Salvage Stem Cell Transplantation Research Articles

Treatment pattern and outcomes of re-induction therapy prior to stem cell transplantation in patients with relapsed/refractory multiple myeloma in Germany

There are limited data guiding choice of re-induction therapies for patients with relapsed/refractory multiple myeloma (RRMM) prior to stem cell transplantation (SCT). We performed a retrospective medical chart review of 171 patients with RRMM in Germany who received re-induction therapy in second line (78%; n = 134) or third line (22%; n = 37) prior to re-SCT. Index therapy was defined as first completed re-induction therapy for planned myeloablative conditioning and SCT in second/third line within the eligibility period (1/2016–12/2019). Most common pre-index first line and maintenance therapy used were bortezomib-based combinations (91%; n = 155/171) and lenalidomide (55%; n = 29/53), respectively. Median duration of index therapy line was 9 months; carfilzomib-based combinations were the most widely used in second/third line re-induction therapy (49%; n = 83/171), followed by daratumumab-based combinations (21%; n = 36/171). Overall response rates in second/third line were 87% after re-induction and 96% after SCT; median time to next treatment line after start of index therapy was 31 months; median progression-free survival (PFS) was 29 months; and median overall survival after index date was not reached. Based on these data, re-induction therapy with salvage SCT appears to be beneficial in selected patients with RRMM in clinical practice in Germany, translating into deep responses, long PFS and prolonged time to next treatment.

Options at the time of relapse after anti-BCMA therapy.

B-cell maturation antigen (BCMA)-directed therapies, including antibody-drug conjugates, bispecific antibodies (BsAbs), and chimeric antigen receptor T cells (CARTs), have shown remarkable efficacy in patients with late-line myeloma with prior exposure to immunomodulatory agents, proteasome inhibitors, and anti-CD38 antibodies. However, optimal sequencing of these agents remains to be determined, and management of these patients once they relapse has become a new unmet need. Fortunately, there are multiple options with demonstrated activity after anti-BCMA therapy, including a different BCMA-directed therapy, non-BCMA-directed CARTs and BsAbs, novel non-T-cell-engaging drugs, and standard triplet/quadruplet regimens or salvage stem cell transplant. Factors to consider when choosing a next therapy after anti-BCMA therapy include patient characteristics and preferences, prior therapies and toxicities, disease biology, timing from last anti-BCMA therapy, and, in the future, BCMA expression and immune profiling. While current data are limited to retrospective studies and small prospective cohorts, the serial use of T-cell-engaging therapies looks particularly promising, especially as BCMA-directed therapies move up earlier in the myeloma treatment course and additional CARTs and BsAbs against alternative targets (eg, G protein-coupled receptor, family C, group 5, member D and Fc receptor-homolog 5) become available. Going forward, ongoing prospective studies, large real-world data sets, and better tools to interrogate antigen expression and immune cell fitness hopefully will provide further insight into how to best individualize therapy for this difficult-to-treat population.

Outcomes of Older Patients with Aplastic Anemia Treated with Frontline Anti-Thymocyte Globulin (ATG)-Based Immunosuppressive Therapy

Background: Advances in the treatment of aplastic anemia (AA), such as the addition of eltrombopag (EPaG) to immunosuppressive therapy (IST) and the expanded use of unrelated and haploidentical stem cell transplant (SCT) have steadily improved outcomes. However, little is known about the characteristics and outcomes of patients (pts) ≥ 60 years (yrs) of age with newly diagnosed AA who have been treated with an ATG-based regimen. Presumed low bone marrow (BM) reserves, higher frequency of underlying clonal hematopoiesis, intolerance to therapy, comorbidities, and challenges in proceeding to salvage SCT have led to the speculation that response and survival of these pts to IST may be inferior than their younger counterparts. Methods: We retrospectively analyzed the characteristics and outcomes of pts ≥ 60 yrs of age (OLDER) at the time of diagnosis of AA treated with frontline (F/L) ATG based therapy at our center and compared them to pts < 60 yrs of age (YOUNG) treated with F/L ATG over the same time period. We captured their clinical characteristics, cytogenetic abnormalities, mutations in DNMT3A (D), ASXL1 (A) and TET2 (T), exposure to EPaG, response, time to response (TTR) and survival. Overall response included complete and partial response per the standard definitions. Relapse free survival (RFS) was tabulated from the time of best response to loss of response, 2nd ATG infusion, salvage SCT or death (whichever was earlier) and overall survival was tabulated from the time of response to death from any cause. Results: From Jan 2011-May 2012, 43 OLDER pts were treated as F/L for AA of whom 41 (95%) received ATG based therapy; 68 YOUNG pts were treated as F/L for AA over the same time period of whom 62 (91%) received ATG based regimen. Four YOUNG pts vs. no pts in the OLDER group received upfront SCT, and 2 pts in each group were treated with non ATG based therapy: single agent CSA, EPaG, or alemtuzumab. Comparative baseline characteristics are depicted in Table 1. There were no differences in the baseline WBC, peripheral blood lymphocyte percentage and platelet counts between the ATG treated OLDER and YOUNG groups. Both groups had similar frequencies of cytogenetic abnormalities and PNH clones, though OLDER pts had mutations in D-A-T genes compared to the YOUNG group (62% vs. 38%, p=0.05). Both groups had equal concurrent exposure to EPaG with ATG. Cumulatively 23/41 (56%) pts in the OLDER group had an overall response (OR) compared to 43/62 (70%) pts in the YOUNG group (p=0.1); 11/23 (48%) and 23/43 (53%) responders in each group attained CR respectively. There were no differences in OR rates in both groups based on concurrent EPaG exposure: 61% vs. 46% with and without EPaG, respectively, in the OLDER group (p=0.5) and 74% vs 60%, respectively, (p=0.38) in the YOUNG group. On logistic regression analysis using baseline platelet counts, PB lymphocyte (%), D-A-T mutations, karyotype, and EPaG use as covariates, none affected the odds of OR in the 2 groups. The median TTR was 111 days (range, 10-323 days) and 177 days (51-410) in YOUNG AND OLDER groups, respectively; and this was not affected by EPaG use in either group. At a median follow of 38 months (mos) from ATG initiation (53 mos for the OLDER group and 32 mos for the YOUNG group), the median RFS was 49 mos and 39 mos (p=0.6) and median OS 55 vs. not reached (NR) (p <0.0001) in OLDER and YOUNG groups respectively (Fig.1). Significantly more pts in the YOUNG group underwent a subsequent SCT (19% vs. 5%) due to loss of response/ no response, possibly accounting for the higher OS rates. Rates of transformation to MDS or AML was 5% in both groups. Conclusion: Frontline ATG based IST in older pts with AA is a feasible and safe treatment option with promising response rates of 56% and median RFS more than 4 years; figures which are comparable to younger pts with AA treated with IST. The overall risks of transformation to MDS/AML on long term follow-up remain low (≈5%). Further studies assessing the response of the ATG+EPaG combination in these pts and the possibilities of clonal evolution with time needs to be conducted. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

