BACKGROUND: Graft-versus-host disease (GVHD) is the major obstacle to successful allogeneic stem cell transplantation (SCT) transplantation. Cyclosporine (Csa) in combination with methotrexate (MTX) ...is the most commonly used prophylactic regimen. The combination of CsA and Mycophenolate Mofetil (MMF) has recently been introduced. In this case-match study we retrospectively analyzed the introduction of MMF as GVHD prophylaxis in comparison with a short course of MTX in the setting of reduced intensity conditioning allogeneic SCT (Alo-RIC).
PATIENTS AND METHODS: We analyzed 59 Alo-RIC recipients who received an Alo-HSCT from an HLA-identical sibling between April 2000 and June 2006. The median follow-up for the whole group was 473 days (8 to 2139 days). The study group included 40 males and 19 females. Median age was 59 years (range 43 to 72). Diagnoses were acute leukemia/myelodisplastic syndrome) (n=19/22), mutiple myeloma (n= 6), chronic myeloid leukemia (n=5) and non- Hodgkin lymphoma (NHL) (n= 4). GVHD prophylaxis consisted of Csa/MTX (MTX group) in 37 patients and Csa/MMF (MMF group) in 22 patients. The conditioning regimen was based on fludarabine in combination with busulfan (42 recipients) or melfalan (17 cases).
RESULTS: The occurrence of mucositis grade 2–4 was higher in the MTX group than in the MMF group (62% vs 28% p= 0.015). No significant differences were found between MMF vs MTX groups in time to neutrophil recovery (16 +/−3 days vs 15 +/− 2days) (p= 0.5). Median time to the achievement of complete T-cell donor chimerism in the MTX and MMF groups was 79 days (range 19–740) and 76 days (range 24–223) respectively (P=0.4). The 1- year non-relapse mortality was similar in MTX and MMF groups 14% (95% C.L. 6–31%) vs 28% (95% C.L. 13–60%) respectively; P=0.2. Cumulate incidence of acute GVHD for MTX and MMF groups was 49% (95% C.L. 35–68%) and 68% (95% C.L. 51–91%) respectively (P= 0.6). Patients in the MTX group showed a trend to a higher incidence of chronic GVHD than the Csa/MMF group, 55% (95% C.L. 40–74%) vs 42% (95% C.L. 23–75%) (P=0.2). No differences were found between MTX vs MMF groups in 1-year overall survival 78%(64–92%) vs 53%(38–76%); P=0.1 nor in 1-year relapse incidence 37% (95%CI 21–64%) vs 19% (95%CI 10–37%) P=0.1) We conclude that the Csa/MMF combination appears to be equivalent to the standard Csa/MTX aGVHD prophylaxis in Alo-RIC. MMF showed significantly less mucositis.
Patients with aggressive non-Hodgkin's lymphomas (NHL) who do not obtain a complete response (CR) after induction chemotherapy have a poor prognosis. However, provided they are sensitive to the first ...regimen of chemotherapy, 25-40% of them with a B-cell phenotype may achieve long-term survival when treated with high dose chemotherapy and autologous stem cell transplantation (HDC/ASCT). The aim of this study was to analyze the efficacy of this therapy in the corresponding patients with peripheral T-cell lymphoma (PTCL).
We retrospectively evaluated the efficacy of ASCT in 35 patients with PTCL from the GEL-TAMO registry, who did not achieve a CR to standard induction chemotherapy regimens for aggressive NHL. Thirty-one patients underwent transplantation after achieving a partial response (PR) and 4 patients were non-responders.
Following HDC/ASCT, 23 (66%) of the patients achieved a CR, 4 (11%) a PR and in 7 (20%) cases the transplant failed. One patient was not evaluated because of early toxic death. With a median follow-up of the survivors of 37.5 months, 18 patients (51%) are alive and 15 patients (43%) are free of disease. Transplant-related mortality rate at 100 days was 11% and at 5 years the probabilities of survival, freedom from progression and disease-free survival for complete responders were 37%, 36% and 55% respectively. Pre-transplant lactate-dehydrogenase level, age-adjusted International Prognostic Index (aa-IPI) and tumor score correlated with survival.
