Infused Autograft Lymphocyte to Monocyte Ratio and Survival in Diffuse Large B Cell Lymphoma

Infused autograft absolute lymphocyte count is a prognostic factor for survival after autologous peripheral hematopoietic stem cell transplantation (APHSCT) for diffuse large B cell lymphoma (DLBCL). CD14⁺ HLA-DR^low/neg immunosuppressive monocytes affect tumor growth by suppressing host antitumor immunity. Thus, we set out to investigate if the infused autograft lymphocyte to monocyte ratio (A-LMR), as a biomarker of host immunity (ie, lymphocytes) and immunosuppression (ie, monocytes), affects survival after APHSCT. From 1994 to 2012, 379 DLBCL patients who underwent APHSCT were studied. The 379 patients were randomly divided into a training set (n = 253) and a validation set (n = 126). Receiver operating characteristic and area under the curve identified an A-LMR ≥1 as the best cut-off value, which was validated by the k-fold cross-validation in the training set. Multivariate analysis showed A-LMR to be an independent prognostic factor for survival in the training set. Patients with an A-LMR ≥ 1.0 experienced superior overall survival (OS) compared with patients with an A-LMR <1.0 (median OS: 167.2 versus 17.6 months; 5-year OS: 73% [95% confidence interval (CI), 63% to 80%] versus 30% [95% CI, 2% to 38%], P < .0001, respectively) in the training set. In the validation set, an A-LMR ≥ 1 showed a median OS of 181.2 months versus 19.5 months for an A-LMR <1, and 5-year OS rates of 67% (95% CI, 52% to 79%) versus 35% (95% CI, 25% to 47%), P < .0001, respectively. The A-LMR provides a platform to engineer immunocompetent autograft to improve clinical outcomes in DLBCL patients undergoing APHSCT.     

Higher Infused Lymphocyte Dose Predicts Higher Lymphocyte Recovery,Which in Turn,Predicts Superior Overall Survival following Autologous Hematopoietic Stem Cell Transplantation for Multiple Myeloma

Autologous stem cell transplantation (ASCT) is the standard of care for patients with multiple myeloma (MM) younger than 70 years. However, despite this aggressive therapy most patients will still die of progressive disease. Recent reports have suggested that lymphocyte recovery is an important predictor of relapse or progressive disease in a number of hematologic malignancies including MM. We have conducted retrospective analysis of factors that could predict overall (OS) and progression free survival (PFS) in patients with MM who had ASCT. One hundred nineteen patients with multiple myeloma underwent ASCT. The median OS and PFS were 64 and 32 months, respectively. Univariate and multivariate analysis using Cox proportional hazards regression model showed that absolute lymphocyte count on day 30 following ASCT (ALC-30), international staging system (ISS) stage at diagnosis, and age at diagnosis significantly influenced OS and PFS following ASCT. OS (96 versus 48 months, P = .04) and PFS (43 versus 29 months, P = .03) following ASCT were higher in patients with ALC-30 ≥1.0 × 10⁹/L compared to patients ALC-30 <1.0 × 10⁹/L. Higher ALC-60, ALC-100, ALC-180, and ALC-365 did not predict superior OS and PFS. Patients with early-stage disease had significantly higher OS (ISS stages I, II, and III: 96, 53, and 29 months, respectively; P = .0023) and PFS (ISS stages I, II, and III: 55.5, 31, and 12 months, respectively; P = .027) compared to patients with advanced-stage disease at diagnosis. On univariate analysis, the type of initial chemotherapy (melphalan, VAD, PCAB), lymphocyte count on day of leukapheresis, and the lymphocyte dose infused (LY-DO) significantly influenced lymphocyte recovery following ASCT. Patients who received higher lymphocyte dose (LY-DO) ≥0.2 × 10⁹/kg had higher median ALC-15 (0.25 versus 0.19 × 10⁹/L; P = .3), ALC-30 (1.20 versus 0.99 × 10⁹/L; P = .08), ALC-60 (1.90 versus 1.01 × 10⁹/L; P = .013), ALC-100 (1.58 versus 1.03 × 10⁹/L; P = .016), and ALC-180 (1.33 versus 1.01 × 10⁹/L; P = .1), compared to patients who received LY-DO <0.2 × 10⁹/kg. In summary, our data suggest that infusing large numbers of lymphocytes improves lymphocyte recovery post-ASCT, and that higher ALC-30 is associated with better PFS and OS. These data suggest that a threshold number of CD34⁺ cells should not be the only parameter considered for an adequate PBSC collection—perhaps a certain number of lymphocytes should be aimed for as well.     

