Introduction: Haplo-cord transplantation - the co-infusion of a single umbilical cord graft with CD34-selected cells from a haplo-identical donor, offers an alternative stem cell source for patients ...lacking HLA-matched donors. The T-cell depleted haplo-graft acts as a myeloid bridge until replaced by durable cord hematopoiesis.
Anti-thymocyte globulin (ATG) is routinely used in haplo-cord preparative regimens to reduce graft failure, graft vs. host disease (GVHD) and graft vs. graft reactions. ATG depletes T-lymphocytes through Fas-mediated apoptosis, but also indirectly stimulates T-cell destruction through antibody-dependent cellular phagocytosis (ADCP) and antibody-dependent cellular cytotoxicity (ADCC) (de Koning, Blood Adv. 2018). Excessive depletion of cord lymphocytes may compromise immune reconstitution and graft vs. tumor effects.
G-CSF administration early post-transplant may sensitize cord lymphocytes to the cytotoxic effects of residual ATG. G-CSF drives myeloid precursor proliferation and activates phagocytosis, facilitating increased ADCP and ADCC of ATG-coated cells (de Koning, Blood Adv, 2018). Prior to the publication of this data, our institutional practice was to administer G-CSF to haplo-cord transplant recipients from day +6 until neutrophil engraftment. In April 2018, we altered our practice - withholding routine G-CSF treatment. We here compare our transplant outcomes 1 year before and after this practice shift.
Methods: We examined consecutive adult patients with hematologic malignancy that underwent haplo-cord transplantation conditioned with fludarabine and melphalan with or without total body irradiation (400 cGy) at Weill Cornell Medicine, between 04/2017 and 04/2019. All patients received rabbit ATG (Thymoglobulin) 1.5 mg/kg on days -5, -3 and -1 (total dose 4.5 mg/kg). Data was collected as part of study 01810588 registered at clinicaltrials.gov.
Probabilities of relapse, relapse-related mortality (RRM) and non-relapse mortality (NRM) were generated using cumulative incidence (CI) estimates to accommodate competing risks. Probabilities of overall survival (OS) and progression-free survival (PFS) were calculated using Kaplan-Meier estimates and inter-group comparison performed by log-rank testing. Variables with potential survival impact were evaluated in a Cox proportional hazards regression model.
Results: The study included 59 haplo-cord recipients - 30 who received G-CSF (GCSF group) and 29 who did not (NO GCSF group). Groups were well matched for age, weight, disease, DRI, baseline lymphocyte count, CMV recipient/donor status and TBI treatment (Table). Neutrophil engraftment occurred at a median of 10 days in the GCSF group vs. 14 days in the NO GCSF group (p=0.0002), and platelet recovery at a median of 20 and 22 days (p=-0.61). Primary graft failure occurred in 1 GCSF patient and 2 NO GCSF patients (p=0.53).
The incidence of acute GVHD (grade II-IV) by day 100 was 10% in both groups (p=0.97). There was no significant difference between GCSF and NO GCSF in the CIs of relapse, RRM or NRM at 1yr. No difference was found in 1yr OS or PFS on univariate analysis (Table). After adjusting for patient age, weight, lymphocyte count prior to ATG, disease subtype, CIBMTR disease risk index (DRI), Karnofsky performance status (KPS), comorbidity score and TBI exposure, in multivariate analysis, no effect on OS or PFS was observed.
CMV reactivation was observed in 40% (GCSF) vs. 21% (NO GCSF) (p=0.11). The trend towards lower reactivations in the NO GCSF may in part be due to the introduction of letermovir prophylaxis for CMV positive transplant recipients in 02/2018. Acknowledging the limited follow up of NO GCSF patients, we note a trend towards improved CD4 counts at 1yr in this group - median 271 cells/μL (n=6, IQR25-75 = 240-342) vs. 155 cells/μL in the GCSF group (n=16, IQR25-75 = 111-473) (p=0.17).
Conclusion: Our data shows that G-CSF can safely be eliminated from haplo-cord transplant. We see a delay in neutrophil engraftment but no adverse effect on early morbidity or mortality outcomes. We continue to withhold early G-CSF while assessing long-term outcomes. Longer follow-up is needed in our cohort to enable a systematic analysis of immune reconstitution. Early CD4+ cell recovery after ATG treatment has been shown to improve OS, PFS, NRM and RRM (Admiraal, Lancet Hem 2015 & 2017).
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Van Besien:Miltenyi Biotec: Research Funding.