One third of the patients with PTCL who fail to achieve CR to the first chemotherapeutic regimen can be rescued with HDC/ASCT. Pre-transplant values of IPI and tumor score risk systems for aggressive lymphomas were useful to predict subsequent survival.
Classical HL patients with relapsed or refractory disease may benefit from alloHCT, but many will be heavily pre-treated and not eligible for myeloablative conditioning and/or may not have an ...available MRD graft source. Herein, we compare the outcomes of two RIC-HCT platforms in cHL: haplo-PTCy-based approaches compared to MRD/CNI-based approaches.
Using CIBMTR registry, included are 596 adult patients who underwent first alloHCT for cHL between 2008-2016, using RIC with either haplo/PTCy-based (n=139) or MRD/CNI-based (n=457) approaches. The primary endpoint was overall survival (OS). Secondary endpoints included acute (a) and chronic (c) GVHD, non-relapse mortality (NRM), relapse/progression and progression-free survival (PFS).
Baseline characteristics are shown in Figure 1. On multivariate analysis, haplo/PTCy was associated with significantly higher risk of grade 2-4 aGVHD (odds ratio OR 1.73, 95% CI 1.16-2.59, p=0.01), but the risk of grade 3-4 aGVHD was not significantly different between the two cohorts (OR 0.61, 95% CI 0.29-1.27, p=0.19). The haplo/PTCy platform showed a significant reduction in cGVHD (hazard ratio HR 0.45, 95% CI 0.32-0.64, p<0.001), as well as a significant reduction in relapse risk (HR 0.74, 95% CI 0.56-0.97, p=0.03). NRM with the haplo/PTCy approach was higher (HR 1.65, 95% CI 0.99-2.77, p=0.06), albeit not statistically significant. Causes of death were infection and organ failure in 20% and 12% of patients in the haplo/PTCy cohort, respectively, compared to 9% and 7% of patients in the MRD/CNI-based cohort. There was no difference in OS (3-year OS 63% vs. 63%) or PFS (3-year PFS 38% vs. 34%) between the haplo-PTCy and MRD/CNI-based cohorts, respectively.
Haplo/PTCy-based approaches are associated with lower incidence of cGVHD and relapse, with PFS and OS outcomes comparable to MRD/CNI-based approaches. These data support that haplo/PTCy-based approaches can result in outcomes for cHL patients that are equivalent to MRD/CNI-based approaches and that HCT should be considered for patients with relapsed/refractory cHL regardless of donor options. Novel approaches to promote immune reconstitution, mitigate organ toxicity, and decrease post-HCT relapse risk may improve outcomes.
We prospectively compared the efficacy of allogeneic PBSCT from an HLA-identical sibling in adults with poor-risk AML or MDS in an early disease status (AML or RAEB type 2 in first CR after ...chemotherapy or RAEB type 1 with poor prognosis). Poor-risk AML/MDS was defined as the presence at diagnosis of one or more of the following: poor-risk karyoype, normal karyotype with flt-3 duplications or MLL mutations, high level of MRD after consolidation (>0.1%), and, in RAEB type 1, an IPSS3Int-2. Based only on the patients' age, the transplant protocol consisted in conditioning with cyclophosphamide-TBI and use of CD34+-selected PBSCT (CyTBI-CD34+ group, if £ 50 y.o.) or a reduced-intensity conditioning (RIC) with fludarabine and oral busulphan (FluBu-RIC, If > 50 y.o.). Between 1998 and 2005, 74 consecutive patients entered the study (35 in the CyTBI-CD34+ and 39 in the FluBu-RIC group). Both groups differed in some baseline characteristics, mainly younger age in the CyTBI-CD34+ group (median 42 vs. 59 years, p<0.01), a higher transplant comorbidity index in the FluBu-RIC group (median 0 vs. 3 points, respectively, P<0.01), a higher proportion of AML (with respect to RAEB) in CyTBI-CD34+ group (82% vs 54%, respectively, P=0.02), and a higher proportion of poor-risk karyorypes in the FluBu-RIC group (32% vs 72%, respectively, P<0.01). The median follow-up exceeds 4 years in both groups. All patients had sustained donor-engraftment by day +60, except for one lethal graft failure in the CyTBI-CD34+ group. The 4-year probability of OS was and LFS were similar in both groups (52% and 53% in the CyTBI-CD34+ group vs. 53% and 53% in the FluBu-RIC group, respectively, P>0.8 for OS and LFS). In addition, the 4-year cumulative incidence of non-relapse mortality (NRM) was 25% (95% CI 11–38%) and 22% (95% CI 5–39%), respectively (P>0.8), while the incidence of relapse was 22% (95% CI 5–39%) and 25% (95% CI 6–44%), respectively (P>0.8). In univariate analysis, the only variable that decreased OS and LFS by increasing NRM was the patient male/donor female sex combination (n=18 cases). The OS and NRM in these 18 cases were 37% and 40%, respectively, while the 56 cases with other sex combinations had much better outcomes (66% OS and 8% NRM, P=0.004 and P==0.001 for the comparison of OS and NRM, respectively). Trends were seen for improved OS and lower NRM in the CyTBI-CD34+ group in patients less than 40 years of age (P=0.1) and in patients receiving higher doses of CD34+ cells/kg in the FluBu-RIC group (P=0.1). Our single-center results suggest comparable outcomes for RIC alloPBSCT in high-risk adults with poor-risk AML and MDS in an early disease phase.