Outcome of Allogeneic Hematopoietic Stem Cell Transplantation in Adult Patients with Philadelphia Chromosome-Positive Acute Lymphoblastic Leukemia in the Era of Tyrosine Kinase Inhibitors: A Registry-Based Study of the Italian Blood and Marrow Transplantation Society (GITMO)

We performed a nationwide registry-based analysis to describe the clinical outcome of adult patients with Philadelphia chromosome-positive acute lymphoblastic leukemia (Ph⁺ ALL) who underwent an allogeneic hematopoietic stem cell transplantation (HSCT) after a tyrosine kinase inhibitor (TKI)-based treatmentA total of 441 patients were included in the study. The median age at HSCT was 44 years (range, 18 to 70 years). All 441 patients (100%) received TKI before HSCT (performed between 2005 and 2016). Of these 441 patients, 404 (92%) were in cytologic complete remission (CR), whereas the remaining 37 (8%) had active disease at the time of HSCT. Molecular minimal residual disease (MRD) was negative in 147 patients (36%) at the time of HSCT. The donor was unrelated in 46% of patients. The most prevalent source of stem cells was peripheral blood (70%). The conditioning regimen was myeloablative in 82% of cases (total body irradiation-based in 50%) and included antithymocyte globulin in 51% of patients. With a median follow-up after HSCT of 39.4 months (range, 1 to 145 months), the probability of overall survival (OS) at 1, 2, and 5 years was 69.6%, 61.1% and 50.3%, respectively, with a median OS of 62 months. Progression-free survival (PFS) at 1, 2, and 5 years was 60.2%, 52.1% and 43.7%, respectively. OS and PFS were significantly better in patients who were in CR and MRD-negative at the time of HSCT compared with patients who were in CR but MRD-positive (50% OS not reached versus 36 months; P = .015; 50% PFS not reached versus 26 months, P = .003). The subgroup of MRD-negative patients both at HSCT and at 3 months after HSCT had a better outcome (5-year OS, 70%). Conversely, the 37 patients who underwent a HSCT with active Ph⁺ ALL had a median OS of 7 months and a median PFS of 5 months. The 5-year cumulative incidence of relapse was significantly lower in MRD-negative patients (19.5% versus 35.4%; P = .001). Nonrelapse mortality (NRM) after 1, 2, and 5 years was 19.1% (95% confidence interval [CI], 15.5% to 22.9%), 20.7% (95% CI, 17% to 24.7%), and 24.1% (95% CI, 20% to 28.5%), respectively. NRM was significantly lower with a modified European Society for Blood and Marrow Transplantation (mEBMT) risk score of 0 to 2 compared with ≥3 (15% versus 25%; P = .016). The median OS for Ph⁺ ALL patients who underwent a TKI-based treatment followed by an allogeneic HSCT, in recent years at the GITMO centers, was 62 months. Evaluation of the mEBMT risk score can be useful to predict NRM. Our data confirm that HSCT is a potentially curative treatment for Ph⁺ ALL with an excellent outcome for the subgroup of MRD-negative patients both at HSCT and at 3 months after HSCT (5-year OS, 70%).     

Long-Term Survival after High-Dose Chemotherapy Followed by Peripheral Stem Cell Rescue for High-Risk,Locally Advanced/Inflammatory,and Metastatic Breast Cancer

Patients with high-risk locally advanced/inflammatory and oligometastatic (≤3 sites) breast cancer frequently relapse or experience early progression. High-dose chemotherapy combined with peripheral stem cell rescue may prolong progression-free survival/relapse-free survival (PFS/RFS) and overall survival (OS). In this study, patients initiated high-dose chemotherapy with STAMP-V (carboplatin, thiotepa, and cyclophosphamide), ACT (doxorubicin, paclitaxel, and cyclophosphamide), or tandem melphalan and STAMP-V. Eighty-six patients were diagnosed with locally advanced/inflammatory (17 inflammatory) breast cancer, and 12 were diagnosed with oligometastatic breast cancer. Median follow-up was 84 months (range, 6-136 months) for patients with locally advanced cancer and 40 months (range, 24-62 months) for those with metastatic cancer. In the patients with locally advanced cancer, 5-year RFS and OS were 53% (95% CI, 41%-63%) and 71% (95% CI, 60%-80%), respectively, hormone receptors were positive in 74%, and HER2 overexpression was seen in 23%. In multivariate analysis, hormone receptor-positive disease and lower stage were associated with better 5-year RFS (60% for ER [estrogen receptor]/PR [progesterone receptor]-positive versus 30% for ER/PR-negative; P < .01) and OS (83% for ER/PR-positive versus 38% for ER/PR-negative; P?相似文献   

Impact of Cytomegalovirus Reactivation and Natural Killer Reconstitution on Outcomes after Allogeneic Hematopoietic Stem Cell Transplantation: A Single-Center Analysis

