•Consolidative autologous hematopoietic cell transplantation is recommended in the first-line treatment of patients with mantle cell lymphoma (MCL) in complete or partial remission.•Chimeric antigen ...receptor T cell therapy should be considered in MCL patients who relapse after (or who are intolerant to) at least one Bruton's tyrosine kinase inhibitor.
Autologous (auto-) and allogeneic (allo-) hematopoietic cell transplantation (HCT) are accepted treatment modalities in contemporary treatment algorithms for mantle cell lymphoma (MCL). Chimeric antigen receptor (CAR) T cell therapy recently received approval for MCL; however, its exact place and sequence in relation to HCT remain unclear. The American Society of Transplantation and Cellular Therapy, Center of International Blood and Marrow Transplant Research, and the European Society for Blood and Marrow Transplantation jointly convened an expert panel to formulate consensus recommendations for role, timing, and sequencing of auto-HCT, allo-HCT, and CAR T cell therapy for patients with newly diagnosed and relapsed/refractory (R/R) MCL. The RAND-modified Delphi method was used to generate consensus statements. Seventeen consensus statements were generated, with a few key statements as follows: in the first line setting, auto-HCT consolidation represents standard of care in eligible patients, whereas there is no clear role of allo-HCT or CAR T cell therapy outside of clinical trials. In the R/R setting, the preferential option is CAR T cell therapy, especially in patients with MCL failing or intolerant to at least one Bruton's tyrosine kinase inhibitor, while allo-HCT is recommended if CAR T cell therapy fails or is infeasible. Several recommendations were based on expert opinion, where the panel developed consensus statements for important real-world clinical scenarios to guide clinical practice. In the absence of contemporary evidence-based data, the panel found RAND-modified Delphi methodology effective in providing a formal framework for developing consensus recommendations for the timing and sequence of cellular therapies for MCL.
The in vivo depletion of recipient and donor T lymphocytes using antithymocyte globulin (ATG; Thymoglobulin) is widely adopted in allogeneic hematopoietic stem cell transplantation (HCT) to reduce ...the incidence of both graft failure and graft-versus-host disease (GVHD). However, excess toxicity to donor lymphocytes may hamper immune reconstitution, compromising antitumor effects and increasing infection. Granulocyte-colony stimulating factor (G-CSF) administered early after HCT may increase ATG-mediated lymphotoxicity. This study aimed to investigate the effect of an interaction between ATG and post-transplantation granulocyte colony-stimulating factor (G-CSF) on allogeneic HCT outcomes, using the Center for International Blood and Marrow Transplant Research (CIBMTR) registry. We studied patients age ≥18 years with acute myelogenous leukemia (AML) and myelodysplastic syndrome (MDS) who received Thymoglobulin-containing preparative regimens for HLA-matched sibling/unrelated or mismatched unrelated donor HCT between 2010 and 2018. The effect of planned G-CSF that was started between pretransplantation day 3 and post-transplantation day 12 was studied in comparison with transplantations that did not include G-CSF. Cox regression models were built to identify risk factors associated with outcomes at 1 year after transplantation. A total of 874 patients met the study eligibility criteria, of whom 459 (53%) received planned G-CSF. HCT with planned G-CSF was associated with a significantly increased risk for nonrelapse mortality (NRM) (hazard ratio HR 2.03; P <.0001; 21% versus 12%) compared to HCT without G-CSF. The 6-month incidence of viral infection was higher with G-CSF (56% versus 47%; P = .007), with a particular increase in Epstein-Barr virus infections (19% versus 11%; P = .002). The observed higher NRM with planned G-CSF led to lower overall survival (HR, 1.52; P = .0005; 61% versus 72%). There was no difference in GVHD risk between the treatment groups. We performed 2 subgroup analyses showing that our findings held true in patients age ≥50 years and in centers where G-CSF was used in some, but not all, patients. In allogeneic peripheral blood HCT performed with Thymoglobulin for AML and MDS, G-CSF administered early post-transplantation resulted in a 2-fold increase in NRM and a 10% absolute decrement in survival. The use of planned G-CSF in the early post-transplantation period should be carefully considered on an individual patient basis, weighing any perceived benefits against these risks.