•Using CIBMTR database we compared the most commonly used rituximab-containing RIC approach (ie, FCR) with the most commonly used nonrituximab-containing RIC approach (ie, Flu/Bu) for FL in the ...United States.•There was a significant reduction in the risk of chronic GVHD with FCR compared with Flu/Bu.•FCR was not associated with improved survival relative to Flu/Bu regimen.•Both FCR and Flu/Bu are reasonable RIC platforms for FL patients undergoing allogeneic HCT.
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.
Abstract 130
In April 2006, the Spanish Myeloma Group (PETHEMA/GEM) activated a randomized phase III trial comparing TD vs. VTD vs. VBMCP/VBAD/Velcadeâ in patients 65 years-old or younger with newly ...diagnosed symptomatic MM, followed by ASCT with MEL-200. The primary end points were response rate after induction and after ASCT and time to progression. TD consisted of thalidomide 200 mg daily (escalating doses in the first cycle) and dexamethasone 40 mg on days 1–4 and 9–12 at 4-week intervals for 6 cycles. The VTD regimen was identical to TD plus Velcade 1.3 mg/m2 on days 1,4,8,11 of each cycle. Combination chemotherapy plus Velcadeâ consisted of 4 cycles of VBMCP/VBAD on an alternating basis followed by 2 cycles of Velcadeâ (1.3 mg/m2 on days 1,4,8, and 11 every 3 weeks). The duration of the induction therapy was 24 weeks in all arms. From April 6, 2006 to August 5, 2009 the 390 planned patients entered the study. As of December 31, 2008, 305 patients (median age: 57 yrs, M: 156, F:149; IgG. 181, IgA: 71, light chain: 43, others: 10) entered the study and are the basis of the current analysis. Fifty-six (18%) patients had soft-tissue extramedullary plasmacytomas (EMP) and the stage according to the ISS was I in 39%, II in 41 %, III in 19 % and unknown in 1%. The prognostic factors, including cytogenetics, was similar in the 3 arms. Fifty-five (18%) patients had high-risk cytogenetics (t(4;14), t(14;16) and/or 17p deletion). Two-hundred and ninety-nine patients (TD:103, VTD: 99 and VBMCP/VBAD/Velcade®: 97) were evaluable for response and toxicity to induction therapy. The ≥ PR rate was 64%, 82% and 75% with TD, VTD and VBMCP/VBAD/Velcade®, respectively (p=NS). The IF negative CR rate was significantly higher with VTD (29%) and with VBMCP/VBAD/Velcade® (25%) than with TD (14%) (p=0.009 and p=0.04, respectively). Progressive disease (PD) was significantly higher with TD than with VTD (21% vs. 8%, p=0.009). In the overall series, PD was significanty higher in patients with EMP (34% vs. 12%, p=0.0002) with a significanty higher PD rate for TD as compared with VTD (40% vs. 14%, p=0.05). In patients with poor cytogenetics the CR rate was significantly higher with VTD than with TD (42% vs. 5%, p=0.009). In this high-risk group the PD rate was higher with TD (37%) and with VBMCP/VBAD/Velcade® (23%) than with VTD (0%) (p=0.009 and p=0.04, respectively). The incidence of thrombotic events ≥ grade 3 was higher in the TD arm (9% vs. 1% vs. 3%, p=0.07 and p=0.01) while ≥3 peripheral neuropathy was higher with VTD (14% vs. 0% and 1%, p<0.0001 and p=0.0003). Treatment was discontinued due to toxicity in 11 patients (TD: 3, VTD: 6, VBMCP/VBAD/Velcade®:2). Eight patients died during induction period (TD:5, VTD: 2, VBMCP/VBAD/Velcade®: 1) One-hundred seventy-seven