Outcomes of salvage haploidentical transplantation using posttransplant cyclophosphamide for graft failure following allogeneic hematopoietic stem cell transplantation.

Haploidentical donors have emerged as an alternative donor source for salvage stem cell transplantation (SCT) after graft failure; however, data regarding salvage haploidentical SCT using posttransplant cyclophosphamide (PTCy) are limited. Using nationwide data (2011-2019), we retrospectively investigated transplant outcomes after salvage haploidentical SCT using PTCy for graft failure (n = 33, median age 34years). The total dose of PTCy was 75-100mg/kg (standard dose) in 26 patients (78.8%) and 40-50mg/kg (lower dose) in 5 patients (15.2%). The neutrophil engraftment rate at 30days was 81.8%. One-year overall survival (OS) and non-relapse mortality (NRM) rates were 47.4% and 46.0%, respectively. The standard-dose group exhibited better OS (61.1% vs. 0.0% at 1year, P = 0.022) and NRM (35.1% vs. 80.0% at 1year, P = 0.052) than the lower-dose group. Moreover, the standard-dose group was less prone to both grades II-IV (11.5% vs. 40.0%) and III-IV (0.0% vs. 40.0%) acute graft-versus-host disease (GVHD). Use of cyclophosphamide in previous SCT and conditioning did not affect OS or NRM. In conclusion, haploidentical salvage SCT using PTCy offers promising survival outcomes. Prospective studies are required to validate the efficacy of salvage haploidentical SCT using PTCy.

Outcomes of Haploidentical Salvage Transplantation Using Post-Transplant Cyclophosphamide for Graft Failure Following Allogeneic Hematopoietic Stem Cell Transplantation