Cytomegalovirus (CMV) reactivation and natural killer (NK) cell reconstitution are well-recognized immunologic events occurring after allogeneic stem cell transplantation (allo-SCT). We aimed to study the outcome of CMV reactivation (CMVR) and NK cell reconstitution in patients with hematologic malignancies after allo-SCT. We retrospectively studied 246 adult patients (152 men, 94 women; median age, 51 years [range, 18 to 69]) who underwent allo-SCT for hematologic malignancies at the Kanagawa Cancer Center. CMVR was defined as initiation of preemptive CMV therapy after pp65 antigenemia surveillance. All patients’ lymphocyte subsets were monitored by flow cytometry at 180, 365, and 730 days post-transplant. The median follow-up period was 3.2 years (range, .8 to 9.6 years). CMVR occurred in 141 patients (57%) at a median of 45 days (range, 15 to 93). In patients without CMVR (CMVR–) versus those with CMVR (CMVR+), 5-year overall survival (OS), nonrelapse mortality (NRM), and cumulative incidence of relapse (CIR) were 79% versus 55% (P < .001), 3% versus 16% (P = .012), and 28% versus 38% (P = .09), respectively. CD8⁺ T cell and CD3^–CD56⁺ NK cell subset were higher in CMVR+ patients at day 100 post-transplant. Multivariate analysis showed that adverse factors for OS were represented by no remission, CMVR, and lower CD16⁺CD57^–NK cell counts. Overall, a higher NK cell subset significantly contributed to a lower CIR. Among subgroups of CMVR+ patients, CD16⁺CD57^–NK cells represented a favorable factor for OS, NRM, and CIR. CMVR was an adverse event after allo-SCT. NK cell reconstitution may contribute to improved outcomes, especially in CMVR+ subgroups.     

Long-Term Follow-Up of a Donor versus No-Donor Comparison in Patients with Multiple Myeloma in First Relapse after Failing Autologous Transplantation

We report the long-term clinical outcomes of a retrospective multicenter study that enrolled 169 patients with multiple myeloma (MM) in first relapse after failing autologous stem cell transplantation (SCT). After HLA typing at relapse, 79 patients with a suitable donor, 72 (91%) of whom eventually underwent salvage allogeneic SCT (allo-SCT), were compared with 90 patients without a donor who were treated with multiple lines of salvage treatment with bortezomib and/or immunomodulatory agents. At a median follow-up of 30 months (range, 2-180 months) for all patients and 110 months (range, 38-180 months) for surviving patients, 7-year progression-free survival (PFS) was 18% in the donor group and 0% in the no-donor group (hazard ratio [HR], 2.495; 95% confidence interval [CI], 1.770-3.517; P?<?.0001). Seven-year overall survival (OS) was 31% in the donor group and 9% in the no-donor group (HR, 1.835; 95% CI, 1.306-2.577; P?<?.0001). By multivariate analysis, chemosensitivity to salvage treatments and presence of a suitable donor were significantly associated with better PFS and OS. The long-term follow-up of this study confirms the significant PFS benefit and provides new evidence of an OS advantage for patients with MM who have a suitable donor and undergo allo-SCT. Allo-SCT should be considered as a treatment option in young relapsed patients with high-risk disease features after first-line treatment.     

Presalvage International Staging System Stage and Other Important Outcome Associations in CD34+-Selected Allogeneic Hematopoietic Stem Cell Transplantation for Multiple Myeloma

Despite ongoing therapeutic advances, multiple myeloma (MM) remains largely incurable, and outcomes in patients who develop resistance to immunomodulatory drugs or proteasome inhibitors remain grim. Allogeneic hematopoietic cell transplantation (alloHCT) is an alternative option that may offer potential for cure. Although rates of transplantation-related morbidity and mortality have decreased in recent years, weighing this approach's potential benefits against nontransplantation therapies demands a thoroughly informed pre-alloHCT assessment. Here we assess the impact of pre-alloHCT variables on important clinical outcomes in a large cohort of relapsed refractory MM (RRMM) CD34⁺-selected alloHCT recipients. We included all patients with MM who underwent CD34⁺-selected alloHCT at our center between June 2010 and December 2015. Patients were conditioned with busulfan (0.8 mg/kg × 10), melphalan (70 mg/m² × 2), and fludarabine (25 mg/m² × 5), followed by infusion of a CD34⁺-selected peripheral blood stem cell graft, without post-alloHCT graft-versus-host disease (GVHD) prophylaxis. The 73-patient cohort had a median age of 55 years (range, 37 to 66 years). Overall survival (OS) and progression-free survival (PFS) rates were 70% and 53%, respectively, at 1 year (95% confidence interval [CI], 58% to 79% and 41% to 64%) and 50% and 30%, respectively, at 3 years (95% CI, 38% to 62% and 19% to 41%). The cumulative incidence of relapse was 25% at 1 year (95% CI, 15% to 35%) and 47% at 3 years (95% CI, 35% to 58%). Nonrelapse mortality at 1 year was 22% (95% CI, 13% to 32%). The cumulative incidence of grade II-IV acute GVHD (aGVHD) was 7% at 100 days (95% CI, 3% to 14%), and that of any chronic GVHD (cGVHD) was 8% at 1 year (95% CI, 3% to 16%). International Staging System (ISS) stage II-III assessed before salvage therapy was associated with poorer 3-year OS (30% versus 54%; P = .037) and 3-year PFS (9% versus 33%; P = .013), and increased 3-year relapse incidence (72% versus 39%; P = .004). Older age and GVHD before 6 months (aGVHD grade II-IV or cGVHD of any grade) were also associated with poorer OS, and a greater number of pre-alloHCT lines of therapy was also associated with increased relapse incidence. Our findings reinforce that CD34⁺-selected alloHCT can achieve prolonged disease control and long-term survival in high- risk, heavily treated refractory MM populations. We also identified numerous pre-alloHCT variables associated with OS, PFS, and relapse. Amongst these, presalvage ISS stage II-III was consistently associated with poorer survival and relapse outcomes. Given the lack of established alternate therapies for patients with RRMM, we advocate the identification of adverse pre-alloHCT variables to inform alloHCT decision making rather than to exclude patient cohorts from this potentially curative treatment option.     