Among newly diagnosed myeloma patients ≥75 years, the stem cell transplant utilization rate was significantly lower in African Americans - females>males, compared to whites, while overall outcomes ...remain excellent for this selected population. Only high-risk cytogenetics were associated with inferior outcomes.
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Survivors of hematopoietic stem cell transplantation (SCT) must adhere to various lifestyle changes and medication regimens to protect their health and recovery, often for an extended time. Little ...evidence describes adherence after SCT or correlates of adherence, although evidence from other populations strongly suggests that adherence will be suboptimal for many survivors. To explore these research questions, we conducted secondary analyses on self-reported data from 255 survivors participating in a larger intervention trial. All had undergone stem cell transplant (SCT) (55% autologous, 45% allogeneic) 9 months to 3 years prior to enrollment for a hematologic cancer. After completing baseline measures, they were randomized to one of 4 study arms that varied the writing instructions they were provided as they completed 4 brief writing assignments (1 per week over 4 weeks) in which they wrote about their SCT experience. The 2x2 factorial design crossed whether they used evidence-based instructions for emotionally expressive writing (yes/no) and whether they were told their writing was to be shared with other patients as a form of peer support (yes/no). Writing instructions were not associated with outcomes in the present analyses and are not further described (see Rini et al, 2014). Participants completed a follow-up assessment 3 weeks after the intervention. Collapsing across study arms, we examined participants' self-reports about whether their medical team currently recommended changes to their diet and social activities (e.g., avoiding crowds or ill people), and whether they were currently supposed to be taking medications related to their SCT; because this was not a primary goal of the research, we did not assess what medications they were prescribed. Survivors who reported a recommendation to engage in each behavior also reported the extent to which they were following recommendations on a scale from 1=not at all to 5=completely. A substantial minority of participants reported that their medical team currently recommended changes to their diet (14.2%) and social activities (18.3%), and that they needed to take SCT-related medications (46.5%). Participants who had undergone SCT more recently (fewer weeks since SCT) were more likely to report recommendations to change their social activities (r = -.18, p = .005). Also, compared to autologous SCT survivors, allogeneic SCT survivors were more likely to report recommendations to change their diet (p = .03) and social activities (p = .004), and the need to take medications (p < .001). Only 55.2% of participants who reported being informed of the need to make dietary changes said they were quite a bit or completely adherent (4 or 5 on the response scale). A greater, but still suboptimal, proportion (74.0%) were quite a bit or completely adherent with recommended social activity changes, and 95.8% were quite a bit or completely adherent with medication use (83.9% completely and 11.9% quite a bit). Depending on the medication in question and survivors' definition of being completely versus quite a bit adherent, these findings may indicate cause for concern. Research on solid organ transplant suggests that even small deviations from recommended dosages can influence graft loss or rejection (Dobbels et al., 2010). With respect to correlates of adherence, better physical functioning (SF-36 physical component scores; r = -.33, p = .04) was associated with lower adherence with dietary changes. For social activity changes, having a higher quality relationship with a partner and having more years of education were associated with greater adherence (r = .41, p = .02, and r = .40, p = .01, respectively) whereas having children was associated with lower adherence (r = -.31, p = .03). For medications, better physical functioning was associated with lower adherence (r=-.19, p =.045). Findings suggest that practical, psychological, and social factors may influence adherence to important lifestyle and medication regimens after SCT. They also provide a rationale for larger scale studies using rigorous measures. Using digital platforms/devices to track adherence would provide needed rigor while enabling development of digital coaching interventions to promote sustained behavior change. In the era of consumerization of medicine, it is important to provide evidence to patients that consumerization also means sustained self-engagement to optimize their outcome.
Munshi:Kite: Speakers Bureau.
