
| Matched related donor | 182 | 1 | 0.004 | ||
| Matched unrelated donor | 231 | 0.60 | 0.43 | 0.85 | 0.004 |
| Progression-free survival | |||||
| Main effect | |||||
| Flu/2GY TBI | 349 | 1 | 0.61 | ||
| Flu/4GY TBI | 64 | 1.09 | 0.78 | 1.54 | 0.61 |
| Remission at HCT | |||||
| Complete remission | 209 | 1 | 0.0001 | ||
| Partial remission | 138 | 1.72 | 1.30 | 2.28 | 0.0002 |
| Resistant | 52 | 1.99 | 1.37 | 2.89 | 0.0003 |
| Untreated/Unknown | 14 | 1.30 | 0.60 | 2.79 | 0.50 |
| Overall survival | |||||
| Main effect | |||||
| Flu/2GY TBI | 349 | 1 | 0.03 | ||
| Flu/4GY TBI | 64 | 1.51 | 1.03 | 2.23 | 0.03 |
| HCT - CI | |||||
| 0 | 116 | 1 | 0.04 | ||
| 1 to 2 | 112 | 1.31 | 0.86 | 2.00 | 0.21 |
| 3+ | 165 | 1.73 | 1.18 | 2.54 | 0.01 |
| missing | 20 | 1.44 | 0.72 | 2.90 | 0.31 |
| Remission at HCT | |||||
| Complete remission | 209 | 1 | 0.05 | ||
| Partial remission | 138 | 1.20 | 0.87 | 1.65 | 0.28 |
| Resistant | 52 | 1.69 | 1.11 | 2.55 | 0.01 |
| Untreated/Unknown | 14 | 0.55 | 0.17 | 1.74 | 0.31 |
Abbreviations: HCT-CI- HCT comorbidity index;
Acute GVHD models used logistic regression.
NRM and relapse/progression
The adjusted cumulative incidence of NRM at 5-years was 28% (95%CI=23–33) and 47% (95%CI=35–59) in the Flu/2Gy TBI and Flu/4Gy TBI groups, respectively (p=0.005; Figure 1a, Table 2). On multivariable regression analysis, Flu/4Gy TBI was associated with a significantly higher risk of NRM (HR=1.79, 95%CI=1.11–2.89, p=0.02) (Table 3). In addition, HCT-CI >3, was independently predictive of higher risk of NRM (HR=2.25; Table 3).
Figure 1.
Adjusted transplantation outcomes of patients receiving Flu/4Gy TBI (interrupted lines) and Flu/2Gy TBI (solid line) regimens. 1a: Cumulative incidence of Relapse. 1b: Cumulative incidence of non-relapse mortality. 1c: Progression-free survival. 1d: Overall survival.
The adjusted cumulative incidence of relapse/progression at 5-years was 37% (95%CI=30–40) and 29% (95%CI=18–40) in the Flu/2Gy TBI and Flu/4Gy TBI groups, respectively (p=0.28; Figure 1b, Table 2). On multivariable regression analysis (Table 3), the two cohorts were not significantly different in terms of risk of relapse/progression (HR=0.78, 95%CI=0.47–1.29, p=0.33). Partial remission (HR=2.30) or resistant disease (HR=2.49) as remission status before HCT were associated with a significantly higher risk of disease relapse/progression, while matched unrelated donor HCT was independently associated with a lower risk of relapse/progression (HR=0.60; Table 3).
Progression-free Survival & Overall Survival
The 5-year adjusted PFS in the Flu/2Gy TBI and Flu/4Gy TBI groups was 37% (95%CI=31–42) and 24% (95%CI=14–34), respectively, p=0.03 (Figure 1c, Table 2). On multivariable regression analysis (Table 3), PFS between the two cohorts was not significantly different (HR=1.09, 95%CI=0.78–1.54, p=0.61). Partial remission (HR=1.72) or resistant disease (HR=1.99) as remission status before HCT were independently associated with a significantly worse PFS (Table 3).
The 5-year OS in the Flu/2Gy TBI and Flu/4Gy TBI cohorts was 51% (95%CI=46–57) and 31% (95%CI=20–41), respectively, p=0.001 (Figure 1d, Table 2). On multivariable regression analysis, Flu/4Gy TBI was associated with a significantly higher risk of mortality (HR=1.51, 95%CI=1.03–2.23, p=0.03) (Table 3). Other factors independently associated with a higher risk of mortality included; resistant disease (HR=1.69) as remission status before HCT and HCT-CI >3 (HR=1.73; Table 3).