Megadose CD34+ Cell Grafts Improve Recovery of T Cell Engraftment but not B Cell Immunity in Patients with Severe Combined Immunodeficiency Disease Undergoing Haplocompatible Nonmyeloablative Transplantation

To determine whether T cell engraftment and recovery of B cell immunity could be improved, we prospectively treated 15 children with severe combined immunodeficiency disease (SCID) with megadoses of haplocompatible CD34⁺ cells and a fixed number of CD3⁺ cells without previous myeloablative chemotherapy. Evidence of T cell engraftment was seen in 73% of patients (95% confidence interval [CI] = 48%-90%). Engraftment was more likely in patients with X-linked SCID and in those with evidence of maternal engraftment at the time of diagnosis. In patients with T cell engraftment, the median time to development of a CD4 count > 200 cells/mm³ and a phytohemagglutinin response > 50% of control was 1.2 and 4.9 months, respectively. Clearance of preexisting infections occurred after a median of 2.8 months. B cell function developed in 33% of engrafted patients (95% CI = 14%-61%). The 1-year event-free survival (EFS) rate was 60% (95% CI = 36%-80%), and the overall survival (OS) rate was 87% (95% CI = 61%-98%), with a median follow-up of 39 months. The use of megadoses of CD34⁺ cells with a fixed number of CD3⁺ cells in nonmyeloablative hematopoietic stem cell transplantation (HSCT) in patients with SCID is associated with excellent engraftment, T cell recovery, and OS; however, B cell function does not recover in most patients.     

Autologous Hematopoietic Stem Cell Transplantation for Male Germ Cell Tumors: Improved Outcomes Over 3 Decades

The curative potential of autologous hematopoietic cell transplantation (autoHCT) for male germ cell tumors (GCTs) is well established. The optimal timing and number (single transplant [ST] versus tandem transplants [TT] versus triple transplants) of autoHCT are controversial, with wide practice variations. We examined survival trends among 2395 recipients of autoHCT for male GCTs between 1990 and 2015 reported to the Center for International Blood and Marrow Transplant Research. Trends and outcomes were analyzed by year of transplantation for intervals 1990 to 1994 (N = 288), 1995 to 1999 (N = 351), 2000 to 2004 (N = 376), 2005 to 2009 (N = 509), and 2010 to 2015 (N = 871). Multivariate analysis was restricted to the subset from 2000 to 2015 with research-level data (n = 267). The median duration of follow-up was 51 months. The median age at autoHCT was 31 years; 633 patients (26%) had primary extragonadal GCT, and 1167 (49%) underwent TT. The 3-year progression-free (PFS) and overall survival (OS) improved from 24% (95% confidence interval [CI], 18% to 31%) and 35% (95% CI, 29% to 40%), respectively, in 1990 to 1994 to 47% (95% CI, 43% to 50%) and 54% (95% CI, 50% to 57%), respectively, in 2010 to 2015 (P < .0001). TT recipients were more likely than ST recipients to undergo autoHCT as first salvage treatment. The proportion of TTs increased from 38% of all autoHCTs in 2000 to 2004 to 77% in 2010 to 2015. Nonseminoma histology, residual disease at autoHCT, >1 line of pretransplantation chemotherapy, and ST versus TT were associated with inferior PFS and OS. Post-transplantation survival has improved significantly over time for relapsed/refractory male GCT and is associated with the increased use of TTs (compared with STs) and performance of autoHCT earlier in the disease course.     

Efficacy and safety of hepatic arterial infusion chemotherapy for advanced hepatocellular carcinoma as first-line therapy

Background/Aims

Hepatic arterial infusion chemotherapy (HAIC) with 5-fluorouracil and cisplatin for intractable advanced hepatocellular carcinoma (HCC) may have survival benefits. We aimed to determine the efficacy and safety of HAIC for advanced HCC as first-line therapy.

Methods

A total of 54 patients who received only HAIC with 5-fluorouracil (750 mg/m² on days 1-4) and cisplatin (25 mg/m² on days 1-4) for advanced HCC from Jan. 2009 to Dec. 2011 were selected. According to Child-Pugh class, the overall survival (OS), progression-free survival (PFS), and adverse events after HAIC were investigated retrospectively.

Results

Median OS and PFS between the Child-Pugh A group (n=24) and the Child-Pugh B/C group (n=30) were 8.7 (95% confidence interval [CI]: 4.7-12.7) vs. 3.7 months (95% CI: 2.0-5.3), and 7.1 (95% CI: 3.8-10.4) vs. 3.6 months (95% CI: 2.0-5.2), respectively. Although median OS and PFS were not statistically significant between the two groups (P=0.079, P=0.196), the Child-Pugh class B/C tended to influence poor OS. Serious adverse events ≥ grade 3 occurred frequently in both groups (83.3 vs. 96.7%, P=0.159). Responders (22.2%, complete or partial response) significantly differed in median OS, compared to non-responders (13.1 vs. 4.4 months, P=0.019). Achievement of complete or partial response was an independent prognostic factor of OS (hazard ratio: 0.4, 95% CI: 0.2-0.8, P=0.011).