Introduction: Graft failure (GF) is a fatal complication after allogeneic stem cell transplantation (SCT). Although salvage SCT is the only curative therapy for GF, optimal donors and strategies for this procedure have not yet been established. Although in the last decade haploidentical donors have emerged as alternative donors, only limited data are available regarding the outcomes after haploidentical salvage SCT using post-transplant cyclophosphamide (PTCy). Therefore, this nationwide retrospective study aimed to evaluate the transplant outcomes and risk factors for survival after haploidentical salvage SCT using PTCy on behalf of the Transplant Complications Working Group of the Japan Society for Transplantation and Cellular Therapy.Methods: Clinical data were provided by the nationwide database of the Japanese Data Center for Hematopoietic Cell Transplantation. Patients who were diagnosed with GF and underwent a second or higher allogeneic SCT from the haploidentical related donor (≥2 antigen-mismatch), using PTCy as graft-versus-host disease (GVHD) prophylaxis, between 2011 and 2019 were included. Organ failure was defined as either ejection fraction ≤50%, serum creatinine ≥2 mg/dL, bilirubin ≥1.5 × upper limit of normal, or aspartate aminotransferase/alanine aminotransferase ≥2.5 × upper limit of normal. Overall survival (OS) probabilities were estimated using the Kaplan-Meier method and differences among groups were analyzed using the log-rank test. The multivariate analysis for OS was performed using the Cox proportional hazard regression model. Factors from the univariate analysis that demonstrated significance with P values < 0.1 were included in the multivariate analysis.Results: A total of 33 patients were included in the study. The median age was 34 years (range, 2-67), while performance status (PS) was 0-1 in 21 patients (64%). At salvage transplantation, 12 (36%) were receiving treatment for active infection, and 5 (15%) had organ failure. The median interval from SCT to salvage SCT was 49 days (range, 26-1,468), and 21 patients (68%) underwent salvage SCT within 100 days after previous SCT. Conditioning regimens consisted of fludarabine (Flu)/ cyclophosphamide (Cy)-based in 10 (31%), Flu/melphalan (Mel)-based in 10 (31%), and Flu/busulfan (Bu)-based in 7 (21%). The total dose of PTCy was 75-100 mg/kg in 26 patients (84%) and 40-50 mg/kg in 5 patients (16%). Most patients (84%) received tacrolimus plus mycophenolate mofetil as GVHD prophylaxis in addition to PTCy. Previous SCT was cord blood transplantation in 22 patients (67%) and haploidentical transplantation in 6 patients (19%), of which 4 patients (13%) received PTCy. The median time for neutrophil engraftment was 18 days, and the cumulative incidence of neutrophil engraftment at 30 days was 82%. Specifically, a patient who had donor-specific human-leukocyte antigen-antibody successfully achieved neutrophil engraftment at 22 days after salvage SCT. The median OS was 359 days, while the OS at 1 year was 47% (Figure A). In the univariate analysis, the OS of patients who received 75-100 mg/kg PTCy was significantly better than those who received 40-50 mg/kg PTCy (61% vs. 0% at 1 year, P = 0.022, Figure B). After adjusting for PS and the presence of active infection and organ failure, 75-100 mg/kg PTCy was significantly associated with better OS (hazard ratio, 0.30; P = 0.036). Although the differences were not significant, patients who received Flu/Mel-based conditioning exhibited numerically better OS than those who received Flu/Cy- or Flu/Bu-based conditioning (80% vs. 40% vs. 57%, P = 0.21).Conclusions: Haploidentical salvage SCT using PTCy offers promising survival outcomes and can be a substantial option for GF after allogeneic SCT. An adequate dose of PTCy (i.e., 75-100 mg/kg) needs to be administered to achieve long-term survival. [Display omitted] DisclosuresNakamae: PPD-SNBL K.K: Research Funding; Bristol-Myers Squibb Company: Honoraria, Research Funding; Alexion: Research Funding; Sumitomo Dainippon Pharma Co., Ltd.: Honoraria; Simon-Kucher & Partners: Honoraria; Takeda Pharmaceutical Company Limited.: Honoraria; Astellas Pharma Inc.: Honoraria; Otsuka Pharmaceutical Co., Ltd: Honoraria; ONO PHARMACEUTICAL CO., LTD.: Honoraria; CMIC HOLDINGS Co., Ltd: Research Funding; Novartis: Honoraria, Research Funding; Pfizer Japan Inc.: Honoraria. Ichinohe: Celgene: Honoraria; Novartis Pharma K.K.: Honoraria; Repertoire Genesis Inc.: Honoraria, Research Funding; Takara Bio Inc.: Research Funding; Zenyaku Kogyo Co.: Research Funding; Taiho Pharmaceutical Co.: Research Funding; Sumitomo Dainippon Pharma Co.: Honoraria, Research Funding; Otsuka Pharmaceutical Co.: Research Funding; Nippon Shinyaku Co: Research Funding; Ono Pharmaceutical Co.: Honoraria, Research Funding; Kyowa Kirin Co.: Honoraria, Research Funding; FUJIFILM Wako Chemicals.: Honoraria, Research Funding; Daiichi Sankyo: Research Funding; Eisai Co.: Honoraria, Research Funding; CSL Behring: Honoraria, Research Funding; Chugai Pharmaceutical: Research Funding; Bristol-Myers Squibb: Honoraria; Takeda Pharmaceutical Co.: Honoraria; AbbVie Pharma: Research Funding; Astellas Pharma: Honoraria, Research Funding. Atsuta: Mochida Pharmaceutical Co., Ltd.: Speakers Bureau; Astellas Pharma Inc.: Speakers Bureau; AbbVie GK: Speakers Bureau; Kyowa Kirin Co., Ltd: Honoraria; Meiji Seika Pharma Co, Ltd.: Honoraria. Nakasone: Takeda Pharmaceutical: Honoraria; Otsuka Pharmaceutical: Honoraria; Bristol-Myers Squibb: Honoraria; Celgene: Honoraria; Pfizer: Honoraria; Novartis: Honoraria; Janssen Pharmaceutical K.K.: Honoraria; Eisai: Honoraria; Chugai Pharmaceutical: Honoraria; Nippon Shinyaku: Honoraria.

Prognostic factors in salvage transplantation for graft failure following allogeneic hematopoietic stem cell transplantation.

Although graft failure (GF) is a fatal complication after allogeneic stem cell transplantation (SCT), no mortality risk assessments after salvage SCT have been reported. We developed a comprehensive prognostic scoring system consisting of patient and comorbidity factors with 470 patients as a training cohort out of 940; these patients underwent salvage SCT for GF. The multivariate analysis demonstrated that older age, poorer performance status, a continuation of antimicrobial treatment, and severe organ dysfunction were independently associated with worse overall survival (OS) and non-relapse mortality (NRM). Based on each factor's hazard ratio, weighted scores of 1-3 were assigned to these factors. Using the summed scores (0-8), a prognostic scoring system successfully stratified outcomes after salvage SCT in the cohort. For patients in the low (0-2, n = 122), intermediate (3-4, n = 209), and high score (5-8, n = 110) groups, the 1-year OS was 62.8%, 40.8%, and 14.2%, respectively (P < 0.001), whereas the 1-year NRM was 24.1%, 43.9%, and 72.7%, respectively (P < 0.001). The prognostic value of the scoring system was confirmed in the validation cohort (n = 470). Our scoring system is useful for predicting survival after salvage SCT.

