Further Evidence to Not Delay Transplant for Continued ARA-C Consolidation in Patients with Intermediate or High Risk AML

Blood ◽  
2015 ◽  
Vol 126 (23) ◽  
pp. 5544-5544
Author(s):  
James K. Feisal ◽  
Nicholas B. Pleat ◽  
Michael Machiorlatti ◽  
Summer Frank ◽  
Sara Vesley ◽  
...  
Keyword(s):  
Overall Survival ◽  
High Risk ◽  
Complete Remission ◽  
Blood Cells ◽  
P Value ◽  
Myeloablative Conditioning ◽  
Risk Status ◽  
Post Transplant ◽  
Preparative Regimen ◽  
Reduced Intensity

Abstract Background: Allogeneic stem cell transplant (alloSCT) is indicated for patients with acute myeloid leukemia (AML) with high-risk disease on presentation or in relapsed or refractory cases. Durable elimination of leukemic burden after achieving a complete remission (CR) is thought to be an important prerequisite for successful transplant. Typically, this is achieved with consolidation treatments with cytarabine (ARA-C) in repeated cycles in non-refractory cases. Previous reports have suggested there is no apparent advantage for post-remission consolidation chemotherapy before reduced intensity transplant, provided a donor is readily available. Aim: To study the impact of the total cumulative dose of ARA-C in the pre-transplant setting before alloSCT either with reduced-intensity conditioning (RIC) or full myeloablative conditioning (MAC). Methods: We conducted a retrospective chart review at the University of Oklahoma and affiliated hospitals in patients with AML in complete remission from October 2006 to December 2014. Appropriate IRB approval was obtained in accordance with Helsinki declaration. Simple descriptive statistics were created for all covariates [mean, SD for continuous covariates and n (%) for categorical variables]. A Cox proportional hazards model was used to assess the association of each covariate with overall survival. Results: Sixty five patients were identified through our local leukemia registry with a mean age of 43, 57 (87.7%) were white, and 42 (64.6%) were male. Based on cytogenetics and molecular markers, 36 patients (55.3%) were intermediate risk and 20 patients (30.7%) were unfavorable risk status. For transplant preparative regimen, MAC was utilized in 50 cases (76.9%) and RIC was utilized in the other 15 (23.0%). Bone marrow stem cells were used in 28 cases (43.0%), peripheral blood cells were used in 26 cases (40.0%), and cord blood cells were used in the remaining 11 cases (16.9%). The mean dose of ARA-C given in consolidation was 43 g/m2 with standard deviation 31.5 g/m2. After adjusting for age and risk status, ARA-C consolidation was not associated with increased overall survival (OS) in the patients (p-value = 0.1776). When only considering those patients with myeloablative conditioning, ARA-C consolidation was still not associated with increased OS (p-value = 0.7533). Conclusions: Prior published data indicates that further ARA-C therapy given during consolidation does not correlate with improved outcomes post-transplant in patients with AML who received a reduced intensity preparative regimen. However, we attempted to expand this data to include patients who received a full myeloablative preparative regimen. Our experience using our single institution retrospective data suggests further ARA-C therapy given in consolidation does not benefit patients who underwent either RIC or MAC in terms of post-transplant survival. This provides further evidence that there should be no delay in moving patients to transplant, provided a suitable donor is available. Disclosures No relevant conflicts of interest to declare.

Hematopoietic Bone Marrow Transplantation (BMT) for Patients with High-Risk Acute Myeloid Leukemia (AML), Acute Lymphoblastic Leukemia (ALL), or Myelodysplastic Syndrome (MDS) Using HLA-Haploidentical Related Donors: A Trial Using Radiolabeled Anti-CD45 Antibody Combined with Immunosuppression Before and After BMT

Blood ◽  
2012 ◽  
Vol 120 (21) ◽  
pp. 4164-4164
Author(s):  
Raya Mawad ◽  
Paul O'Donnell ◽  
Ted A. Gooley ◽  
Joseph G Rajendran ◽  
Darrell R. Fisher ◽  
...  
Keyword(s):  
Bone Marrow ◽  
T Cell ◽  
High Risk ◽  
Complete Remission ◽  
Maximum Tolerated Dose ◽  
Blast Phase ◽  
Post Transplant ◽  
Before And After ◽  
Preparative Regimen ◽  
Reduced Intensity