Causes of Death
At last follow-up, 150 Flu/2Gy TBI cohort and 33 Flu/4Gy TBI cohort recipients had died (Table 4). Recurrent/progressive lymphoma was the primary cause of death in 55 (Flu/2Gy TBI patients (35.7%) and 10 Flu/4Gy TBI patients (30.3%). GVHD was the primary cause of death in 24 Flu/2Gy TBI cohort patients (15.6%) compared to 3 Flu/4Gy TBI cohort (9.1%) subjects. Infectious complications accounted for 6.5% (n=10) of deaths in Flu/2Gy TBI group and 3% (n=1) in the Flu/4GY TBI group.
Table 4.
Causes of death.
| Flu/2Gy TBI | Flu/4Gy TBI | |
|---|---|---|
| Total number of deaths (%) | 150 | 33 |
| Primary disease | 55 (35.7) | 10 (30.3) |
| Infection | 10 (6.5) | 1 (3) |
| Acute respiratory distress syndrome/idiopathic pneumonia syndrome | 5 (3.2) | 1 (3) |
| Graft-versus-host disease | 24 (15.6) | 3 (9.1) |
| Organ Failure | 20 (13) | 5 (15.2) |
| Second malignancy | 2 (1.3) | 0 |
| Other1 | 30 (19.5) | 10 (30.3) |
| Not reported | 8 (5.2) | 3 (9.1) |
Other:
Flu/2GY TBI: 24 other HCT related cause, NOS; 1 encephalopathy and stroke; 1 hypoxic respiratory failure; 1 stroke; 1 pulmonary embolism; 1 toxic encephalopathy; 1 acute left basal ganglia stroke.
Flu/4GY TBI: 7 other HCT related cause, NOS; 1 septic shock; 1 suicide; 1 possible MI.
DISCUSSION
Prospective, randomized studies assessing the relative importance of TBI dose-intensity within the context of RIC/NMA alloHCT conditioning regimens in NHL patients have not been performed. Hence, utilizing the observational database of the CIBMTR we compared 2Gy vs. 4Gy TBI conditioning in NHL patients and make several important observations. First, higher 4Gy TBI dose in Flu/TBI regimen was not associated with a higher risk of acute or chronic GVHD. Second, lower 2Gy TBI dose was not associated with a higher risk of graft failure. Third, Flu/4Gy TBI did not reduce the risk of disease relapse/progression or therapy failure. Finally, higher TBI dose intensity was associated with a higher risk of NRM and overall mortality.
Limited data are available comparing 2Gy TBI conditioning with 4Gy TBI in patients with myeloid malignancies16. In a single center, retrospective analysis, Sobecks et al.17 compared outcomes of Flu/2Gy TBI (n=42) with Flu/4Gy TBI (n=40) in a heterogenous group of patients with hematological malignancies (predominantly myeloid disorders). The authors found no significant difference between the cohorts in terms of hematopoietic recovery, graft failure, GVHD and survival outcomes. While limited by sample size, interestingly in this analysis17 the median survival of lymphoma patients receiving Flu/2Gy TBI (n=12) was 50months compared to 15months in subjects undergoing Flu/4Gy TBI (n=9) conditioning.
Increased doses of TBI in conditioning regimens have been associated with a higher risk of tissue injury and subsequently higher risk of GVHD. Prior CIBMTR data7 comparing NMA alloHCT outcomes among lymphoma patients undergoing 2Gy TBI-based conditioning vs. non-TBI RIC approaches showed a higher risk of GVHD with TBI-containing approaches. In the current analysis, we found no increase in the risk of either acute or chronic GVHD with increasing TBI dose from 2Gy to 4Gy (Table 2), consistent with the data reported by Cleveland Clinic group17. In addition, unlike the recent data for non-malignant blood disorders, where 4Gy TBI containing conditioning approach in patients undergoing haploidentical transplantation was shown to substantially reduce the risk of graft failure8, our analysis did not yield a similar benefits, albeit our patient population carries a vastly different clinical profile (NHL patients receiving HLA matched grafts).
In our current study 2Gy TBI dose in NHL patients was associated with superior OS due to the significantly lower NRM seen in this group. This is noteworthy considering the fact that the Flu/2Gy TBI cohort included more patients with a higher comorbidity burden, and worse performance score. Cause of death data (Table 4) suggest that this higher NRM does not appear to be related to a higher incidence of second malignancies or GVHD related mortality in the 4Gy TBI cohort, but due to other causes of death (that potentially can be a result of late effects of higher TBI dose). The nature of data reported to the registry precludes a more granular assessment of causes of death across two cohorts.
While the optimal RIC regimen for NHL patients is unknown, a recent CIBMTR report comparing various RIC regimens commonly utilized for NHL demonstrated a higher NRM and inferior OS with RIC platforms with relatively higher intensity (fludarabine/melphalan 140mg/m2), compared to lower intensity RIC options (e.g. fludarabine/busulfan 6.4mg/kg iv, fludarabine/cyclophosphamide-based regimens)18. These data collectively along with our current analysis suggest that more intense conditioning options are unlikely to improve alloHCT outcomes in NHL patients.