Comparison of the outcomes after haploidentical and cord blood salvage transplantations for graft failure following allogeneic hematopoietic stem cell transplantation.

Graft failure (GF) is a life-threatening complication after allogeneic stem cell transplantation (SCT). Although salvage SCTs can be performed with haploidentical donor (HID) or cord blood (CB), no study has compared the performances of these two sources. Using nationwide registration data, we compared the transplant outcomes of patients who developed GF and underwent salvage transplantation from HID (n = 129) and CB (n = 570) from 2007 to 2016. The HID group demonstrated better neutrophil recovery (79.7 vs. 52.5% at 30 days, P < 0.001). With a median follow-up of 3 years, both groups demonstrated similar overall survival (OS) and nonrelapse mortality (NRM; 1-year OS, 33.1 vs. 34.6% and 1-year NRM, 45.1 vs. 49.8% for the HID and CB groups). After adjustments for other covariates, OS did not differ in both groups. However, HID was associated with a lower NRM (hazard ratio, 0.71; P = 0.038) than CB. The incidence of acute graft-versus-host disease (GVHD)-related deaths was significantly higher in the HID group, although infection-related deaths were observed more frequently in the CB group. HID may be a promising salvage SCT option after GF due to its faster engraftment and low NRM.

High-Dose Chemotherapy with Early Autologous Stem Cell Transplantation Compared to Standard Dose Chemotherapy or Delayed Transplantation in Patients with Newly Diagnosed Multiple Myeloma: A Systematic Review and Meta-Analysis

Autologous stem cell transplantation (SCT) is the standard of care for all transplantation-eligible patients diagnosed with multiple myeloma (MM). Various studies have compared clinical outcomes with frontline SCT ("early SCT") versus standard-dose therapy (SDT) alone, with or without salvage SCT ("SDT/late SCT"). In this meta-analysis, we compare overall survival (OS) and progression-free survival (PFS) outcomes between these 2 treatment approaches. Twelve studies were identified, including a total of 3633 patients, of whom 1811 received early SCT and 1822 received SDT/late SCT. In our analysis of all 12 studies, OS was not significantly different between the 2 groups (hazard ratio [HR], .86; 95% confidence interval [CI], .70 to 1.04), but PFS was better with early SCT (HR, .67; 95% CI, .54 to .82). In a subgroup analysis of 3 studies in which novel agents were used for induction, OS again was similar in the 2 groups, and PFS was favorable with early SCT (HR, .50; 95% CI, .36 to .70). This analysis shows that over the years, early SCT has been associated with prolonged PFS, but this did not consequently translate into prolonged OS in patients with newly diagnosed MM. The benefit of early SCT in terms of OS is less clear in the era of novel agents, given the limited follow-up of these studies.

Allogeneic Stem Cell Transplantation for Patients with Natural Killer/T Cell Lymphoid Malignancy: A Multicenter Analysis Comparing Upfront and Salvage Transplantation

Natural killer (NK)/T cell lymphoid malignancy comprises extranodal NK/T cell lymphoma (ENKTL) and aggressive NK cell leukemia (ANKL), and the outcomes for advanced or relapsed/refractory ENKTL and ANKL remain poor. Allogeneic stem cell transplantation (SCT) can be used as a frontline consolidation treatment to prevent the relapse of advanced disease or as salvage treatment after chemotherapy for relapsed sensitive disease.We retrospectively analyzed 36 patients (ENKTL, n = 26; ANKL, n = 10) who underwent upfront (n = 19) and salvage allogeneic SCT (n = 17) at 6 hospitals. Patients received myeloablative (n = 25) or reduced-intensity (n =11) conditioning regimens depending on the institute's policy.The median age at the time of allogeneic SCT was 37 years (range, 17 to 62), and more patients with ANKL (8/10) received upfront allogeneic SCT than ENKTL patients (11/26). Disease status before allogeneic SCT, conditioning regimen, and donor source did not differ between upfront and salvage allogeneic SCT groups. Febrile neutropenia (n = 20) and acute graft-versus-host disease (n = 16) were common adverse events. The median overall survival (OS) and progression-free survival (PFS) after allogeneic SCT were 11.8 months and 10.0 months, respectively. Twelve patients died from disease relapse and 12 from nondisease-related causes. Ten deaths occurred within 100 days after allogeneic SCT (10/24); these were mostly related to disease relapse (n = 8). The OS after allogeneic SCT did not differ between ENKTL and ANKL (P = .550) or between upfront and salvage SCT (P = .862). Complete chimerism was significantly associated with better PFS (P < .001). No significant differences in PFS were observed based on the conditioning regimen or source of stem cells (P > .05).Allogeneic SCT may be beneficial for patients with ENKTL and ANKL given that some patients were able to maintain their remission after allogeneic SCT. However, allogeneic SCT should only be performed in highly selected patients because the risks of disease relapse and nondisease-related mortality remain high.