Conclusions

Achievement of response after HAIC provide a survival benefit in patients with advanced HCC, but HAIC should be administered cautiously in patients with Child-Pugh class B/C, because of a relatively low survival and high incidence of serious adverse events.     

Outcomes of Haploidentical Transplantation in Patients with Relapsed Multiple Myeloma: An EBMT/CIBMTR Report

Allogeneic hematopoietic cell transplantation (allo-HCT) using siblings and matched donors has the potential for long-term disease control in a subset of high-risk patients with multiple myeloma (MM); however, the data on using haploidentical donors in this disease are limited. We conducted a retrospective analysis to examine the outcomes of patients with MM who underwent haploidentical allo-HCT within European Society for Blood and Marrow Transplantation/Center for International Blood and Marrow Transplant Research centers. A total of 96 patients underwent haploidentical allo-HCT between 2008 and 2016. With a median follow-up of 24.0 months (range, 13.2 to 24.9 months), 97% (95% confidence interval [CI], 93% to 100%) of patients had neutrophil engraftment by day 28, and 75% (95% CI, 66% to 84%) achieved platelet recovery by day 60. Two-year progression-free survival (PFS) was 17% (95% CI, 8% to 26%), and overall survival (OS) was 48% (95% CI, 36% to 59%). At 2 years, the cumulative risk of relapse/progression was 56% (95% CI, 45% to 67%), and 1-year nonrelapse mortality (NRM) was 21% (95% CI, 13% to 29%). The incidences of acute graft-versus-host-disease (GVHD) grades II-IV by 100 days and chronic GVHD at 2 years were 39% (95% CI, 28% to 49%) and 46% (95% CI, 34% to 59%), respectively. On univariate analysis, use of post-transplantation cyclophosphamide (PT-Cy) (54% [95% CI, 41% to 68%] versus 25% [95% CI, 1% to 48%]; P =.009) and use of bone marrow as source of stem cells (72% [95% CI, 55% to 89%] versus 31% [95% CI, 17% to 46%]; P?=?.001) were associated with improved OS at 2 years. Disease status, patient sex, intensity of conditioning regimen, recipient/donor sex mismatch, and cytomegalovirus serostatus had no impact on OS, PFS, or NRM. Haploidentical transplantation is feasible for patients with multiply relapsed or high-risk MM, with an encouraging 2-year OS of 48% and an NRM of 21% at 1 year, supporting further investigation of haploidentical allo-HCT in suitable candidates with MM.     

Promising Progression-Free Survival for Patients Low and Intermediate Grade Lymphoid Malignancies after Nonmyeloablative Umbilical Cord Blood Transplantation

Nonmyeloablative hematopoietic cell transplantation (HCT) has been used to treat patients with advanced or high-risk lymphoid malignancies. We studied 65 patients (median age 46 years) receiving an umbilical cord blood (UCB) graft after a single conditioning regimen consisting of cyclophosphamide (50 mg/kg) on day −6, fludarabine (40 mg/m²) daily on days −6 to −2, as well as a single fraction of total-body irradiation (TBI) (200 cGy) along with cyclosporine mycophenolate mofetil immunosuppression. Median time to neutrophil and platelet recovery was 7.5 days (range: 0-32) and 46 days (range: 8-111), respectively. Cumulative incidences of grade II-IV, grade III-IV acute, and chronic graft-versus-host disease (aGVHD, cGVHD) were 57% (95% confidence interval [CI]: 43%-70%), 25% (95% CI: 14%-35%), and 19% (95% CI: 9%-29%), respectively. Transplant-related mortality at 3 years was 15% (95% CI: 5%-26%). Median follow-up was 23 months. The progression free-survival (PFS), current PFS and overall survival (OS) were 34% (95% CI: 21%-47%), 49% (95% CI: 36%-62%), and 55% (95% CI: 42%-70%) at 3 years. Based on our data, we conclude that a nonmyeloablative conditioning regimen followed by UCB transplantation is an effective treatment for patients with advanced lymphoid malignancies who lack a suitable sibling donor.     

Early Failure of Frontline Rituximab-Containing Chemo-immunotherapy in Diffuse Large B Cell Lymphoma Does Not Predict Futility of Autologous Hematopoietic Cell Transplantation