patients were evaluable for response after ASCT. The post-ASCT CR rate with TD, VTD and VBMCP/VBAD/Velcade® was 40%, 59% and 48%, respectively, being significantly higher with VTD than with TD (p=0.05). The estimated overall survival at 2 years is 82% with no significant differences among the 3 arms. TTP and PFS were significantly shorter with TD (p=0.05 and p=0.012, respectively). In summary, VTD results in a higher pre- and post-ASCT CR rate as well as in a lower PD rate than TD, particularly in patients with high-risk cytogenetics or with EMP. The TTP and PFS are shorter with TD. Intermediate results are observed with VBMCP/VBAD/Velcade®. Longer follow-up is needed to establish whether or not these results will translate into a significantly different long-term outcome. Updated data will be presented at the meeting.
Rosiñol:Janssen-Cilag: Honoraria; Celgene: Honoraria. Off Label Use: Thalidomide and bortezomib are not yet approved in Spain. Cibeira:Jansse-Cilag: Honoraria; Celgene: Honoraria. Mateos:Janssen-Cilag: Honoraria; Celgene: Honoraria. Oriol:Janssen-Cilag: Honoraria; Celgene: Honoraria. García-Laraña:Janssen-Cilag: Honoraria; Celgene: Honoraria. de la Rubia:Janssen-Cilag: Honoraria; Celgene: Honoraria. Sureda:Janssen-Cilag: Honoraria; Celgene: Honoraria. Palomera:Janssen-Cilag: Honoraria; Celgene: Honoraria. Díaz-Mediavilla:Janssen-Cilag: Honoraria; Celgene: Honoraria. de Arriba:Janssen-Cilag: Honoraria; Celgene: Honoraria. Alegre:Janssen-Cilag: Honoraria; Celgene: Honoraria. Lahuerta:Janssen-Cilag: Honoraria; Celgene: Honoraria. San Miguel:Janssen-Cilag: Honoraria; Celgene: Honoraria. Blade:Janssen-Cilag: Honoraria; Celgene: Honoraria.
Abstract 3
In elderly pts with newly diagnosed MM, the VISTA trial has demonstrated that the combination of bortezomib plus melphalan – prednisone (VMP) is significantly superior to MP alone. ...However, it remains to be elucidated which agent is the optimal partner for bortezomib: an alkylating agent or an immunomodulatory drug. In order to answer this question, Spanish Myeloma Group activated a phase III trial comparing VMP versus VTP (T for thalidomide) as induction therapy. To evaluate if the treatment regimen could be further optimized by decreasing the toxicity while maintaining efficacy, the intensity of both schedules of induction was reduced as compared with the VISTA regimen but supplemented with maintenance therapy. Between April 2005 and October 2008, 260 pts were randomized to receive 6 cycles of VMP vs VTP as induction therapy followed by maintenance with VT vs VP for up to three yrs. In the VMP arm pts received bortezomib 1.3 mg/m2 twice weekly (days 1, 4, 8, 11; 22, 25, 29 and 32) for one 6-week cycle, followed by once weekly (days 1, 8, 15 and 22) for five 5-week cycles in combination with oral melphalan 9 mg/m2 and prednisone 60 mg/m2 once daily on days 1–4 of each cycle. In the VTP arm pts received the same bortezomib and prednisone, but instead of melphalan they received thalidomide at a dose of 100 mg daily. Following the 6 cycles of induction, pts moved into maintenance that consisted in a conventional cycle of bortezomib, 1.3 mg/m2 twice weekly (days 1, 4, 8, 11) administered every three months in combination with either continuous thalidomide, 50 mg daily (VT) or prednisone, 50 mg on alternate days (VP).