Abstract Abstract 4164 Patients with advanced leukemia or high-risk MDS undergoing conventional hematopoietic cell transplantation (HCT) have a significant risk of both relapse and non-relapse mortality. We previously conducted a series of studies in patients with high-risk AML, ALL or MDS using radiolabeled anti-CD45 antibody as part of an allogeneic HCT preparative regimen employing HLA-matched donors. This approach has made it possible to deliver high doses of radiation relatively specifically to sites of disease while sparing normal organs. This advance may also allow us to maximize the anti-tumor effect and minimize toxicity of a preparative regimen. We have now extended this therapeutic strategy to patients without HLA-matched donors, often patients of mixed ethnicity or belonging to ethnic minority groups. We and others have utilized a combination of immunosuppressive agents, including cyclophosphamide (CY) administered before and after HCT with non-T-cell depleted bone marrow (BM) from HLA-haploidentical donors, to facilitate engraftment and delete highly alloreactive T-cell clones presumably involved in graft-versus-host disease (GvHD). We report a Phase I/II study using 131I-BC8 antibody at escalating doses in combination with a less toxic reduced-intensity conditioning regimen in the setting of haploidentical BMT. This dose escalation study was designed to determine the maximum tolerated dose of 131I-anti-CD45 (BC8) antibody that can be combined with fludarabine (FLU) and 2Gy total body irradiation (TBI) in addition to pre-and post-BMT CY. Ten patients over 18 years of age with advanced AML, ALL or high-risk MDS (>5% blasts) have been treated with a median of 508 mCi (range: 300–818) of 131I delivering a median of 7.9 Gy (range: 1.8–42) to the BM, a median of 74.6 Gy (range: 45.6–178.8) to the spleen, and a median of 15.8 Gy (range: 12.2–22.1) to the liver (does-limiting organ). Patients then received FLU (30 mg/m2 daily for 5 days), 2 Gy TBI, CY (14.5 mg/kg daily for 2 days), and HLA-haploidentical BM grafts, with GvHD prophylaxis consisting of post-transplant CY, tacrolimus and mycophenolate mofetil. The median age of patients was 47.2 years (range: 31–64). Six patients had AML: one patient was in second complete remission, 2 patients had MDS that progressed to AML, 2 had primary refractory disease, and 1 patient had relapsed after previous HCT. One patient had high-risk MDS, one patient had ALL in second remission with minimal residual disease (MRD) and two patients had CML presenting in blast crisis (one in myeloid blast phase and one in lymphoid blast phase). All AML patients had intermediate or high-risk disease by cytogenetic and molecular criteria. Treatment with the 131I-BC8 Ab/FLU/TBI regimen produced a complete remission in all 10 patients, and 8 had 100% donor CD3+ and CD33+ cell engraftment by day 28 post-transplant. The remaining 2 patients were not tested on day 28, however they achieved 100% donor CD3+ and CD33+ by day 56 chimerism evaluation. The absolute neutrophil count surpassed 500/μL at a median of 14 days (range: 12–16) after BMT, and platelets became self-sustained at ≥ 20,000/μL at a median of 22 days (range: 12–35) after BMT. Four patients are surviving relapse-free for a median of 2.8 years (range: 1.6–4.2) after BMT. Five patients experienced disease relapse at 1.8 to 10.7 months after transplant. The overall day-100 non-relapse mortality was 10%, with one death attributed to sepsis in the setting of steroid-refractory GvHD. This study demonstrates that, in addition to a reduced intensity transplant regimen, 131I labeled anti-CD45 antibody can deliver an average of 14.2 Gy of targeted radiotherapy to BM, and an average of 89.2 Gy to the spleen, without a marked increase in 100-day mortality. The maximum tolerated dose of absorbed radiation has not been estimated, and we continue to escalate the radiation dose, with the most recently enrolled patient receiving 24Gy to the liver. This study shows that anti-CD45 radioimmunotherapy yields encouraging results with haploidentical BMT for patients who lack an HLA-matched donor. Disclosures: No relevant conflicts of interest to declare.