In this registry-based analysis, some important limitations should be considered. Any observational study comparing different interventions is subject to preferences of the treating centers/physicians owing to the complex criteria for selection that underlie the choice of a given intervention. Our analysis cannot adjust for unknown variables that could have prompted a given center or a physician to pick one conditioning option over the other. Since CIBMTR does not capture donor cell chimerism at TED level data, in the current analysis we cannot assess any possible differences in donor cell chimerism kinetics between the two cohorts. We caution extrapolating these observations to patients with myeloid malignancies (where benefit conditioning dose intensity is well established) to other TBI-based RIC platforms in NHL. We did not include patients receiving Flu/cyclophosphamide/TBI based conditioning in the current analysis since 4Gy TBI dose was rarely reported with that regimen in CIBMTR registry. Our study included a variety of NHL subtypes (that have varying degrees of relapse risk), but we found no interaction between the main effect (the two conditioning regimens) and lymphoma subtype for any of the outcomes analyzed (i.e. the impact of conditioning regimen did not vary according to NHL histology), justifying inclusion of different NHL subtypes in this analysis. Small sample size of 4Gy TBI group is another limitation to acknowledge.
In conclusion, our analysis provides compelling evidence of the higher toxicity and lack of a survival advantage with the use of a higher 4Gy TBI dose in NHL patients undergoing Flu/TBI-based conditioning as part of their RIC. 2Gy TBI should be considered the optimal dose in this setting.
Highlights.
Augmentation of TBI dose from 2Gy to 4Gy for NHL patients undergoing RIC alloHCT is associated with higher NRM and inferior OS
Higher dose of TBI does not result in improved disease control.
ACKNOWLEDGEMENTS
CIBMTR Support List
The CIBMTR is supported by Public Health Service Grant/Cooperative Agreement U24-CA076518 from the National Cancer Institute (NCI), the National Heart, Lung and Blood Institute (NHLBI) and the National Institute of Allergy and Infectious Diseases (NIAID); a Grant/Cooperative Agreement 5U10HL069294 from NHLBI and NCI; a contract HHSH250201200016C with Health Resources and Services Administration (HRSA/DHHS); two Grants N00014-13-1-0039 and N00014-14-1-0028 from the Office of Naval Research; and grants from *Actinium Pharmaceuticals; Allos Therapeutics, Inc.; *Amgen, Inc.; Anonymous donation to the Medical College of Wisconsin; Ariad; Be the Match Foundation; *Blue Cross and Blue Shield Association; *Celgene Corporation; Chimerix, Inc.; Fred Hutchinson Cancer Research Center; Fresenius-Biotech North America, Inc.; *Gamida Cell Teva Joint Venture Ltd.; Genentech, Inc.;*Gentium SpA; Genzyme Corporation; GlaxoSmithKline; Health Research, Inc. Roswell Park Cancer Institute; HistoGenetics, Inc.; Incyte Corporation; Jeff Gordon Children’s Foundation; Kiadis Pharma; The Leukemia & Lymphoma Society; Medac GmbH; The Medical College of Wisconsin; Merck & Co, Inc.; Millennium: The Takeda Oncology Co.; *Milliman USA, Inc.; *Miltenyi Biotec, Inc.; National Marrow Donor Program; Onyx Pharmaceuticals; Optum Healthcare Solutions, Inc.; Osiris Therapeutics, Inc.; Otsuka America Pharmaceutical, Inc.; Perkin Elmer, Inc.; *Remedy Informatics; *Sanofi US; Seattle Genetics; Sigma-Tau Pharmaceuticals; Soligenix, Inc.; St. Baldrick’s Foundation; StemCyte, A Global Cord Blood Therapeutics Co.; Stemsoft Software, Inc.; Swedish Orphan Biovitrum; *Tarix Pharmaceuticals; *TerumoBCT; *Teva Neuroscience, Inc.; *THERAKOS, Inc.; University of Minnesota; University of Utah; and *Wellpoint, Inc. The views expressed in this article do not reflect the official policy or position of the National Institute of Health, the Department of the Navy, the Department of Defense, Health Resources and Services Administration (HRSA) or any other agency of the U.S. Government.
*Corporate Members
Footnotes
Publisher's Disclaimer: This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.
Conflict of interest or Competing interests: MH reports Research Support/Funding: Takeda Pharmaceutical Company; Spectrum Pharmaceuticals. Consultancy: Incyte Corporation; ADC Therapeutics; Pharmacyclics, Omeros, Tenebio. Speaker’s Bureau: AstraZeneca; Sanofi Genzyme. M.A.K-D reports consultancy for Pharmacyclics and Daiichi Sankyo. FTA reports consultancy for Celgene, Kite, Genentech, Gilead, Pharmacyclics, Janssen, Abbvie, Astrazeneca, Blueprint Medicine, Sunesis, Dava Oncology, Karyopharm
REFERENCES
- 1.D’Souza A, Lee S, Zhu X, Pasquini M. Current Use and Trends in Hematopoietic Cell Transplantation in the United States. Biol Blood Marrow Transplant. 2017;23:1417–1421. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 2.NCI. SEER Cancer Stat Facts: Non-Hodgkin Lymphoma. . 2019.