Background: Most older patients (pts) with relapsed or refractory (R/R) AML cannot tolerate intensive treatment and are not eligible for curative allogeneic hematopoietic cell transplant (alloHCT). ...131I-apamistamab, an anti-CD45 radioimmunoconjugate, delivers high dose targeted radiation to hematopoietic cells, allowing for myeloablation and eradication of leukemic cells. 131I-apamistamab led induction and conditioning can provide these pts with access to alloHCT. Methods: SIERRA (NCT02665065) was a multi-center, randomized, controlled phase 3 study comparing the efficacy of 131I-apamistamab led induction and conditioning versus physician's choice of conventional care (CC) in pts ≥55 years of age with active, R/R AML. Pts were randomized (1:1, n=153) to CC or 131I-apamistamab with fludarabine and total body irradiation (2 Gy) followed by alloHCT. Primary endpoint was durable complete remission (dCR), defined as CR ≥6 mos with or without platelet recovery (CRp). Pts not achieving CR in CC could crossover (CO) to receive 131I-apamistamab. Treatment with 131I-apamistamab was prescribed as an individualized dose for each pt following a dosimetric infusion and biodistribution analysis, with the prescribed activity of 131I set to deliver a maximum estimated radiation dose to the liver as the dose limiting organ of 24 Gy (determined as the maximum tolerable dose (MTD)) in earlier studies), thereby providing the highest dose to the diseased bone marrow and circulating leukemic cells without exceeding individual organ radiation dose tolerances. Here, we performed an analysis to determine whether a radiation dose-response relationship could be established based on either 1) administered radiation dose to liver and the rate of achieving the primary endpoint of dCR (with 95% binomial confidence intervals) or 2) dCR rate and the ratio of bone marrow/liver absorbed radiation dose as an indicator of favorable biodistribution between target/risk organ. Results: All pts receiving the therapeutic dose of 131I-apamistamab (n=66) were able to receive an alloHCT, and the primary endpoint (dCR) was achieved in 13 pts receiving 131I-apamistamab vs 0 pts in CC (p<0.0001). The median absorbed liver dose was 21.6 Gy (IQR: 21.0 - 22.8 Gy), median absorbed dose to bone marrow was 16.0 Gy (IQR: 11.5 - 22.3 Gy), and median ratio between marrow/liver dose was 0.79 (IQR: 0.52 - 1.02). Table 1 shows the distribution and rate of dCR for pts who received above or below 22 Gy administered dose to liver (24 Gy to liver was the established MTD from earlier studies, in which doses were escalated in 2 Gy increment and thus, 22 Gy represented MTD-1), and for pts stratified by marrow/liver dose ratio (higher ratio representing more favorable biodistribution). Pts with ≤22 Gy liver dose had a dCR rate of 13.5% vs. 27.6% for pts with >22 Gy liver dose, and pts with <median dose to bone marrow had a dCR rate of 12.1% vs. 27.3% for pts with ≥median estimated marrow dose. Importantly, pts with increasingly favorable biodistribution had nominally higher dCR rates of 10.0%, 20.0% and 26.9% for a marrow/liver ratio <0.6, 0.6-0.9 and >0.9, respectively, as illustrated in Figure 1. Taken together this demonstrates a radiation dose-response for the primary endpoint in this study. Overall, safety was similar across doses to the liver. Conclusion: 131I-apamistamab led induction and conditioning followed by alloHCT resulted in statistically significant improvement in dCR at 6 mos vs conventional care. A dose-response was demonstrated for pts receiving 131I-apamistamab with those receiving a liver dose closer to the MTD of 24 Gy having about twice the dCR rate compared to pts 22 Gy (MTD-1) or less. We also found pts with higher marrow/liver ratio experienced considerably higher rates of dCR which highlights the importance of maximizing the dose to target tissues, within the limits of established risk organ dose tolerances.
Introduction: Umbilical cord blood (UCB) transplant supported by third party CD34-selected cells results in rapid count recovery, UCB mediated GVL effects and low rates of chronic GvHD. For patients ...lacking haplo-identical relatives, other sources of CD34 progenitors are needed.
Methods: We identified partially matched unrelated donors for patients lacking suitable haplo-identical donors -including second-degree relatives - and who otherwise were candidates for haplo-cord transplant. Most were treated on prospective studies (clinicaltrials.gov 00943800 and 01810588). For 5 patients, UCB were obtained through NCT01351545.
Results: Between 12/2014 to 7/2018 of 126 candidates for haplo-cord transplant, 26 (21%) had no suitable related donor. Most common reasons were: no first or second degree partially matched donors, ill or unavailable relative, high titers of HLA-antibodies against all relatives, or evidence of hematological familial hereditary syndrome. Diagnoses were: 16 AML/MDS, 5 ALL, 2 MPN, 1 NHL, 1 plasma cell leukemia and 1 SAA. Median age was 57 (24-75). 50% were women. 42% non-Hispanic white (NHW), 19% non-Hispanic blacks (NHB), 19% Hispanic, 8% other minorities. CIBMTR Disease Risk Index (DRI): 46% intermediate, 38% high and 8% very high. Median HCT-CI was 3.5 (25%-75% IQR 2-6). Conditioning: 16 Flu/Mel/TBI (94% 400cGray), 8 Flu/Mel,1 Flu/Cy, 1 Etoposide/TBI. All except 1 received ATG 4.5 mg/kg and all received post-transplant Tacrolimus and MMF. UCB matching was 4/8, 5/8, 6/8 or 7/8 HLA in 12%, 27%, 23%, and 38%, respectively. HLA matching for unrelated haplos was 5-6/12, 7-8/12, >9/ 12 HLA in 15%, 54% and 19%, respectively. For UCB, median cells collected were 2.1 (range1.1-4.0) ×107 TNC/kg. CD34 cell dose of unrelated donor graft was 3-5 ×106 CD34/kg. Median time to ANC engraftment was 11 days (range 9-35) and platelet engraftment was 18 days (range11-124). Chimerism on day 56 are shown in figure 1. There were three patients with graft failures: Pt #5 with complete graft rejection, autologous reconstitution, but ongoing clinical remission that persists to date (Day+ 1223); Pt #13 with graft failure and subsequent relapse, rescued with second UCB HSCT but died of progression of disease; and pt #18 who died from infectious complications after graft failure. Acute GvHD occurred in 35% of patients (4 Grade I-II, 4 Grade III, and 1 Grade IV). cGvHD was rare: One patient with mild severity and a second with severe lung involvement. After a median follow up of 209 days, 6 months cumulative incidence of relapse (CIR) was 16% and non-relapse mortality (NRM) was 20%. Median OS was 14 months (95%CI 7-27).