24 - High Dose Chemotherapy with Early Autologous Stem Cell Transplantation Compared to Standard Dose Chemotherapy or Delayed Transplantation in Patients with Newly Diagnosed Multiple Myeloma: A Meta-Analysis

Background: Upfront high dose chemotherapy with stem cell transplantation (SCT) is often used for patients with newly diagnosed multiple myeloma (MM). This approach has shown variable benefits in various randomized clinical trials (RCTs) when compared to standard dose therapy (SDT) with or without delayed SCT. The aim of this meta-analysis was to evaluate difference in overall survival (OS) and progression-free survival (PFS) in various RCTs including patients who underwent high dose chemotherapy with early SCT compared to those who received SDT or delayed SCT. Methods: We searched different databases, including PubMed, Embase and Cochrane, to identify RCTs comparing early high dose therapy with autologous SCT versus SDT in patients with newly diagnosed MM. Efficacy outcome measures included were OS and PFS reported at the maximum follow-up period. The overall effect was pooled using the DerSimonian random effects model. A subgroup analysis was conducted to evaluate influence of the novel agents (e.g. immunomodulatory agents, proteasome inhibitors) on OS and PFS. Results: Twelve studies were identified, including a total of 3829 patients, which compared high dose chemotherapy with early SCT versus SDT/delayed SCT. Of these, 1824 patients were treated with early high dose chemotherapy and SCT while 2005 were treated with SDT or delayed SCT. Four of these included treatments with novel agents. Patients who received early SCT had no difference in OS compared to patients assigned to SDT or salvage SCT [hazard ratio .86 (95% CI .70-1.04)] (Figure 1). On the other hand, there was noted an improvement in PFS in patients who received early SCT [hazard ratio .73 (95% CI .56-.94)] (Figure 2). In a subgroup analysis of studies that utilized novel agents, both groups had similar outcomes in terms of OS [hazard ratio .85 (95% CI .46-1.6)] and PFS [hazard ratio .68 (95% CI .37-1.25)] (Figure 3).Figure 2Progression-free survival for all studies.View Large Image Figure ViewerDownload Hi-res image Download (PPT)Figure 3Overall survival and Progression-free survival for studies including novel agents.View Large Image Figure ViewerDownload Hi-res image Download (PPT) Conclusions: This analysis shows that over the years, early SCT was associated with a prolonged PFS but did not translate into a prolongation of OS, in patients with newly diagnosed MM. Our results show that in the era of novel agents, the benefit of early SCT is less clear; and for selected cases, delaying SCT remains an acceptable option.

The Addition of Sorafenib to Standard AML Treatment Results in a Substantial Reduction in Relapse Risk and Improved Survival. Updated Results from Long-Term Follow-up of the Randomized-Controlled Soraml Trial

The Addition of Sorafenib to Standard AML Treatment Results in a Substantial Reduction in Relapse Risk and Improved Survival. Updated Results from Long-Term Follow-up of the Randomized-Controlled Soraml Trial

De novo CD5+ diffuse large B-cell lymphoma: Adverse outcomes with and without stem cell transplantation in a large, multicenter, rituximab treated cohort.

De novo CD5+ diffuse large B-cell lymphomas (DLBCL) are a distinct subgroup of DLBCL with poor prognosis. However the role of rituximab-containing therapy and salvage stem cell transplantation in this patients' population remain to be defined. We retrospectively reviewed clinical features and outcomes of 102 patients with de novo CD5+ DLBCL treated with rituximab-containing therapy at nine different institutions. By Hans' criteria, 64 patients had activated B-cell (ABC) subtype, 24 germinal center B-cell (GCB) subtype, and 14 were not evaluated. No patients had a myc translocation. Eighty-three patients were treated with rituximab, cyclophosphamide, doxorubicin, vincristine, prednisone (R-CHOP), 7 with rituximab, etoposide, cyclophosphamide, doxorubicin, vincristine, prednisone (R-EPOCH), and 6 with R-CHOP with methotrexate, 3 g/m(2) . The overall response rate to front-line therapy was 85%. The 3-year progression free survival (PFS) and overall survival (OS) for all patients were 40 and 65%, respectively. The 3-year PFS for ABC- and GCB-subtypes was 34 and 45%, respectively. The 3-year OS for ABC- and GCB-subtypes was 62 and 67%, respectively. The median time to second treatment failure was 3 months and 1 month for ABC- and GCB-subtypes, respectively. Twenty of 28 (71%) transplanted patients with autologous, allogeneic, or both, relapsed. This study confirms the poor prognosis of de novo CD5+ DLBCL in a large multi-center cohort despite initial rituximab-containing chemotherapy and suggests that stem cell transplantation fails to salvage the majority of these patients. Approaches to prevent recurrence and/or novel therapies for relapsed disease are needed for this subgroup of DLBCL patients.

Salvage Tandem Autologous Stem Cell Transplant with Consolidation for Relapsed Multiple Myeloma