The poor prognosis for patients with diffuse large B cell lymphoma (DLBCL) who relapse within 1 year of initial diagnosis after first-line rituximab-based chemo-immunotherapy has created controversy about the role of autologous transplantation (HCT) in this setting. We compared autologous HCT outcomes for chemosensitive DLBCL patients between 2000 and 2011 in 2 cohorts based on time to relapse from diagnosis. The early rituximab failure (ERF) cohort consisted of patients with primary refractory disease or those with first relapse within 1 year of initial diagnosis. The ERF cohort was compared with those relapsing >1 year after initial diagnosis (late rituximab failure [LRF] cohort). ERF and LRF cohorts included 300 and 216 patients, respectively. Nonrelapse mortality (NRM), progression/relapse, progression-free survival (PFS), and overall survival (OS) of ERF versus LRF cohorts at 3 years were 9% (95% confidence interval [CI], 6% to 13%) versus 9% (95% CI, 5% to 13%), 47% (95% CI, 41% to 52%) versus 39% (95% CI, 33% to 46%), 44% (95% CI, 38% to 50%) versus 52% (95% CI, 45% to 59%), and 50% (95% CI, 44% to 56%) versus 67% (95% CI, 60% to 74%), respectively. On multivariate analysis, ERF was not associated with higher NRM (relative risk [RR], 1.31; P = .34). The ERF cohort had a higher risk of treatment failure (progression/relapse or death) (RR, 2.08; P < .001) and overall mortality (RR, 3.75; P < .001) within the first 9 months after autologous HCT. Beyond this period, PFS and OS were not significantly different between the ERF and LRF cohorts. Autologous HCT provides durable disease control to a sizeable subset of DLBCL despite ERF (3-year PFS, 44%) and remains the standard-of-care in chemosensitive DLBCL regardless of the timing of disease relapse.     

T Cell-Replete Haploidentical Transplantation with Post-Transplantation Cyclophosphamide for Hodgkin Lymphoma Relapsed after Autologous Transplantation: Reduced Incidence of Relapse and of Chronic Graft-versus-Host Disease Compared with HLA-Identical Related Donors

Allogeneic hematopoietic stem cell transplantation (SCT) represents a potential curative strategy for patients with Hodgkin lymphoma (HL) relapsing after autologous SCT (ASCT), but the incidence of disease relapse is still high. We performed a retrospective study on 64 patients with HL relapsing after ASCT to compare outcomes after HLA-identical SCT (HLAid-SCT; n?=?34) and haploidentical SCT with post-transplantation cyclophosphamide (PT-Cy) (Haplo-SCT; n?=?30). All patients engrafted, with a significantly shorter median time for neutrophil and platelet engraftment after HLAid compared with Haplo-SCT (14 days versus 19 days and 11 days versus 23 days, respectively; P?<?.005). With a median follow-up of 47 months, 3-year overall survival (OS), 3 -year progression-free survival (PFS), and 1-year nonrelapse mortality (NRM) were 53%, 44% and 17%, respectively. Recipients of Haplo-SCT were less likely to experience disease relapse (3-year cumulative incidence of relapse, 13% versus 62%; P?=?.0001) and chronic graft- versus-host disease (GVHD; 3% versus 32%; P?=?.003), resulting in improved PFS (60% versus 29%; P?=?.04) and GVHD-free/relapse-free survival (47% versus 17%; P?=?.06). The 3-year OS did not differ between the 2 groups (56% versus 54%; P?not significant), and NRM was higher after Haplo-SCT, but the difference did not reach statistical significance (26% versus 9%; P?=?.09). On multivariate Cox regression analysis, receipt of Haplo-SCT (hazard ratio [HR], .17; P?=?.02) and achieving optimal disease control (complete remission before SCT: HR, .6; P?<?.0001) were the only independent variables associated with a reduced risk of disease relapse. Haplo-SCT is a valid option for patients with HL relapsing after ASCT, with a reduced incidence of relapse compared with HLAid SCT.     

Fludarabine and Busulfan versus Fludarabine,Cyclophosphamide, and Rituximab as Reduced-Intensity Conditioning for Allogeneic Transplantation in Follicular Lymphoma

Large, multicenter studies comparing commonly used reduced-intensity conditioning (RIC) approaches in follicular lymphoma (FL) have not been performed. Using the Center for International Blood and Marrow Transplant Research database, we report the outcomes of the 2 most commonly used RIC approaches, fludarabine and busulfan (Flu/Bu) versus fludarabine, cyclophosphamide, and rituximab (FCR) in FL patients. We evaluated 200 FL patients undergoing allogeneic hematopoietic cell transplantation (allo-HCT) who received RIC with either Flu/Bu (n?=?98) or FCR (n?=?102) during 2008 to 2014. All patients received peripheral blood grafts, and graft-versus-host disease (GVHD) prophylaxis was limited to calcineurin inhibitor–based approaches. Median follow-up of survivors in the Flu/Bu and FCR groups was 48 months and 46 months, respectively. On univariate analysis in the Flu/Bu and FCR groups, the 3-year rates of nonrelapse mortality (11% versus 11%, P?=?.94), relapse/progression (18% versus 15%, P?=?.54), progression-free survival (PFS) (71% versus 74%, P?=?.65), and overall survival (OS) (73% versus 81%, P?=?.18) were not significantly different. On multivariate analysis no difference was seen between the FCR and Flu/Bu cohorts in terms of grades II to IV (relative risk [RR],?1.06; 95% confidence interval [CI],?.59 to 1.93; P?=?.84) or grades III to IV (RR,?1.18; 95% CI, .47 to 2.99; P?=?.72) acute GVHD, nonrelapse mortality (RR,?.83; 95% CI, .38 to 1.82; P?=?.64), relapse/progression (RR,?.99; 95% CI, .49 to 1.98; P?=?.97), PFS (RR,?.92; 95% CI, .55 to 1.54; P?=?.76), or OS (RR,?.70; 95% CI, .40 to 1.23; P?=?.21) risk. However, RIC with FCR was associated with a significantly reduced chronic GVHD risk (RR,?.52; 95% CI, .36 to .77; P?=?.001). RIC with either Flu/Bu or FCR in patients with FL undergoing allo-HCT provides excellent 3-year OS, with acceptable rates of nonrelapse mortality. FCR-based conditioning was associated with a lower risk of chronic GVHD.     