Background: Autologous hematopoietic cell transplantation (AHCT) is an effective treatment to achieve deep and durable remission in multiple myeloma (MM). Typically, AHCT is offered to patients <70 ...years of age, although the median age of diagnosis of MM is 70 years. We compared the outcomes of upfront AHCT across age groups for newly diagnosed MM in the era of novel therapies using the Center for International Blood and Marrow Transplant Research (CIBMTR) database.
Methods: We analyzed the outcomes of 15,999 MM patients aged 20 years and older from the USA who received a single AHCT with melphalan conditioning within 12 months of diagnosis between 2013 and 2017 and reported to the CIBMTR. Multivariate analysis was performed for non-relapse mortality (NRM), relapse/progression (REL), progression-free survival (PFS) and overall survival (OS) using Cox proportional hazards model with age at transplant in decades as the main effect. Hazard ratio (HR) with 95% confidence intervals (CI) are reported. Because of the large sample size, a p-value of <0.01 was considered significant a priori.
Results: Table 1 shows patient, disease and treatment characteristics by age group at diagnosis. All age groups had similar distribution of gender, race, ethnicity, Karnofsky performance score (KPS), comorbidity index (HCT-CI), stage III by Durie-Salmon/International Staging System. There was a higher proportion of high-risk cytogenetics in patients ≥70 years (30%), compared to age group 40-49 years (24%) and 20-39 years (20%) in this population. Older patients were more likely to be White compared to younger patients: 85% ≥70 compared to 64% 20-39 years. While 82% of the overall population received melphalan 200 mg/m2, 58% of the ≥70% received Mel 140 mg/m2. There were more ASCT performed in the ≥70-year age group in 2017 (28%) compared to 2013 (15%). Univariate outcomes by age groups shown in Table 2 revealed that 100-day NRM was higher in ≥70 years at 1% compared to younger patients (p <0.01) and 2-year OS was lower in ≥70 years at 86 (85-88)% compared to 60-69 years, 89 (88-89)% (p<0.01). When adjusted for other variables (Table 3), compared to reference age group of 60-69 years, patients ≥70 had similar NRM (HR 1.3, 95% CI 1, 1.7, p 0.06), REL (HR 1.03, 95% CI 0.9, 1.1, p 0.6), PFS (HR 1.06, 95% CI 1, 1.2, p 0.2), and OS (HR 1.2, 95% CI 1, 1.4, p 0.02). The leading cause of death across all age groups was primary disease. Among the ≥70 years cohort, melphalan dose was a surrogate for worse outcomes including NRM at 100 days (Mel 140, 1 (1-2)% vs Mel 200 0 (0-1)%, p 0.003, PFS at 2 years Mel 140 64 (60-67)% vs Mel 200 69 (66-73)%, p 0.003, and OS at 2 years (Mel 140 85 (82-87)% vs Mel 200 89 (86-91)%, p 0.01) (Figure).
Conclusions: This is the largest study of AHCT in older adults with MM. More MM patients ≥70 years are being transplanted in the US over time. While our data may highlight referral and access biases regarding which older patients may be referred for ASCT, our results confirm that patients ≥70 years can undergo transplant safely and achieve similar benefits as 60-69 years' old patients. Our results also suggest that melphalan 200 mg/m2 may be given safely in the ≥70 years population. While melphalan conditioning dose 140 mg/m2 in the ≥70 group is associated with worse outcomes, this is likely a surrogate for higher frailty and comorbidities in this cohort of patients. Our analysis confirms that AHCT has similar benefits in terms of disease control (REL and PFS) in both young and older MM patients. This benefit is seen even in a contemporaneous era where proteasome inhibitors and/or immunomodulator drugs are used in upfront treatment. Thus, AHCT remains a safe consolidation therapy across all age groups of MM patients.