Conclusion: 20% of adults without matched related or unrelated donors, also lack suitable first or second degree haplo-identical donors. UCB transplant with partially matched unrelated donor accessory cells provides an alternative for transplantation. Engraftment is rapid, rates of acute GVHD are acceptable and incidence of chronic GVHD is very low. Prolonged survival is encouraging in this patient cohort with adverse characteristics and who would not be candidate for haplo-identical HSCT.
No relevant conflicts of interest to declare.
The use of mismatched donors is rapidly increasing for pts with hematological malignancies in need of allo HCT. Here we compared the outcomes of melphalan based reduced-intensity conditioning (RIC) ...using haplo-identical transplantation with post transplant cyclophosphamide (PTCy) and haplo cord transplantation where a CBU graft is supplemented with CD34 selected haplo-identical cells to accelerate engraftment.
Patients and Methods:
217 pts underwent Haplo transplants at MDACC. Conditioning consisted of fludarabine (flu)-melphalan 140 mg/m2 (mel) (47) flu-mel-thiotepa (129), or flu-mel-TBI 200 cGy (37). Dose of Mel was 140 mg/m2 for 128 and 100 mg/m2 for 88.GVHD prophylaxis was PTCy, tacro and mycophenolate (MMF). Graft source was bone marrow in 206 pts and PBSC in 11. 224 pts underwent HC HCT at Weill Cornell, New York and at the University of Chicago. Conditioning consisted of Flu-Mel (178) or Flu-Mel-TBI 400 cGy (46). Dose of Mel was 140 mg/m2. GVHD prophylaxis was ATG, tacro and MMF. Pt characteristics are in Table 1. 58% of haplo vs 67% of HC recipients had AML or MDS (P=0.01). 36% of HC vs 20% of Haplo were 60 and older (P=0.007) and 56% of HC vs 34% of Haplo had HCTCI >=3 (P=0.0000). Median F/U was 30 mo for HC vs 21 mo for Haplo group.
Results
Median time to neutrophil recovery was 11 days after HC vs 19 after Haplo SCT (p<0.001). Time to plt recovery was 22 d after HC vs 26 Haplo SCT (p =0.001). CI of gr II-IV aGVHD was 21% by d150 after HC vs35% after Haplo SCT (p=0.0005). CI of gr III-IV aGVHD was identical at 11% in each group. CI of all chronic GVHD was 2% at one year after HC vs 16% after Haplo SCT (p<0.001). Overall survival, PFS, CI Relapse and NRM were not significantly different. In multivariable analysis, graft source did not correlate with OS, PFS, Relapse or NRM. In multivariable analysis Disease Risk Index (DRI) and Age>=60 were the major determinants of OS and PFS. For patients with Low and Intermediate DRI under age 60, 2 Y OS was 60% for haplo and 59% for HC.
Conclusions: Melphalan based RIC result in similar and encouraging survival and progression free survival with HC or haplo grafts. HC HCT was associated with more rapid neutrophil and a lower rate of acute and of chronic GVHD.
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Liu:Karyopharm: Research Funding; BMS: Research Funding.
Introduction:
Kidney dysfunction is an important problem in adult recipients of allogeneic stem cell transplantation (HSCT) and independently predicts overall survival and non-relapse mortality. ...Kidney dysfunction occurs in ~50% of transplant recipients. More than 20% of all survivors of HSCT in long-term follow up develop chronic kidney disease. However, there is currently limited data on the cause and consequences of kidney dysfunction in adult recipients after allogeneic HSCT.
Common causes of kidney dysfunction after HSCT include chemotherapy or radiation toxicity, infections, sepsis, hepatic sinusoidal obstruction, drug toxicities due to immunosuppressive medications, thrombotic microangiopathy, as well as acute or graft versus host disease (GvHD). Kidney biopsies are seldom obtained and hence the tissue diagnosis in these patients often remains speculative. Early identification of the causes of kidney dysfunction may help define preventive and therapeutic strategies and improve outcome.
Hence, in August 2016, we designed a prospective study at our center to systematically evaluate kidney dysfunction in adult recipients of allogeneic HSCT. Herein we present our initial report of 8 kidney biopsies.