The value of augmented preparative regimens combined with an autologous bone marrow transplant for the management of relapsed or refractory Hodgkin disease: a Southwest Oncology Group phase II trial.

Several single-institution pilot studies have suggested that augmented preparative regimens, including those containing total body irradiation combined with an autologous bone marrow transplantation, are superior to standard regimens for the treatment of relapsed or refractory Hodgkin disease. On the basis of these data, we undertook, in the cooperative group setting, a phase II trial of augmented preparative regimens for patients experiencing treatment failure with conventional chemotherapy. Eighty-one patients with either sensitive or refractory (induction failures or chemoresistant) relapse received etoposide (60 mg/kg), cyclophosphamide (100 mg/kg), and either total body irradiation (12 Gy) or, if previously irradiated, carmustine (15 mg/kg), followed by an autologous bone marrow transplantation. Progression-free (PFS) and overall (OS) survival were estimated, and a Cox regression model was used to assess potential prognostic variables. The 5-year PFS and OS for the 74 eligible patients treated at 20 Southwest Oncology Group centers were 41% (95% confidence interval [CI], 29%-53%) and 54% (95% CI, 43%-65%), respectively, despite a median remission after initial chemotherapy of only 6 months. The 3-year OS for those whose induction therapy failed was 72% (95% CI, 52%-93%). There was 1 (1.4%) early treatment-related death, 2 late deaths due to lung toxicity, and only 1 death due to myelodysplasia. There were no differences in PFS or OS on the basis of regimen or chemosensitivity. A Cox prognostic factor analysis determined that >2 prior regimens, relapse in a radiated field, and extranodal disease were adverse prognostic factors. Among the 46 patients who received prior radiotherapy, the 5-year OS was 38% (95% CI, 14%-61%) for patients with 2 or 3 adverse factors, versus 60% (95% CI, 42%-78%) for those with 0 factors or 1 adverse factor. Augmented preparative regimens seem promising for the treatment of relapsed or refractory Hodgkin disease, without an increase in regimen-related mortality. A poor-prognosis group was identified that should be treated with novel therapies.     

The International Prognostic Index assessed at relapse predicts outcomes of autologous transplantation for diffuse large-cell non-Hodgkin's lymphoma in second complete or partial remission.

Autologous hematopoietic stem cell transplantation (auto HSCT) has become the standard treatment for patients with relapsed diffuse large-cell non-Hodgkin's lymphoma (NHL) responding to conventional salvage chemotherapy. Nevertheless, more than half of these patients will relapse following auto HSCT and die. This study was undertaken to determine whether the International Prognostic Index (IPI) assessed at time of relapse (IPI-R) could be used to identify patients with greater probability for long-term survival following auto HSCT. Eighty patients, median age 47 years (range 19-68 years), with diffuse large cell lymphoma in either second complete remission (CR 2, n = 27) or partial remission (PR 2, n = 53) were treated between 1984 and 2002 with auto HSCT. Clinical features predictive of overall survival (OS) and progression-free survival (PFS) were analyzed. Post-auto HSCT, CR was achieved in 73 patients (91%). With a median follow-up of 5 years (range 1.0-14.2 years), OS and PFS at 5 years were 38% (95% confidence interval [CI] 27%-50%) and 32% (95% CI 22%-42%), respectively. Two risk groups with significantly different OS and PFS were identified by the IPI-R. The high-risk group (3, 4, or 5 IPI factors) had 2.0 times (95% CI 1.1-4.0, P = .03) the risk of death and 2.2 times (95% CI 1.2-4.0, P = .01) the risk of relapse as the low-risk group (0, 1, or 2 IPI factors). The median OS was 5 months versus 27 months and the median PFS was 2 months versus 8 months for the high- and low-risk IPI-R groups, respectively. In Cox regression analysis, high-risk IPI-R status (relative risk [RR] 2.4, 95% CI 1.2-4.8, P = .02) and bone marrow (BM) involvement at diagnosis (RR 2.9, 95% CI 1.3-6.4, P = .01) were independent predictors for poor OS. Similarly, high-risk IPI-R status (RR 2.5, 95% CI 1.3-4.7, P = .01) and BM involvement at diagnosis (RR 3.9, 95% CI 1.7-8.7, P = .001) were independent predictors for poor PFS. These results suggest that the IPI-R predicts OS and PFS following auto HSCT for patients with aggressive NHL in CR 2 or PR 2. Patients with high-risk IPI-R should be considered for novel therapeutic approaches.     