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Hari:Celgene: Consultancy, Honoraria, Research Funding; Takeda: Consultancy, Honoraria, Research Funding; BMS: Consultancy, Research Funding; Janssen: Consultancy, Honoraria; Kite: Consultancy, Honoraria; Amgen: Research Funding; Spectrum: Consultancy, Research Funding; Sanofi: Honoraria, Research Funding; Cell Vault: Equity Ownership; AbbVie: Consultancy, Honoraria. Kumar:Janssen: Consultancy, Research Funding; Takeda: Research Funding; Celgene: Consultancy, Research Funding. Shah:Poseida: Research Funding; Bristol-Myers Squibb: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Nkarta: Consultancy, Membership on an entity's Board of Directors or advisory committees; Kite: Consultancy, Membership on an entity's Board of Directors or advisory committees; Celgene, Janssen, Bluebird Bio, Sutro Biopharma: Research Funding; University of California, San Francisco: Employment; Genentech, Seattle Genetics, Oncopeptides, Karoypharm, Surface Oncology, Precision biosciences GSK, Nektar, Amgen, Indapta Therapeutics, Sanofi: Membership on an entity's Board of Directors or advisory committees; Indapta Therapeutics: Equity Ownership; Amgen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Teneobio: Consultancy, Membership on an entity's Board of Directors or advisory committees. Qazilbash:Genzyme: Other: Speaker; Bioclinical: Consultancy; Amgen: Consultancy, Other: Advisory Board; Autolus: Consultancy. D'Souza:EDO-Mundapharma, Merck, Prothena, Sanofi, TeneoBio: Research Funding; Prothena: Consultancy; Pfizer, Imbrium, Akcea: Membership on an entity's Board of Directors or advisory committees.
Background: Salvage autologous hematopoietic stem cell transplantation (HSCT) is an effective treatment for patients with relapsed multiple myeloma (MM). Adequate HPSC after multiple cycles of ...dose-intense melphalan (mel) can be harvested, cryopreserved, and stored to allow for such future transplants. Many investigators reported sustained CD34+ cell viability using in vitro assays such as colony forming units (CFU-GM) potency of HPSCs after long term storage. Data on engraftment outcomes using these products demonstrating in vivo viability are limited. This study describes a large single center experience evaluating the engraftment potential of HPSC used in salvage transplantation after long-term storage in patients with MM, in comparison to initial treatment.
Study Design and Methods: We conducted a retrospective chart review of patients with MM undergoing salvage HSCT, whose initial cell collection occurred between January 2002 and May 2016. This review identified 59 patients, all conditioned for initial transplants with dose-intense Mel 200 mg/m2, and who received autologous HPSC stored > 1 year after initial HSCT. HPSC were cryopreserved and stored in vapor phase liquid nitrogen at a temperature of ≤-150°C. Conditioning regimens for salvage transplants were mel (n=11), mel/bortezomib (bor) (n=32), mel/bor/thalidomide (n=6), BEAM (n=1), and Super BEAM (n=9). Patients who received a planned tandem transplant only (less than a year apart) were excluded. For patients receiving tandem HSCT followed by salvage HSCT, the first of the tandem HSCTs was considered for this analysis (n=5). Differences in CD34+ cell doses and days to engraftment between first and salvage transplant were tested using a paired 2-tailed t-test. Univariate and multivariable linear regressions were used to determine association between storage time and days to engraftment.
Results: From 2002 to 2017, transplant data from 59 MM patients were analyzed (Table 1). Forty-nine (83%) patients had a Salmon Durie stage IIIA or IIIB at first diagnosis. The median age at first diagnosis was 57.5 (range, 36-73) years. A median collection dose of 16.0 × 106 CD34+ cells per kilogram (range, 7.9-62.5) was reached during HPSC collection with a median of 3 collections (range, 1-7) per patient. All 59 patients collected upon first mobilization attempt. The median age of patients at time of first and salvage transplants was 59 and 62 years, respectively. As predicted, the patient's age at salvage transplant was significantly greater than the age at first transplant (p<0.001). The median storage time between day of initial collection and salvage transplant was 4.0 years (range 1-14.6), with 37% (n=22) and 8% (n=5) stored for over 5 and 8 years, respectively. The median time between first and salvage transplants was 4.0 years (range 1-14.5). Patients achieved sustained neutrophil engraftment (ANC>500 /uL) at a median of 11 days after both the first and salvage transplant (ranges, 9-18 and 8-15 respectively, p=0.041) (Figure 1). The median time to sustained platelet engraftment (>20 x 109/L) was 13 days (range, 9-36) after first HSCT and 14 days (range 8-45) after salvage HSCT (p=0.842) (Figure 1). The CD34 dose for the salvage transplant was significantly higher than the first transplant, with patients undergoing the first HSCT receiving a median CD34+ cell dose of 5.3 × 106/kg (range 3.0-14.1), compared to a median of 6.1 × 106/kg (range 3.4-13.8) for the salvage HSCT (p=0.04). There was no association between the CD34 dose infused and days to ANC (p=0.755) or platelet (p=0.669) engraftment. After adjusting for age at transplant and CD34 dose, there was no association between duration of cryopreservation and days to ANC (p=0.658) and platelet (p=0.725) engraftment (Figure 2). There were no graft failures reported in either the first or salvage HSCT.