Methods:
All adult HSCT recipients with kidney dysfunction were evaluated by Nephrologists to determine the need for kidney biopsy. Kidney dysfunction was defined as either (i) acute kidney failure or (ii) proteinuria. Acute kidney failure was defined by the ‘ Kidney Disease: Improving Global Outcomes (KDIGO)‘ criteria. Proteinuria was defined as (i) spot urine albumin to creatinine ratio of ≥1 (equivalent to ≥1 g in 24 hours). Kidney biopsies were done under ultrasound guidance and the tissue specimens were interrogated by light, immunofluorescence and electron microscopy.
Results:
A total of 8 HSCT recipients (including one patient who had a biopsy prior to Aug 2016) underwent kidney biopsies. The patient and transplant characteristics are summarized in Table 1.
Seven of the 8 pts had AML. One patient had NHL in CR2. Four patients received a MUD transplant. Two received MRD transplants. Two received combined haploidentical and single unit cord blood transplant (haplo-cord). Six of the 8 patients received conditioning with fludarabine and melphalan. One patient received additional 400 Gy TBI. One patient received additional azacytidine.
Median time to neutrophil engraftment was 13.5 days (range 9-20). Median time to platelet engraftment was 19 days (range 14-76). There were no cases of graft failure. All patients also demonstrated either acute or chronic GvHD of other organs - most commonly skin.
All kidney biopsies were performed without complications. Kidney biopsies were done at median 254 days after transplantation (range 126-680). Baseline serum creatinine (mg/dL) prior to transplant was 0.95 (median, range 0.65-1.1, reference range: 0.64-1.27 mg/dL). Creatinine at time of biopsy: 3.0 (median, range 1.53-5.07). Urine albumin/creatinine ratio: 832 (median, range 55-2864, reference range: <30).
The kidney biopsy findings are summarized in Table 2. All patients had evidence of endothelial cell injury, either acute or chronic. Three patients had features suggestive of GvHD of the kidney while one patient had BK virus nephropathy.
Four of the 8 recipients died; 80 days (median, range 39-124) from the biopsy, 346 days (median, range 178-804) from transplantation. The clinical outcome is summarized in Table 3.
Conclusions:
Kidney biopsies post-transplant are an important diagnostic tool that should be considered for prolonged kidney dysfunction or proteinuria, particularly in the setting of other post-transplant complications. Our single-center biopsy results highlight the under-recognition of kidney dysfunction complications and complexities observed post-transplant. All kidney biopsies performed were instrumental in treatment planning. Further investigation is needed to define criteria for diagnosis and to understand the pathophysiology. This requires multi-disciplinary engagement as well as a proactive approach for obtaining kidney biopsies. With appropriate transfusion support, percutaneous kidney biopsies were performed safely without complication.
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No relevant conflicts of interest to declare.
Background: Epstein-Barr virus (EBV) reactivation and EBV-positive post-transplant lymphoproliferative disorder (EBV+PTLD) are often fatal complications following allogeneic hematopoietic stem cell ...transplant (HSCT). Risk factors for the development of EBV+PTLD after HSCT include human leukocyte antigen (HLA) mismatches, T cell depletion (TCD) and older age, among others. It has been proposed that specific HLA haplotypes are associated with the development of EBV+PTLD after solid organ transplant (SOT) and that pre-emptive use of Rituximab can reduce the risk of EBV+PTLD. We present a retrospective analysis of patients who underwent HSCT in order to determine the impact of donor source, TCD, age, HLA-A1 haplotypes and use of Rituximab prior to HSCT on the development of EBV reactivation and EBV+PTLD after HSCT.
Methods: We retrospectively reviewed patients who had undergone allogeneic HSCT at our Institution between January 2012 and December 2016. We analyzed the cumulative incidence of EBV reactivation and EBV+PTLD and the impact of known and novel risk factors.
Results: Of 474 patients, 10% developed EBV reactivation and 6% were diagnosed with EBV+PTLD. The cumulative incidence of EBV reactivation and EBV+PTLD was 15% and 11%, respectively, after haplo-cord HSCT, compared to 3% and 2% after MRD HSCT and 8% and 5% after MUD HSCT (p=0.0004 and p=0.02, respectively). EBV reactivation was associated with receipt of ATG compared to Alemtuzumab (p=0.03) and age older than 60 years (p=0.004). The presence of HLA-A1 haplotype in the recipient did not affect the incidence of EBV reactivation and EBV+PTLD (p=0.2 and p=0.9, respectively). The cumulative incidence of EBV reactivation and EBV+PTLD was lower in patients with Rituximab exposure prior to HSCT, although this did not reach statistical significance (p=0.2 and p=0.15, respectively). In a multivariate analysis, donor source (haplo-cord vs HLA-matched) and age older than 60 were found to be independent risk factors for the development of EBV reactivation (HR 1.9; p=0.038 and HR 2.6; p=0.002, respectively) and EBV+PTLD (HR 1.9; p=0.020 and HR 3.5; p=0.004, respectively). PTLD was fatal in 8 of 27 patients (29%) with PTLD and 17% of all patients with EBV reactivation. One patient died of disseminated EBV disease without PTLD.