Background: Therapeutic options for patients with Multiple myeloma (MM) whose disease has relapsed after a prior autologous stem cell transplant (SCT) include an expanding armamentarium of novel agents, often combined with traditional chemotherapy, or a second SCT, with no clear standard of care. Upfront tandem transplantation has been shown to improve both progression free survival and overall survival. But currently, there is little data regarding the application of tandem SCT in relapsed multiple myeloma patients.Methods: We retrospectively analyzed the outcomes of patients who underwent salvage melphalan-based tandem SCT for relapsed MM at University of Iowa Hospitals and clinics. Progression free survival (PFS) was defined as the time from date of the first salvage SCT to disease progression or death, whereas overall survival (OS) was defined from the date of the first salvage SCT to the date of death from any cause.Results: Between 2012 and 2015, 12 patients with MM received tandem autograft (total 24 transplants) for relapsed disease at our center. Conditioning was with VDT-melphalan 200mg/m2 (21/24), VDT-MEL 140mg/m2 (2/24) and Velcade, gemcitabine, BCNU, melphalan and dexamethasone (1/24). The median age at the salvage SCT was 48 years (range 37-58); 7 patients were female. 17% had high risk cytogenetics (including t(4;14), +1q, p53 loss) at the time of salvage SCT. Median time between previous transplant and progression of disease was 34 months (range 8-108). Of the 7 patients, who received re-induction therapy, 71% had chemotherapy refractory disease prior to salvage SCT. Response was assessed at 2-3 months post-SCT. Overall response rate was 92%. 7/12 (58%) patients achieved stringent complete remission, one patient achieved CR, one patient achieved near CR, 2/12 patients achieved VGPR and 1/12 had stable disease (SD). Following salvage tandem SCT, all patients received consolidation therapy with three drug combination, intended to be given for two years. Three patients have shown progressive disease at the time of analysis. The median PFS was 390 days (range 265- 1085) (Table-1); the median OS was 517 days (range 338-1085) (Table-2). Rate of progression free survival in the 10 evaluable patients at one year was 80%. There was no transplant related mortality. One patient died of progressive disease.Conclusions: Salvage tandem SCT is an effective strategy for relapsed MM and is especially effective in patients who had received less intensive therapy initially (single transplant and no maintenance therapy). Incorporation of novel agents (monoclonal antibodies and high doses of carfilzomib) into maintenance strategies may further improve outcomes. [Display omitted] [Display omitted] DisclosuresFarooq:Kite Pharma: Research Funding.

Quizartinib Significantly Improves Overall Survival in FLT3-ITD Positive AML Patients Relapsed after Stem Cell Transplantation or after Failure of Salvage Chemotherapy: A Comparison with Historical AML Database (UK NCRI data)

Introduction: The prognosis of patients with a FLT3-ITD mutation in acute myeloid leukemia (AML) is worse than FLT3 wild type patients, with increased early relapse including after allogeneic stem cell transplantation (SCT) and with a poor response to salvage. FLT3-ITD mutant patients who relapse after SCT or fail salvage chemotherapy have a dismal prognosis with no approved treatment options. Quizartinib (AC220), an oral FLT3 receptor tyrosine kinase inhibitor, has shown a remission rate of 44%, and median overall survival of 23 weeks in FLT3-ITD mutant patients who were relapsed or refractory to 2nd line treatment, or relapsed following SCT in a non-randomised phase 2 study [1]. While these outcomes compare favourably to published data, which give a median survival of 1.5 months in all comers [2], and median survival in FLT3-ITD mutant patients of 13 weeks following first relapse [3], there is an overall paucity of data available for the FLT3-ITD+ subpopulation examined in the quizartinib studies . The UK NCRI database is the largest dataset for FLT3-ITD+ AML patients, containing 6872 patients with ITD status (1388 mutant) and systematic collection of data from diagnosis with follow-up for at least 5 years or to death.Methods: 97 FLT3-ITD+ patients from the AC220-002 study who had received intensive chemotherapy, and had either relapsed following SCT (n=39); or were relapsed (n=53) or refractory (n=5) following salvage therapy prior to enrolment were identified. The equivalent eligibility criteria were applied to the UK MRC/NCRI database of AML trial patients treated intensively from 1988-2013 who had confirmed FLT3-ITD mutation: 183 patients matching the same criteria were identified (post-SCT n= 65; relapsed n=99; refractory n=19). Patients in this group received only recognised intensive chemotherapy regimens prior to fulfilling the eligibility criteria. To reflect the screening period in AC220-002, patients in the MRC/NCRI cohort entered the analysis 14 days following being identified as relapsed/refractory. The primary endpoint was overall survival. Multivariable Cox/logistic regression was performed stratified for known prognostic factors, including route to eligibility (post SCT/relapsed/refractory). Sensitivity analyses were performed excluding deaths within 14 and 28 days from eligibility from the MRC/NCRI cohort only to allow for patients who might not have been considered for quizartinib treatment on grounds of fitness.Results: There was no significant difference in the ages of the two cohorts (median age AC220-002 47y vs. MRC 48y). Outcomes in the MRC/NCRI cohort did not improve over time from 1988-2013 (p=0.7). Analyses were performed adjusted for route to eligibility, ITD allelic ratio, duration of remission (in relapsed patients), and cytogenetics. Overall survival was improved in the Quizartinib patients (adjusted hazard ratio (HR) 0.40 (0.29-0.55) p<.0001), with no interaction with route to eligibility (p=0.4). Median survival was 231 vs 60 d for relapse post SCT, 128 vs 53 d in relapsed patients, and 146 vs 61 d in refractory patients. Response rates (CRc) overall were 43% vs 11% (adjusted OR 0.24 (0.10-0.61) p=0.002). In sensitivity analyses excluding deaths within 14 days (HR 0.50 (0.36-0.69), p<.0001) and 28 days (HR 0.5 (0.38-0.76) p=0.0004) within the MRC/NCRI cohorts quizartinib retained superiority.Discussion: Quizartinib has previously shown activity in relapsed/refractory patients in a large Phase 2 single arm study, and is currently being studied in a randomized Phase 3 study vs. standard salvage chemotherapy. This analysis examines a patient population that has failed salvage therapy or SCT and for whom there is no standard therapy. It confirms the prolonged overall survival seen in the Phase 2 study when compared to an equivalent large historical cohort of previously intensively treated patients from the UK MRC/NCRI trials, with median survival in quizartinib patients was 159 days compared to 56 days in the historical cohort. Even if deaths within 28 days are excluded entirely from the MRC/NCRI group, there is a highly significant survival benefit for quizartinib. Overall, the activity seen in the AC220-002 Phase 2 study is greater than that seen in comparable patients in a large historical cohort.[1] Levis M et al. ASH meeting Abstr 615, 2014. [2] Giles F et al. Cancer 104 (3), p547, 2005. [3] Ravandi F et al. Leukemia Research 34, p752, 2010. [Display omitted] DisclosuresOff Label Use: Quizartinib for AML. Gammon:Ambit: Employment. Trone:Ambit: Employment.