Age Is a Prognostic Factor for the Overall Survival of Patients with Multiple Myeloma Undergoing Upfront Autologous Hematopoietic Stem Cell Transplantation

In this retrospective analysis, we evaluated the impact of age on the outcome of patients with multiple myeloma who received an autologous hematopoietic stem cell transplantation (auto-HCT) at our institution. A total of 1128 patients were divided into the older (>70 years; 182 [16%]) and the younger (≤70 years; 946 [84%]) groups. Compared with the younger cohort, older patients had a higher International Staging System (ISS) stage (ISS-II, 57 [31%] versus 215 [23%]; ISS-III, 52 [28%] versus 211 [22%]; P = .01), higher use of reduced-dose melphalan as a conditioning regimen (140 mg/m², 59 [32%] versus 29 [3%]; P < .001), and a higher comorbidity index (median, 3 versus 2; P = .01). Nonrelapse mortality at 1 year after auto-HCT was significantly higher in older patients (7 [4%] versus 9 [1%]; hazard ratio [HR], 4.1; P = .005). Complete remission rates after auto-HCT for the older and the younger groups were 41% and 46%, respectively. With a median follow-up of 52 months, the 5-year progression-free survival (PFS) was 24% (95% confidence interval [CI], 17% to 32%) and 37% (95% CI, 33% to 40%) in the older and younger groups, respectively (HR, 1.3; P = .02). Five-year OS for the older and younger groups was 56% (95% CI, 47% to 64%) and 73% (95% CI, 70% to 76%; P < .001), respectively. Older age emerged as one of the predictors of shorter OS but not PFS in the multivariate classification and regression tree analysis. In conclusion, age ≥70 years was associated with shorter PFS and OS in patients with multiple myeloma who underwent an auto-HCT.     

High-Dose Chemotherapy with Autologous Stem Cell Transplantation in Primary Central Nervous System Lymphoma: Data From the Japan Society for Hematopoietic Cell Transplantation Registry

High-dose chemotherapy (HDT) with autologous stem cell transplantation (ASCT) has been shown to improve the prognosis of patients with central nervous system (CNS) lymphoma. We queried the Japan Society for Hematopoietic Cell Transplantation Registry for 2006 to 2015 to analyze the outcomes of 102 patients with primary CNS lymphoma (PCNSL) who underwent first HDT/ASCT. The median patient age was 54 years (range, 20 to 74 years), and 65 patients were treated in an upfront setting. With a median duration of follow-up of 44 months, the 5-year overall survival (OS) and progession-free survival (PFS) were 54.9% and 38.4%, respectively. There were no significant differences in OS and PFS between upfront and salvage HDT/ASCT. Because thiotepa, a key agent in HDT/ASCT for PCNSL, has been unavailable since 2011 in Japan, the HDT regimens used were not uniform. Thiotepa-containing HDT was received by 16 out of 32 patients before 2010, but by only 2 of 70 patients after 2011. Thiotepa-containing HDT was associated with better PFS (P = .019), lower relapse (P = .042), and a trend toward a survival benefit. In multivariate analysis, noncomplete remission at HDT/ASCT was an independent predictor for OS (hazard ratio [HR], 2.40; 95% confidence interval [CI], 1.25 to 4.58; P = .008) and thiotepa-containing HDT remained significant for PFS (HR, .42; 95% CI, .19 to .95; P = .038). These results confirm the activity of thiotepa-containing regimens.     

Tandem Autologous-Autologous versus Autologous-Allogeneic Hematopoietic Stem Cell Transplant for Patients with Multiple Myeloma: Long-Term Follow-Up Results from the Blood and Marrow Transplant Clinical Trials Network 0102 Trial

Allogeneic hematopoietic cell transplant (HCT) may improve long-term multiple myeloma (MM) control through the graft-versus-myeloma effect. The Blood and Marrow Transplant Clinical Trials Network 0102 trial was a biologic assignment trial comparing tandem autologous transplant (auto-auto) versus autologous followed by reduced-intensity allogeneic (auto-allo) transplant in patients with newly diagnosed MM with standard-risk (n = 625) or high-risk (n = 85; β₂-microglobulin at diagnosis ≥ 4 mg/dL or deletion of chromosome 13 by conventional karyotyping) disease. Although the initial 3-year analysis showed no difference in progression-free survival (PFS) between arms in either risk group, we hypothesized that long-term follow-up may better capture the impact of the graft-versus-myeloma effect. Median follow-up of survivors was over 10 years. Among standard-risk patients there was no difference in PFS (hazard ratio [HR], 1.11; 95% confidence interval [CI], .93 to 1.35; P = .25) or OS (HR, 1.03; 95% CI, .82 to 1.28; P = .82). The 6-year PFS was 25% in the auto-auto arm versus 22% in the auto-allo arm (P = .32), and 6-year overall survival (OS) was 60% and 59%, respectively (P = .85). In the high-risk group, although there was no statistically significant difference in PFS (HR, .66; 95% CI, .41 to 1.07; P = .07) and OS (HR, 1.01; 95% CI, .60 to 1.71; P = .96), a reduction in 6-year risk of relapse of 77% versus 47% (P = .005) was reflected in better PFS of 13% versus 31% (P = .05) but similar OS, at 47% versus 51% (P = .69). Allogeneic HCT can lead to long-term disease control in patients with high-risk MM and needs to be explored in the context of modern therapy.