Conclusion: Long-term cryopreservation did not affect engraftment outcomes in patients with MM receiving salvage autologous HSCT, despite the addition of salvage chemotherapy. There was no association between engraftment kinetics and storage duration in patients receiving a salvage transplant when controlling for CD34 dose and recipient age. Although it is possible that these cell products may have lost HPSC viability but still contained more than adequate viable HSC for HSCT, there was no evidence of delayed engraftment, particularly of platelets, suggestive of low numbers of viable HSCT.
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Biran:Celgene: Consultancy, Honoraria; Bristol Meyers Squibb: Research Funding; Takeda: Consultancy, Honoraria; Janssen: Consultancy, Honoraria, Research Funding; Merck: Research Funding; Amgen: Consultancy, Honoraria, Research Funding. Goldberg:Bristol-Myers Squibb: Consultancy; Cancer Outcomes Tracking and Analysis (COTA) Inc.: Equity Ownership; COTA: Equity Ownership. Siegel:Takeda: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Janssen: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Bristol-Myers Squibb Company: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Celgene: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Amgen: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau. Rowley:Allergan: Equity Ownership; Fate Therapeutics: Consultancy.
Rationale:
ASCT remains a standard-of-care as consolidation or salvage for multiple myeloma (MM), post-salvage consolidation for Diffuse Large B-Cell Lymphoma (DLBCL) and upfront consolidation or ...salvage for Peripheral T-Cell Lymphomas (PTCL) Pts with high-risk disease still show poor outcome and frequent progression within the first 18 months. Maintenance strategies post ASCT, particularly in lymphomas, have failed to show benefit, underlining the need for novel approaches to help disease control following ASCT. We have previously reported on the preliminary safety and efficacy of checkpoint inhibitor consolidation with Ipi and Nivo following ASCT trying to take advantage of the immunological milieu during post-ASCT recovery (Skarbnik et al., ASH 2017). Here we present updated data from our Phase I CPIT-001 trial.
Methods:
Pts with high-risk DLBCL, PTCL or MM (as defined in Table 1, divided in cohorts) were eligible if they experienced at least stable disease after most recent salvage therapy (NHL, PTCL or relapsed MM) or after induction therapy for high-risk MM.
Pts were enrolled prior to ASCT, starting in July 2016. All pts with DLBCL/PTCL received BEAM (carmustine 300 mg/m2 day -6, etoposide 200 mg/m2 and cytarabine 200 mg/m2 days -5 to -2, melphalan 140 mg/m2 day -1) as conditioning regimen for ASCT, all pts with MM received melphalan 200 mg/m2 on day -1
For pts who achieved appropriate hematologic recovery (ANC >800/mm3 and platelets > 20,000/mm3), Ipi/Nivo were started between days 14 and 28 post ASCT. The infusion schedule was: •Ipi: 1 mg/kg; 6 doses Weeks 1, 4, 7, 10, 16, 22•Nivo: 3 mg/kg; 12 doses Weeks 1, 4, 7, 10, 12, 14, 16, 18, 20, 22, 24, 26
Primary objectives were: Safety profile evaluation; PFS and OS at 18 months (PFS18 and OS18).
Cox proportional hazards regression was utilized to determine predictors of outcome.