A Rare Esophageal Complication After Autologous Stem Cell Transplantation

Question: A 58-year-old white man with refractory stage IIIA immunoglobulin G kappa multiple myeloma (MM) developed severe nausea, vomiting, and coffee-ground emesis during an extended hospitalization after salvage stem cell transplantation (SCT). The patient was initially diagnosed with MM 5 years before presentation, and had been treated with multiple antineoplastic therapies, including bortezomib/dexamethasone, lenalidomide, cyclophosphamide, pomalidomide, daratumumab, carfilzomib, and a failed autologous SCT.

P05.01 * OUTCOME OF THE PEDIATRIC MEDULLOBLASTOMA PATIENTS: SINGLE INSTITUTION EXPERIENCE FROM SAUDI ARABIA

PROPOSE: This is a retrospective study to review the outcome of pediatric patients with medulloblastoma (MBL) in the era of the modern therapy. PATIENTS AND METHODS: The medical charts of 36 cases of pediatric medulloblastoma (≤ 15 years) diagnosed between January 2001 and December 2011 were reviewed as regard the initial presentation, surgical, chemotherapy, and radiotherapy treatment. Survival analysis was done to determine the prognosis. RESULTS: The mean age of the group was a 7 ± 3 year, 8% (3 patients) were under the age of 3 years, and 21 patients (58%) were boys while 15 patients (42%) were girls. Headache, vomiting and ataxia were the most common presentations reported in 92%, 86%, and 64% of the patients respectively. Nineteen patients (53%) presented with M0 disease, 1 patient (3%) with M2 and 16 patients (44%) with M3. Fifteen patients (42%) were in the average-risk group, while 21 (58%) were in the high-risk group. Total resection of the tumor was done in 16 patients (44%), near total resection in 5 patients (14%), partial resection (biopsy) in 15 patients (42%). Twenty nine (81%) patients received initial first line chemotherapy and radiotherapy. At a mean follow up of 39 ± 29 months, 11 patients relapse, 4 patient underwent 2nd salvage surgery, 9 patients received second line chemotherapy, 3 patients received salvage radiotherapy. Three patients underwent salvage stem cell transplant. The 3 and 5 years disease free survival (DFS) and overall survival (OS) were 68 % & 53 % and 71% & 65% respectively. The only significant factors for OS were the age (≤3 Vs. >3 years P 0.005) and treatment per MBL protocol (P 0.021). On the other hand, age was also the significant factor for DFS (P 0.043). CONCLUSION: In the modern era, the use of combined modality treatment approach including safe surgical resection, neuroaxis radiotherapy and chemotherapy become the standard of care for treatment of Medulloblastoma, In our series, the age and the use of chemotherapy protocol emerging as significant factors for OS. Patients under 3 years had poor DFS and OS.

Role of Front-Line High Dose Therapy with Stem Cell Transplant in Peripheral T-Cell Lymphomas. A Single Center Experience.

AbstractAbstract 2733 Introduction:The best treatment of peripheral T-cell lymphomas (PTCLs) currently remains a matter of debate. Some retrospective study and few phase II trials have shown that first line high dose therapy (HDT) with autologous stem cell transplant (SCT) may apparently offer better results. However, no comparative trials are currently available. Material and Methods:We retrospectively evaluated the outcome of previously untreated patients with PTCL, excluding mycosis fungoides and Sézary syndrome, referred to our Center between 1996 and 2012. An in-house histologic revision was performed to confirm the diagnosis according to the latest WHO criteria. From this analysis we excluded patients with diagnosis of ALK positive anaplastic large cell lymphoma (ALCL). We stratify patients according to treatment. Conventional therapy (CT) consisted of CHOP, CHOEP or MACOP(-B). From early 90s at our Center was adopted the strategy to consolidate response to initial treatment with either autologous or allogeneic SCT, whenever possible, in patients aged <65 years. These patients were assigned to HDT group. Results:The specific diagnosis of the 124 patients evaluated was PTCL-not otherwise specified (n=70), angioimmunoblastic T-cell lymphoma (n=21), ALCL ALK negative (n=19), other subtypes (n=14). At diagnosis, 43 patients were planned to receive HDT plus SCT but only 26 (60%) eventually received it (22 autologous, 4 allogeneic) while the remaining experienced early death (8 patients), progression (8 patients) or mobilization failure (1 patient). The median age of this first cohort was 47.9 years (range 23–63), that also showed an advanced Ann-Arbor stage (III-IV) or an int-high/high IPI in 77% and 58% of the cases, respectively. The rate of complete remission (CR) was 57% with 21% of patients dying during treatment (5 patients not evaluable for response, 3 responders and 1 with progressive disease). Eighty-one patients were treated according to a CT strategy. The median age of this latter group was 66.7 years (25–85), an advanced stage (III-IV) or an int-high/high IPI was present in 73% and 61%, respectively. The CR rate was 57% with 19% of the patient dying during treatment (11 patients not evaluable for response, 2 responders and 1 with progressive disease). With a median follow up of 1.63 years (0–25) and 82 deaths, by intention to treat analysis the 5-years overall survival (OS) was 43% and 32% for HDT and CT (p=.90, figure 1), respectively, while the 5-years OS of those patients eventually receiving SCT was 64%. Irrespectively from the adopted treatment strategy, patients who achieved a CR showed a similar 5-years OS and disease free survival that were 57% and 52% in the CT group and 80% and 64% in the HDT cohort (p=.43 and p=.44), respectively. Of the 54 patients with relapsed or refractory disease, 9 underwent salvage SCT (4 autologous, 5 allogeneic) with 3 patients achieving a sustained remission. Conclusions:The overall clinical outcome of most PTCL patients remains unsatisfactory, with a large fraction of patients not responding to front-line treatment. The advantage of a post-remission consolidation with SCT has to be confirmed by appropriate ad hoc designed clinical studies. On the contrary, allogeneic SCT, despite remaining a potentially curative treatment option for these patients, unfortunately has a limited applicability due to the frequent advanced age and comorbidities as well as to the difficulty in finding a donor. [Display omitted] Disclosures:No relevant conflicts of interest to declare.