Conclusions: The cumulative incidence of EBV viremia and PTLD after allogeneic HSCT was 10% and 6%, respectively, and led to death in 2% of the patients. Haplo-cord grafts and age older than 60 years were independent risk factors for EBV reactivation and EBV+PTLD. Rituximab use prior to HSCT may confer protection against EBV reactivation and its use in the conditioning regimen of patients undergoing HSCT, at high risk for EBV reactivation, should be studied prospectively. Further studies are needed to determine the impact of HLA haplotypes on the incidence of EBV reactivation in patients after HSCT.
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No relevant conflicts of interest to declare.
Background: Allogeneic stem cell transplant remains the only curative modality for myelodysplastic syndrome (MDS), yet there is significant controversy and individual practice variation in offering ...pre-transplant therapy with the goal of reducing disease burden and/or improving marrow function. In this study, we analyze the impact of bone marrow response prior to transplant on the post-transplant overall survival and relapse.
Methods: We collected data from 2007 to 2018 from patients undergoing allogeneic transplant for MDS at Weill Cornell Medicine. Patients with MDS transformed to AML were excluded. P values for survival analyses were derived from Cox models. All statistical tests were 2 sided with 0.05 alpha levels.
Results: We analyzed 85 patients who underwent an allogeneic stem cell transplant for MDS and had all pertinent data available. Response to pre-transplant treatment was not a pre-requisite for proceeding to transplant. The donor source was MUD, MRD and cord blood in 40%, 37.65%, and 22.35% of patients, respectively. Median age at the time of transplant was 61 years (32.94% females). IPSS-R at diagnosis was low, intermediate, high and very high-risk in 12.94 %, 31.76 %, 24.71% and 30.59% of patients, respectively. Most (80%) patients were treated with hypomethylating agents (HMA) prior to transplant.
Within 2 months of transplant, 27.06% of patients achieved CR, with 8% cytogenetic response. Hematological improvement (HI) only (without marrow CR), marrow CR and stable disease/no response were seen in 9.41%, 18.83% and 42.35% of patients, respectively. Bone marrow blasts were 0-5%, 5-10% and 11-19% in 77.5%, 18.75% and 3.75% of patients pre-transplant, respectively. Median overall survival after transplant was 28.6 months (range 14.9-48.5). 90-day transplant related mortality was 10.7 %. One-year survival after transplant was 65.7%; with a relapse rate of 30.6% at median follow up of 12 months. The incidence of grade 3 and 4 GVH of any kind was 33.33%.
Using univariate models, age at transplant (HR 1.049, 95% C.I. 1.017-1.083, p value 0.002) and a high IPSS-R (p value.004) at diagnosis were associated with inferior post-transplant survival, while gender and use of HMA prior to transplant did not impact post-transplant survival. In multivariate cox regression analyses adjusting for other confounding variables, achieving a CR or HI was significantly associated with higher post-transplant survival, compared to stable disease/no response prior to transplant (HR 0.46, 95% C.I. 0.23-0.90, p value 0.02). Achievement of a marrow CR resulted in a trend toward higher post-transplant OS (HR 0.45, 95% C.I. 0.18-1.09, p value 0.07). Pre- transplant blast percentage (<5, 5-10 or >10%) or cytogenetic response only (without CR) did not impact survival outside the presence of a CR. In the multivariate models IPSS-R very high risk at baseline (HR 4.75, 95% C.I. 1.81-12.43, p value 0.001) was associated with reduced post-transplant OS compared to low risk. There was no association between the types of marrow response on RFS post-transplant. Of note, among 34 patients with baseline mutations in ASXL1, ETV6, EZH2, RUNX1 and TP53, mutation clearance at the time of transplant was observed in only 6/34 (17.6%) patients. The presence of a mutation in any of these 5 genes prior to transplant did not impact RFS (HR 1.12, 95% C.I. 0.38-3.26, p value 0.04) or OS (HR 3.09, 95% C.I. 0.86-11.11, p value 0.08). However, we were not able to assess the effect of individual mutations (e.g. TP53) due to small numbers. We did not see an effect of GVHD type (acute or chronic) or grade on RFS or OS.
Conclusions: Achievement of CR or hematological improvement (HI) prior to allogeneic transplant was associated with superior survival post-transplant, while marrow CR and cytogenetic response did not impact post-transplant survival any different than going into allogeneic transplant with stable disease/no response. IPSS R score at diagnosis was associated with inferior post-transplant survival. The presence of mutations in ASXL1, ETV6, EZH2, RUNX1 or TP53 genes prior to transplant did not appear to impact OS or RFS post-transplant, but the total numbers were small. Although CR or HI after pre-transplant treatment improved OS post-transplant, only one third of patients achieved these responses prior to transplant. Better MDS directed treatments and conditioning regimens are needed to improve outcomes after allogeneic transplantation.