Front-Line FLAG-IDA and Nove-HiDAC Chemotherapy Improves Overall Survival (OS) and Complete Remission Rates (CR) for Patients with Secondary or Therapy-Related AML Compared to 3&7

Blood ◽  
2015 ◽  
Vol 126 (23) ◽  
pp. 4893-4893
Author(s):  
Sita D. Bhella ◽  
Eshetu G Atenafu ◽  
Andre C Schuh ◽  
Mark D. Minden ◽  
Aaron D. Schimmer ◽  
...  
Keyword(s):  
Overall Survival ◽  
High Risk ◽  
Complete Remission ◽  
Invasive Aspergillosis ◽  
Myeloproliferative Neoplasm ◽  
Rank Test ◽  
P Value ◽  
Front Line ◽  
First Line ◽  
Poor Risk

Abstract Background: Therapy for patients (pts) with high risk AML remains unsatisfactory. Retrospective studies have demonstrated activity of fludarabine, cytarabine, GCSF and idarubicin (FLAG-IDA) and of mitoxantrone, etoposide and cytarabine (NOVE-HiDAC) as salvage therapy in pts with relapsed or refractory AML. A recent randomized trial indicated high complete remission (CR) rates with improved relapsed-free survival when FLAG-IDA is administered as frontline induction therapy (Burnett et al. J Clin Oncol 2013). Since 01/2011, we have used FLAG-IDA as a first line therapeutic option in pts with high risk AML (poor risk cytogenetics, antecedent myeloproliferative neoplasm or myelodysplastic syndrome, and/or therapy-related AML) in an attempt to improve CR rates and permit more patients with AML to advance to allogeneic hematopoietic cell transplantation (alloHCT). Prior to 2011, either 3&7 or NOVE-HiDAC was used as first line therapy in patients with AML. Methods: We conducted a retrospective review of consecutive patients with high risk AML treated with front-line (a) FLAG-IDA between 01/2011 to 03/2015, (b) NOVE-HiDAC from 01/2006 to 12/2014, or (c) 3&7 from January 01/2011 to 12/2014 at the Princess Margaret Cancer Centre, to determine the CR rates and overall survival (OS) associated with the different regimens. Results: Patients characteristics are in Table 1. Fifty-two, 32, and 30 pts received FLAG-IDA, NOVE-HiDAC or 3&7 as first induction, respectively. Patients receiving FLAG-IDA had more high-risk features (i.e. complex cytogenetics, more azacytidine failures) compared to those receiving 3&7. Overall CR rate (i.e. CR + [CRi] + [CRp]) with FLAG-IDA, NOVE-HiDAC, and 3&7 respectively was 86% (n=42/49), 84% (n=21/25) and 50% (n=13/26), respectively. Median CR duration, censored at time of transplant, for pts receiving FLAG-IDA, NOVE-HiDAC and 3&7 was 3 mos (0.5-15), 3.5 mos (1-9) and 5.5 mos (0.5-42), respectively. OS at 1 year with FLAG-IDA, NOVE-HiDAC and 3&7 was 61% (95% CI, 41% -75%), 55% (95% CI, 34%-72%) and 21.6% (95% CI, 7.4%-40.7%), respectively (log-rank test p-value=0.0076). On subgroup analysis, there was no statistical difference in OS for pts ≥70 years. Of those with a donor identified, 35% (n=13/37), 73% (n=11/15) and 29% (n=5/17) of pts who were treated with FLAG-IDA, NOVE-HiDAC and 3&7 underwent an alloSCT, respectively. Pts with sAML may have had a higher transplant rate due to donor searches initiated earlier. Probable and possible invasive aspergillosis infections in pts receiving FLAG-IDA, NOVE-HiDAC and 3&7 were 50%, 34% and 33% respectively. Institution of earlier bronchoscopies led to increased fungal detection in the FLAG-IDA group. Median length of stay and ICU transfers were similar between groups. Induction deaths were secondary to sepsis, respiratory failure, invasive aspergillosis, and hemorrhage; these were similar across groups. Two pts receiving NOVE-HiDAC, with prior MPN, died of progressive splenomegaly and liver failure. Conclusions: Toxicities associated with frontline FLAG-IDA and NOVE-HIDAC induction are acceptable. FLAG-IDA and NOVE-HiDAC induction can result in durable CR, permitting patients with high risk AML to proceed to alloSCT and providing more favourable survival rates than frontline 3&7. Randomized studies are needed to confirm these findings for pts with poor-risk sAML and tAML. Table 1. Patient Characteristics FLAG-IDA(2013-2015) NOVE-HiDAC(2006-2014) 3&7(2011-2014) N=52 N=32 N=30 Median Age,y (range) Age <70 Age ≥ 70 Sex (M:F) 59.5 (21-76) 47 (90%) 5 (10%) 25:27 54.5 (24-74) 31 (97%) 1 (3%) 18:14 61.5 (20-78) 21 (70%) 9 (30%) 23:7 Cytogenetics by MRC Classification Good Intermediate Poor Not available 0 (0%) 25 (48%) 23 (44%) 4 (8%) 0 (0%) 18 (56%) 9 (28%) 5 (16%) 0 (0%) 20 (67%) 6 (20%) 4 (13%) Molecular (Pts ≤70 y with normal karyotype) FLT3-NPM1+ FLT3+ NPM1+ FLT3+ NPM1- FLT3-NPM1- 1/11 (9%) 5/11 (45%) 2/11 (18%) 3/11 (27%) 0/7 (0%) 2/7 (29%) 1/7 (14%) 4/7 (57%) 0/7 (0%) 1/7 (14%) 0/7 (0%) 6/7 (86%) WBC (x 109/L) (range) 5.15 (0.6 -239) 13 (1.3-182.4) 3.2 (0.7-164) sAML IBMFS MPN MDS Prior AZA 27 (52%) 0/27 (0%) 10/27 (37%) 17/27 (63%) 9/17 (53%) 29 (91%) 1/29 (4%) 15/29 (51%) 13/29 (45%) 2/13 (15%) 20 (67%) 2/20 (10%) 0/20 (0%) 18/20 (90%) 5/18 (28%) Therapy-Related (%) 14 (27%) 6 (19%) 15 (50%) De Novo AML with Complex Cytogenetics FLT3+ Other (ie MLL) 15 (29%) 7/15 (47%) 5/15 (33%) 3/15 (20%) 0 (0%) 0 (0%) Donor Identified (%) 37(71%) 16(50%) 17(57%) Disclosures Gupta: Novartis: Consultancy, Membership on an entity's Board of Directors or advisory committees; Incyte: Honoraria, Research Funding.