Outcomes Following Salvage Autologous Stem Cell Transplant for Multiple Myeloma

AbstractAbstract 1353 Background:High-dose therapy and stem cell transplant (SCT) has improved the progression-free and overall survival of patients with MM. However all patients eventually develop disease recurrence. In the era of effective novel agents (such as bortezomib, lenalidomide and thalidomide), the optimal salvage strategy is undefined. Methods:We retrospectively analyzed the outcomes of patients who underwent salvage melphalan-based SCT for relapsed MM at Memorial Sloan-Kettering Cancer Center. Results:Between 1995 and 2010, 53 patients with MM received a second autograft for relapsed disease at our center. Conditioning was with melphalan 100 (N=8), 140 (N=18) or 200mg/m2 (N=27). The median age at 2nd SCT was 60 years (range 36–75) and 62% (N=33) were male. Twenty-three percent (N=12) had high risk cytogenetics (including t(4;14), +1q, p53 loss, or del 13q by karyotype) while 77% had standard risk or cytogenetic studies were not available. The median interval between SCTs was 34 mos (range 6.2–88.7). Of evaluable patients, 79% (37/47) had chemotherapy sensitive disease prior to salvage SCT and 21% were chemoresistant. Response was assessed at 2–3 mos post-SCT and 70% of evaluable patients achieved >= partial response (PR), 17% had stable disease (SD), and 13% progressed despite salvage SCT. Following salvage SCT, 6 patients received maintenance therapy and 7 went on to allogeneic SCT. The median progression-free survival (PFS) following second autograft was 13.1 mos (95% CI: 10.1–18.4). Patients with high-risk cytogenetics at the time of second SCT had higher risk of progression (HR 2.5, 95% CI: 1.15–5.24, P = 0.02) compared to patients who had standard risk cytogenetics. However, interval from first to second SCT, chemosensitivity, and response following second transplant had no significant impact on PFS. The median OS following salvage SCT was 24 mos (95% CI: 18 – 41) and was superior for patients with standard versus high risk cytogenetics (HR 3.51, 95% CI: 1.57–7.86, P = 0.002). Again, interval since prior SCT and response following salvage SCT did not impact survival. Chemosensitivity was associated with reduced risk of death (HR 0.42, 95% CI: 0.18–0.96, P = 0.04). Although the sample size was small, the OS was not significantly extended for patients who received maintenance therapy or allogeneic SCT following salvage autologous SCT. Conclusion:Salvage SCT is an effective strategy for relapsed MM following initial autograft and results in responses in the majority of patients. Although OS and PFS following salvage SCT is similar to other salvage strategies, novel conditioning regimens and/or effective maintenance strategies may improve this approach. Disclosures:Comenzo:Millenium Pharmaceuticals: Membership on an entity's Board of Directors or advisory committees; Elan Pharmaceuticals: Consultancy; Genzyme: Research Funding; Celgene: Research Funding; Ortho: Research Funding.

Tumor flare reactions and response to lenalidomide in patients with refractory classic Hodgkin lymphoma

Patients with Hodgkin lymphoma (HL) failing salvage stem cell transplantation are candidates to investigational strategies. Lenalidomide represents an attractive option as it targets several signaling pathways, which regulate survival of HL cells and their microenvironmental interactions. We report the occurrence of Grades 2 and 3 tumor flare reactions in the first three patients entered a lenalidomide-based compassionate program for treatment-refractory HL. Flares occurred in concomitance of the scheduled week-off lenalidomide and upon withdrawal of symptomatic steroid treatment, and were associated with changes in B-cell regulatory cytokines and the concurrent expansion of polyclonal B-cells. Flares mimicked tumor progression but were effectively managed with anti-inflammatory treatment and followed by a clinical response, suggesting that they may mirror the pleiotropic actions of lenalidomide on HL microenvironment.