- 3.D’Souza AZX. Current Uses and Outcomes of Hematopoietic Cell Transplantation (HCT): CIBMTR Summary Slides, 2016. Available at http://www.cibmtr.org.
- 4.Dreger P, Sureda A, Ahn KW, et al. PTCy-based haploidentical vs matched related or unrelated donor reduced-intensity conditioning transplant for DLBCL. Blood Adv. 2019;3:360–369. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 5.Epperla N, Ahn KW, Litovich C, et al. Allogeneic hematopoietic cell transplantation provides effective salvage despite refractory disease or failed prior autologous transplant in angioimmunoblastic T-cell lymphoma: a CIBMTR analysis. J Hematol Oncol. 2019;12:6. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 6.Avivi I, Canals C, Vernant JP, et al. Matched unrelated donor allogeneic transplantation provides comparable long-term outcome to HLA-identical sibling transplantation in relapsed diffuse large B-cell lymphoma. Bone Marrow Transplant. 2014;49:671–678. [DOI] [PubMed] [Google Scholar]
- 7.Hong S, Le-Rademacher J, Artz A, McCarthy PL, Logan BR, Pasquini MC. Comparison of non-myeloablative conditioning regimens for lymphoproliferative disorders. Bone Marrow Transplant. 2015;50:367–374. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 8.Bolanos-Meade J, Cooke KR, Gamper CJ, et al. Effect of increased dose of total body irradiation on graft failure associated with HLA-haploidentical transplantation in patients with severe haemoglobinopathies: a prospective clinical trial. Lancet Haematol. 2019;6:e183–e193. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 9.Cheson BD, Pfistner B, Juweid ME, et al. Revised response criteria for malignant lymphoma. J Clin Oncol. 2007;25:579–586. [DOI] [PubMed] [Google Scholar]
- 10.Przepiorka D, Weisdorf D, Martin P, et al. 1994 Consensus Conference on Acute GVHD Grading. Bone Marrow Transplant. 1995;15:825–828. [PubMed] [Google Scholar]
- 11.Shulman HM, Sullivan KM, Weiden PL, et al. Chronic graft-versus-host syndrome in man. A long-term clinicopathologic study of 20 Seattle patients. Am J Med. 1980;69:204–217. [DOI] [PubMed] [Google Scholar]
- 12.Olsson R, Remberger M, Schaffer M, et al. Graft failure in the modern era of allogeneic hematopoietic SCT. Bone Marrow Transplant. 2013;48:537–543. [DOI] [PubMed] [Google Scholar]
- 13.Zhang X, Loberiza FR, Klein JP, Zhang MJ. A SAS macro for estimation of direct adjusted survival curves based on a stratified Cox regression model. Comput Methods Programs Biomed. 2007;88:95–101. [DOI] [PubMed] [Google Scholar]
- 14.Zhang X, Zhang MJ. SAS macros for estimation of direct adjusted cumulative incidence curves under proportional subdistribution hazards models. Comput Methods Programs Biomed. 2011;101:87–93. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 15.Commenges D, Andersen PK. Score test of homogeneity for survival data. Lifetime Data Anal. 1995;1:145–156; discussion 157–149. [DOI] [PubMed] [Google Scholar]
- 16.Hallemeier CL, Girgis MD, Blum WG, et al. Long-term remissions in patients with myelodysplastic syndrome and secondary acute myelogenous leukemia undergoing allogeneic transplantation following a reduced intensity conditioning regimen of 550 cGy total body irradiation and cyclophosphamide. Biol Blood Marrow Transplant. 2006;12:749–757. [DOI] [PubMed] [Google Scholar]
- 17.Sobecks RM, Dean R, Rybicki LA, et al. 400 cGy TBI with fludarabine for reduced-intensity conditioning allogeneic hematopoietic stem cell transplantation. Bone Marrow Transplant. 2008;42:715–722. [DOI] [PubMed] [Google Scholar]
- 18.Ghosh N, Ahmed S, Litovich C, et al. Comparison of Reduced-Intensity Conditioning (RIC) Regimens for Allogeneic Hematopoietic Cell Transplantation (alloHCT) in Non-Hodgkin Lymphomas (NHL)-a Center for International Blood & Marrow Transplant Research (CIBMTR) Analysis. American Society of Hematology Annual meeting. 2019;Abs 319. [Google Scholar]