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Desai:Cellerant Inc: Consultancy; Argenx: Consultancy. Lee:LAM Therapeutics: Research Funding; AstraZeneca: Consultancy; Karyopharm Therapeutics Inc: Consultancy; Amgen: Consultancy; Clinipace: Consultancy. Ritchie:Novartis: Consultancy, Other: Travel, Accommodations, Expenses, Research Funding, Speakers Bureau; Astellas Pharma: Research Funding; Pfizer: Consultancy, Research Funding; Incyte: Consultancy, Speakers Bureau; NS Pharma: Research Funding; ARIAD Pharmaceuticals: Speakers Bureau; Bristol-Myers Squibb: Research Funding; Celgene: Consultancy, Other: Travel, Accommodations, Expenses, Speakers Bureau. Roboz:Orsenix: Consultancy; AbbVie: Consultancy; Sandoz: Consultancy; Roche/Genentech: Consultancy; Celltrion: Consultancy; Aphivena Therapeutics: Consultancy; Otsuka: Consultancy; Bayer: Consultancy; Celltrion: Consultancy; Argenx: Consultancy; Sandoz: Consultancy; Argenx: Consultancy; Novartis: Consultancy; Pfizer: Consultancy; Daiichi Sankyo: Consultancy; Eisai: Consultancy; Cellectis: Research Funding; Cellectis: Research Funding; Janssen Pharmaceuticals: Consultancy; AbbVie: Consultancy; Eisai: Consultancy; Novartis: Consultancy; Bayer: Consultancy; Astex Pharmaceuticals: Consultancy; Aphivena Therapeutics: Consultancy; Pfizer: Consultancy; Daiichi Sankyo: Consultancy; Celgene Corporation: Consultancy; Roche/Genentech: Consultancy; Otsuka: Consultancy; Jazz Pharmaceuticals: Consultancy; Astex Pharmaceuticals: Consultancy; Celgene Corporation: Consultancy; Janssen Pharmaceuticals: Consultancy; Orsenix: Consultancy; Jazz Pharmaceuticals: Consultancy.
Introduction: Mutations at diagnosis in acute myeloid leukemia (AML) patients have prognostic implications. For AML patients undergoing allogeneic stem cell transplant (SCT), the prognostic impact of ...molecular mutations pre-transplant and immediately post-transplant are less well characterized. Here we examine the mutation status of AML patients at different time points in relation to allogeneic SCT and their implications in relapse and survival.
Methods: AML patients who underwent allogeneic SCT after achieving complete remission with available molecular mutation testing at diagnosis, prior to transplant (within 4 weeks), and 28 days post-transplant were included in the analysis. Multivariable cox regression analysis was adjusted for age, gender, CIBMTR disease risk index (DRI), type of transplant, and genetic mutation. Backward selection method was used to select the best combination of genes that is associated with OS and relapse-free survival (RFS).
Results: A total of 110 AML patients with molecular genetic data available from 2014 to2018 at Weill Cornell Medicine were included in the analysis. Clinical characteristics of the patients are summarized in Table 1. The median age was 58 years (20-77). Twenty-three molecular mutations analyzed at baseline, pre-transplant, and at 28 days are listed in Table 2.
With a median follow-up time of 31.6 month, the median overall survival for the cohort was 37.1 months. Eighty-one patients had molecular testing at diagnosis. The presence of mutations in TP53 at diagnosis was associated with worse OS by both univariate (HR 3.67, p=0.0030, CI 1.56-8.68) and multivariate analysis (HR 4.75, p=0.0014, CI 1.82-12.39) with median OS reduced from 49.3 to 19.3 months (p=0.002). High CIBMTR DRI (HR 0.17, p=0.0018, CI 0.05-0.51) predicted reduced RFS, but not OS on multivariate analysis.
Seventy-seven patients had molecular testing prior to transplant and 27 patients had persistent mutations (Table 2). The presence of mutations in ETV6 and FLT3-ITD were independently associated with worse RFS ((HR 49.7, p=0.001, CI 5.0-528) & (HR 36.4, p<0.0001, CI 6.6-200)) and OS ((HR 38.31, p=0.0035, CI 3.31-443.37) & (HR 10.57, p=0.0038, CI 2.14-52.27)). The presence of NRAS mutations was associated with worse RFS (HR 105, p=0.0004, CI 8.1-1350), but not OS. Mutations in TP53 were associated with worse RFS (HR 70.97, p=0.0026 CI 4.44-1135) and OS on univariate (HR 9.82, p=0.0327, CI 1.21-79.82), but not on multivariate analysis.
At 28 days post-transplant, only 9 of the 84 patients had persistent mutations. Persistence of FLT3-ITD conferred worse RFS and OS in both univariate ((HR 11.92, p=0.0218, CI 1.43-98.98) & (HR 25.16, p=0.0052, CI 2.62, 241.92)) and multivariate ((HR 18.13, p=0.0089, CI 2.07-158.86) & (HR 35.47, p=0.0028, CI 3.41-368.81)) analysis.