Results:
31 pts received at least one dose of Ipi/Nivo following ASCT and were included in the intent-to-treat population. Median follow up for the whole cohort is 16 months. As of February 2018, the FDA has halted all studies including checkpoint inhibitors for pts with MM. At that time, only one pt with MM was actively receiving Ipi/Nivo, which was then discontinued.
At 18 months post ASCT, estimated PFS for the entire cohort was 67% and OS was 84% (Figures 1 and 2). Disease-specific PFS18 and OS18 are described in Table 2.
At study entry, 48% of pts were in CR (NHLs) or stringent CR (sCR, MMs). At most recent follow-up (range 2-25 months) 71% of pts were in CR (NHL) or sCR (MM). Disease status at study entry (i.e. CR vs <CR) didn't correlate with PFS nor OS.
65% of pts developed immune-related adverse events (irAEs) grade 2 or higher, requiring treatment with systemic steroids. Most common irAEs of any grade were: colitis (58%), rash (48%), thrombocytopenia (45%), anemia (45%) and transaminitis (32%). One pt (3%) died from complications of pneumonitis related to study drugs. All other irAEs resolved. Median time from 1st Ipi/Nivo to development of irAEs was 4 weeks. Median time to improvement to Grade 1 or baseline was 1 week after high-dose steroids were initiated. Treatment-related AEs of any grade that led to discontinuation of Ipi/Nivo occurred in 6 pts (19%).
Development of irAEs, use of steroids or length of steroid-exposure did not correlate with PFS or OS.
Conclusion:
At 18 months post-ASCT, PFS for pts with high-risk hematological malignancies is 67%. This number underscores the potential for longer remissions by associating checkpoint inhibition with ASCT. For patients in the transplant-naïve MM with high-risk cytogenetics cohort, the 71% PFS18 (fig 3) is particularly striking, when compared to median PFS of 13-15 months in previous reports of ASCT alone in this patient population (Sonneveld et al, Blood 2016). In addition, the primary-refractory DLBCL population (43% of which were not in CR at time of ASCT) presented with a PFS18 of 83% (fig 4), while the reported PFS18 for this patient population with ASCT alone is 50% (Crump et al, Blood 2017). The cohort of pts with DLBCL relapsed within 1 year of induction had the poorest outcomes, possibly related to these pts being the most heavily pretreated in the whole cohort (median of 3 prior lines of therapy), with 57% of pts in this cohort refractory to most recent line of therapy.
The manageable toxicity profile, coupled with the encouraging efficacy outcomes warrant further evaluation of this approach in a Phase II trial, which is currently planned.
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Skarbnik:Pharmacyclics: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Jazz Pharmaceuticals: Honoraria, Speakers Bureau; Abbvie: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Gilead Sciences: Honoraria, Speakers Bureau; Novartis: Honoraria, Speakers Bureau; Seattle Genetics: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Genentech: Honoraria, Speakers Bureau. Munshi:Kite: Speakers Bureau. Siegel:BMS: Consultancy, Honoraria, Speakers Bureau; Amgen: Consultancy, Honoraria, Speakers Bureau; Karyopharm: Consultancy, Honoraria; Merck: Consultancy, Honoraria, Speakers Bureau; Novartis: Honoraria, Speakers Bureau; Janssen: Consultancy, Honoraria, Speakers Bureau; Celgene: Consultancy, Honoraria, Research Funding, Speakers Bureau; Takeda: Consultancy, Honoraria, Speakers Bureau. Feldman:Pharmacyclics: Speakers Bureau; KITE: Speakers Bureau; Portola: Research Funding; Celgene: Speakers Bureau; Seattle Genetics: Research Funding, Speakers Bureau; Johnson and Johnson: Speakers Bureau; Janssen: Speakers Bureau. Biran:BMS: Research Funding; Amgen: Consultancy, Speakers Bureau; Takeda: Consultancy, Speakers Bureau; Celgene: Consultancy, Honoraria, Speakers Bureau; Merck: Research Funding. Atkins:BMS: Consultancy; Merck: Consultancy.
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