253 pts are evaluable for response to induction; 125 were assigned to receive VMP and 128 to VTP. Regarding baseline characteristics, both arms were well balanced. Response rate to induction therapy was similar in both arms: ≥ PR in 81 and 79% of pts treated with VMP and VTP respectively, with a CR rate of 22% vs 27% (p=NS) and CR+nCR of 36% in both arms. Only two pts progressed under induction treatment in each arm. After a median follow-up of 22m (8-40), there weren't significant differences in terms of 2-y TTP (VMP 75% vs VTP 70%), PFS (VMP 71% vs VTP 61%) and OS (VMP 81% vs VTP 84%). 178 pts were randomized to maintenance and 143 are evaluable for efficacy. Overall, maintenance therapy was able to increase the CR rate from 25% (mean obtained after induction therapy) up to 42%, with no significant differences between VT and VP arms (46 and 38%). After a median duration of maintenance of 13 m there is a trend in favour of VT in terms of 1-y TTP (84% vs 71%; p=0.05), without differences in 1-y OS (92% for VT vs 89% for VP).
27 pts presented high-risk cytogenetic abnormalities (CA) ((4;14)t, (14;16)t, del17p); the CR rate was similar in this high-risk group as compared with standard risk group (26% vs 25% after induction and 42% after maintenance in both groups). There aren't differences between high-risk and standard-risk pts in the 2-y TTP (74% vs 73%) and 2-y OS (77% vs 81%) from inclusion; however, there is a trend to lower 1 y-TTP from the time to randomization to maintenance for the high-risk group compared to the standard-risk (68% vs 79%) without differences in 1 y-OS (90% vs 93%).
Regarding toxicity, during the induction therapy, VMP resulted in higher incidence of ≥G3 neutropenia than VTP (37 vs 21%) and this translated into more ≥G3 infections (7 vs <1%); 8,5% of pts receiving VTP developed ≥G3 cardiac events (cardiac failure (5), atrial fibrillation (2), hypotension (2), heart attack (1) and AV blockage (1)). The incidence of ≥G3 PN was 5% in VMP and 9% in VTP (p=NS). During maintenance therapy, the most relevant ≥G3 toxicities included: cardiac events in 2 pts in VT (supraventricular arritmia (1) and heart attack (1)) vs 1 in VP (cardiac failure); G-I events in 4 pts in VT vs 1 in VP; finally, only one patient in VT arm died during the maintenance therapy due to sepsis. In summary the current results indicate that: 1. both modified induction schedules (VMP and VTP) are highly effective with similar ORR and CR rates, but a clear different toxicity profile (more neutropenia, but less cardiac toxiciety and PN with VMP); 2. maintenance therapy with either VT and VP markedly improve the quality of responses with a good safety profile; and finally 3. the combination of these induction and maintenance schedules seems to overcome the poor prognosis of high-risk CA in elderly MM patients.
Mateos:Janssen Cilag: Honoraria, Speakers Bureau; Celgene corporation: Honoraria, Speakers Bureau. Off Label Use: VTP is not approved for the treatment of untreated MM patients. Cibeira:Jansen-Cilag: Honoraria; Celgene: Honoraria. Gutiérrez:Janssen Cilag: Honoraria; Celgene: Honoraria. García-Laraña:Janssen-Cilag: Honoraria; Celgene: Honoraria. Palomera:Janssen-Cilag: Honoraria; Celgene: Honoraria. de Arriba:Janssen-Cilag: Honoraria; Celgene: Honoraria. San-Miguel:Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees; Millennium: Honoraria, Membership on an entity's Board of Directors or advisory committees; Janssen–Cilag: Honoraria, Membership on an entity's Board of Directors or advisory committees.
Darbepoetin- alpha , a novel hyperglycosylated erythropoiesis-stimulating protein, was administered to 20 patients with myelofibrosis with myeloid metaplasia and anaemia. The initial weekly dose, 150 ...mu g, was increased to 300 mu g when no response was observed after 4-8 weeks. Eight patients (40%) responded to treatment, including six complete and two partial responses, and five maintained their response at a median follow-up of 12 months (range 4-22). Univariate analysis indicated that older age was the only factor associated with a favourable response to treatment (P = 0.006). None of the patients with appropriate serum erythropoietin levels responded. Treatment was usually well tolerated.
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