Conclusions: Persistent presence of mutations in ETV6 and FLT3-ITD prior to stem cell transplant were associated with shorter RFS and OS independent of CIBMTR DRI. Persistent mutations in NRAS and CBL prior to stem cell transplant were associated with poor RFS and OS respectively. This analysis further supports association of adverse outcomes in AML patients with selected persistent mutations prior to stem cell transplant. Utility of serial mutation testing prior to transplant should be further investigated in prospective studies.
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Lee:AstraZeneca: Consultancy; Clinipace: Consultancy; Karyopharm Therapeutics Inc: Consultancy; LAM Therapeutics: Research Funding; Amgen: Consultancy. Ritchie:NS Pharma: Research Funding; Incyte: Consultancy, Speakers Bureau; Novartis: Consultancy, Other: Travel, Accommodations, Expenses, Research Funding, Speakers Bureau; ARIAD Pharmaceuticals: Speakers Bureau; Astellas Pharma: Research Funding; Bristol-Myers Squibb: Research Funding; Pfizer: Consultancy, Research Funding; Celgene: Consultancy, Other: Travel, Accommodations, Expenses, Speakers Bureau. Desai:Argenx: Consultancy; Cellerant Inc: Consultancy. Roboz:Eisai: Consultancy; Pfizer: Consultancy; AbbVie: Consultancy; Roche/Genentech: Consultancy; Aphivena Therapeutics: Consultancy; Eisai: Consultancy; AbbVie: Consultancy; Daiichi Sankyo: Consultancy; Argenx: Consultancy; Novartis: Consultancy; Janssen Pharmaceuticals: Consultancy; Jazz Pharmaceuticals: Consultancy; Orsenix: Consultancy; Celgene Corporation: Consultancy; Daiichi Sankyo: Consultancy; Novartis: Consultancy; Cellectis: Research Funding; Celltrion: Consultancy; Celgene Corporation: Consultancy; Celltrion: Consultancy; Argenx: Consultancy; Astex Pharmaceuticals: Consultancy; Bayer: Consultancy; Cellectis: Research Funding; Sandoz: Consultancy; Astex Pharmaceuticals: Consultancy; Janssen Pharmaceuticals: Consultancy; Sandoz: Consultancy; Orsenix: Consultancy; Otsuka: Consultancy; Jazz Pharmaceuticals: Consultancy; Roche/Genentech: Consultancy; Otsuka: Consultancy; Bayer: Consultancy; Aphivena Therapeutics: Consultancy; Pfizer: Consultancy.
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Background: Although current antiretroviral therapies have effectively changed the course of HIV-1 infection, it remains an incurable illness. The C-C chemokine receptor type 5 (CCR5) is the key ...co-receptor for HIV entry into CD4+ T cells. Homozygous 32 deletion (delta32) in CCR5 genes leads to resistance to HIV-1 infection 1. Allogeneic stem cell transplant from a donor with CCR5 delta32/32 mutation was curative for HIV in an HIV-1-infected man (Berlin Patient) with AML 2. It has been challenging to replicate this experience. We present our experience with a single case of successful engraftment of CD34-selected, related haploidentical peripheral blood and CCR5delta32 cord blood stem cell transplant (haplo-cord) in an HIV-1-infected woman who, like the Berlin patient, developed AML and is now doing well at almost one-year post transplantation.
Clinical case: A 60-year-old African-American woman was diagnosed with HIV-1- infection in June 2013 and was started on an antiretroviral treatment (ART) regimen consisting of tenofovir, emtricitabine and raltegravir. Her pre-ART viral load and CD4 counts were 1,000,000 copies/ml and 1003 cells/mm3, respectively. In Nov, 2013 she had viral load < 20 copies/ml with CD4 counts of 980 cells/mm3 and her HIV-1 infection was relatively asymptomatic. In March 2017, she was diagnosed with AML with monosomy 7. Her HIV therapy after the AML diagnosis was changed to abacavir- lamivudine -dolutegravir- combination. She achieved morphologic and cytogenetic remission after 1 cycle of standard idarubicin/cytarabine induction chemotherapy. In addition, she received 1 cycle of HiDAC consolidation and was referred for allogeneic stem cell transplant. We identified a CCR5 delta32/32 mutated cord blood unit (CBU) which was 5/8 HLA matched and contained 1.3 x 107 nucleated cells/kg and 3.2 x 104 CD34+ cells/kg.
She underwent a combined CD34-selected, haploidentical peripheral blood and CCR5delta32 cord blood stem cell transplant (haplo-cord) in August 2017. Her conditioning regimen was with fludarabine/melphalan/and TBI400 and she also received ATG/MMF/tacrolimus for GVHD prophylaxis. Her neutrophils and platelets engrafted on day 10 and 16, respectively and she was discharged on day +16 post-transplant. Her post-discharge hospital course was complicated by CMV reactivation (no organ involvement) 2 months post-transplant with peak viral level of 1374 copies/ml. She did not have evidence for EBV re-activation or graft-vs-host disease. Her plasma HIV viral load remained undetectable post- transplant while remaining on abacavir/lamivudine and dolutegravir-based ART.
Her day+180 bone marrow showed continued AML remission and she remains in clinical remission near one year post-transplant. CD3 chimerism showed 82% haploidentical donor and 8% CBU and 10% recipient on day +15 post-transplant (Figure 1). The chimerism composition switched to 96% CBU by day+34, and became and remained 100% CBU since day+55. CD33 chimerism showed 98% haploidentical donor and 2% cord donor on day+15 post-transplant. It was 81% haploidentical donor and 19% cord on day+55 and became 100% cord by day+100. She has continued CD4, CD8, NK and CD19 cell recovery, with normal T cell subsets currently (Figure 2). Her CD4 count dropped to 27 cells/mm3 at one-month post-transplant and currently is at 673cells/mm3. She is currently 11 months post-transplant and is back to her normal daily activities
Conclusion: Haplo-cord transplantation with CCR5 delta 32/32 CBU resulted in rapid engraftment and immune replacement with dominance of the CCR5 delta 32/32 CBU graft in an HIV-1-infected woman. Successful suppression of HIV-1-replication to clinically undetectable levels was maintained throughout the transplant period for up to one year. . Correlative viral and immunological studies are ongoing, along with effects on the latent reservoir, which was detectable pre-transplant. It is possible to identify appropriate CCR5 delta 32/32 CBU units for haplo-cord transplantation in HIV-1- infected patients with implications for HIV-1 cure.
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No relevant conflicts of interest to declare.
Background:
Autologous stem cell transplantation (ASCT) performed early in the disease course or at first relapse leads to improved progression-free and overall survival in transplant-eligible ...patients with multiple myeloma (MM). Filgrastim, a recombinant granulocyte colony-stimulating factor (G-CSF), when used after ASCT has been shown to accelerate time to neutrophil engraftment (TNE), and in some studies, it has been associated with reduced length of hospitalization, infectious complications, and antibiotic use. Strategies that reserve G-CSF administration to when neutrophil recovery is delayed, have attempted to show that there is no difference in infectious complications, length of hospitalization or TNE when compared to early administration of G-CSF on the day after stem cell infusion (DOT). However, the optimal timing for administering G-CSF has not yet been determined in patients with MM undergoing ASCT.
Methods:
This is a retrospective, single-center analysis of patients with MM undergoing ASCT from mobilized peripheral blood stem cells. Patients enrolled in a clinical trial of high-dose lenalidomide and melphalan as conditioning therapy which mandated the administration of filgrastim from day +1 after DOT (Lenalidomide Plus Melphalan as a Preparative Regimen for Autologous Stem Cell Transplantation in Relapsed Multiple Myeloma, NCT01054196) were assigned to the early strategy group (ES). Patients receiving filgrastim as per our institutional guideline (starting on day +12 if ANC < 1000 cells/uL, or at the physician's discretion) were included in the delayed strategy group (DS). Patients were excluded from the analysis if their conditioning regimen included a different agent other than melphalan or lenalidomide. DOT was defined as the day of stem cell infusion. Date of neutrophil engraftment was defined as the first of three consecutive days with an ANC ≥ 500 cells/uL. TNE was calculated as the time from DOT to the date neutrophil engraftment. Total duration of neutropenia was defined as the time from onset of neutropenia (ANC < 500 cells/uL) to date of neutrophil engraftment. Length of hospitalization was defined as the time from DOT to the day of discharge.
Results:
We identified 59 patients in the ES group and 39 patients in the DS group from 08-16-2010 to 05-22-2019, for a total of 98 included in this analysis. Median age was 60 and 65 years in the ES and DS groups, respectively. Patients received a comparable dose of CD34+ cells, 5.05x106/kg in the ES group vs 4.66x106/kg in the DS group (p = 0.48). The ES group started filgrastim administration earlier (day +1 vs +9, p < 0.001) and received a greater median number of doses (10 vs 4, p < 0.001) as compared to patients in the DS group. Median time to neutrophil engraftment was shorter in the ES group compared to the DS group (10 vs 12 days, p < 0.001), as was the total duration of neutropenia (5 vs 6 days, p < 0.001). Documented infections were just as likely in both groups, 37% in the ES group and 39% in the DS group (p = 1). Length of hospitalization was shorter in the ES group as compared to the DS group (15 vs 17 days, p = 0.01).
Discussion:
Filgrastim use guided by an ES decreased the time to neutrophil engraftment, the duration of neutropenia and the length of hospitalization compared to a DS. Further analyses to identify predictive factors associated with a reduction in infectious complications and length of stay are underway, with the aim of developing a risk-adapted strategy for the use of filgrastim in patients with MM undergoing ASCT.
Van Besien:Miltenyi Biotec: Research Funding. Coleman:Kite Pharmaceuticals: Equity Ownership; Merck: Research Funding; Pharmacyclics: Speakers Bureau; Gilead, Bayer, Celgene: Consultancy, Research Funding, Speakers Bureau. Rosenbaum:Janssen: Research Funding; Honoraria Akcea: Other: Accordant Health. Rossi:Janssen, Celgene, Amgen: Consultancy; BMS: Research Funding. Niesvizky:Takeda, Amgen, BMS, Janssen, Celgene: Consultancy, Research Funding.
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