scholarly journals Clinical Relevance of Morphologic and Molecular Complete Remission in AML Patients Undergoing Reduced Intensity or Non-Myeloablative Conditioning

Blood ◽  
2020 ◽  
Vol 136 (Supplement 1) ◽  
pp. 29-29
Author(s):  
Madlen Jentzsch ◽  
Dominic Brauer ◽  
Juliane Grimm ◽  
Marius Bill ◽  
Donata Backhaus ◽  
...  
Keyword(s):  
High Risk ◽  
Complete Remission ◽  
Risk Stratification ◽  
Genetic Risk ◽  
Research Funding ◽  
Myeloablative Conditioning ◽  
Remission Status ◽  
Active Disease ◽  
Reduced Intensity

Introduction: For most acute myeloid leukemia (AML) patients (pts) an allogeneic stem cell transplantation (HSCT) offers the best chance for relapse-free long-term survival. Evaluation of measurable residual disease (MRD) at HSCT allows risk stratification additionally to genetic risk at diagnosis. Pts with active AML or with positive MRD status (MRD+) pre-HSCT have similar and dismal outcomes following myeloablative conditioning. Reduced intensity (ric) or non-myeloablative (nma) conditioning regimes have been developed to allow HSCT also in AML pts with higher age or comorbidities. Here, we analyzed and compared the clinical relevance of morphologic and MRD-based remission status in AML pts prior to nma- or ric-HSCT. Methods: We analyzed 345 AML pts who received an allogeneic peripheral blood HSCT at a median age of 63 (range 21-77) years with active disease (34%), or in first (49%) or second (17%) complete remission (CR, 87% of pts in remission) or CR with incomplete peripheral recovery (CRi, 13% of pts in remission) after nma (75%) or ric (25%) conditioning. Donors were HLA matched related (11%), matched unrelated (67%), antigen mismatched unrelated (21%) or haploidentical related (1%). At diagnosis, cytogenetics and the mutation status of CEBPA, NPM1 and presence of FLT3-ITD were assessed. Using a next-generation targeted amplicon sequencing approach we analyzed a panel comprising 54 recurrently mutated genes in myeloid malignancies on the MiSeq platform (Illumina). Pre-HSCT morphologic remission status as well as MRD status in pts in morphologic CR/CRi based on NPM1 mutations, BAALC, MN1 and WT1 expression were evaluated. MRD+ pts were defined by being positive for any of the analyzed markers. Median follow up after HSCT was 2.2 years. Results: Pts transplanted with active disease differed from pts in remission with or without MRD pre-HSCT: they were less likely to have de novo AML (P=.02 & P=.09, respectively) and had higher genetic risk including a higher frequency of an abnormal (P=.001 & P&lt;.001, respectively), a complex (P=.06 & P=.04, respectively) or a monosomal karyotype (P&lt;.001 & P=.003, respectively), a lower frequency of NPM1 mutations (P&lt;.001 & P&lt;.001, respectively) and worse ELN genetic risk (P&lt;.001 & P&lt;.001, respectively). They were also more likely to receive ric-HSCT (P&lt;.001 & P&lt;.001) because pts with active AML were frequently transplanted after FLAMSA conditioning. Pre-HSCT MRD- pts only differed from pre-HSCT MRD+ pts regarding a lower white blood count (P=.006) and lower circulating blasts at diagnosis (P=.05) while the proportion of pts transplanted in CR or CRi did not differ between MRD- and MRD+ AML pts. Also the number of applied chemotherapy cycles prior to HSCT did not differ between the three pts groups. Pre-HSCT MRD- pts had a significantly lower cumulative incidence of relapse/progression (CIR) compared to both MRD+ pts (P&lt;.001) and pts transplanted with active disease (P&lt;.001) while CIR did not differ between MRD+ pts and pts transplanted with active disease (P=.24, Figure 1A). Pre-HSCT MRD- pts had longer overall survival (OS) than pre-HSCT+ pts (P=.04) who again had longer OS than pts transplanted with active disease (P=.01, Figure 1B). In multivariate analyses, the MRD corrected remission status prior to HSCT remained a significant factor for CIR (Hazard Ratio 1.65, Confidence interval [CI] 1.31-2.06) after adjustment for ELN risk and for OS (Odds Ratio 0.63, CI 0.49-0.84) after adjustment for ELN risk, hemoglobin and platelet count at diagnosis. Conclusion: AML pts transplanted with active disease showed a variety of high-risk diagnostic parameters compared to pre-HSCT MRD- or MRD+ pts, as secondary disease and adverse genetic risk. In contrast, pre-HSCT MRD- and MRD+ pts could not be discriminated by high risk factors at diagnosis, underlining the importance of a dynamic risk stratification during remission. Both pts with active disease or a MRD+ status in CR/CRi prior to nma- or ric-HSCT showed dismal outcomes with higher CIR and shorter OS than MRD- pts. However, while CIR was comparable in pts with molecular or morphologic detectable disease, OS was worst in pts transplanted with active disease, indicating that MRD+ pts might still be salvageable after suffering relapse and able to achieve long-term outcomes. Figure Disclosures Jentzsch: JAZZ Pharmaceuticals: Honoraria; Novartis: Honoraria. Platzbecker:AbbVie: Consultancy, Honoraria; Janssen: Consultancy, Honoraria, Research Funding; Takeda: Consultancy, Honoraria; Amgen: Honoraria, Research Funding; Geron: Consultancy, Honoraria; BMS: Consultancy, Honoraria; Novartis: Consultancy, Honoraria, Research Funding. Schwind:Pfizer: Honoraria; JAZZ Pharmaceuticals: Honoraria; Novartis: Honoraria, Research Funding.

Treatment of High Risk Inherited Lysosomal and Peroxisomal Disorders Using Reduced Intensity Hematopoietic Cell Transplantation.

Blood ◽  
2009 ◽  
Vol 114 (22) ◽  
pp. 3399-3399
Author(s):  
Angela Smith ◽  
Jakub Tolar ◽  
Teresa J Kivisto ◽  
Troy Lund ◽  
Paul Orchard
Keyword(s):  
Overall Survival ◽  
High Risk ◽  
Graft Failure ◽  
Hematopoietic Cell Transplantation ◽  
Conditioning Regimen ◽  
Peroxisomal Disorders ◽  
Enzyme Replacement ◽  
Preparative Regimen ◽  
Risk Patients ◽  
Reduced Intensity

Abstract Abstract 3399 Poster Board III-287 Introduction: Several treatment approaches have been utilized for inherited metabolic diseases (IMD), including enzyme replacement therapy and hematopoietic cell transplantation (HCT). Because enzyme replacement therapy is of minimal use in lysosomal and peroxisomal diseases that affect the central nervous system (CNS), HCT has been the mainstay of therapy for diseases such as metachromatic leukodystrophy (MLD) and X-linked cerebral adrenoleukodystrophy (ALD). Unfortunately, these diseases may be difficult to diagnose and patients are often not referred for definitive therapy until there has been significant neurologic damage. These high risk patients fare poorly with standard myeloablative HCT, perhaps due to additional neurologic toxicity associated with the preparative regimen. To offer therapy for these high risk patients with no other treatment options, we developed a reduced intensity preparative regimen that was designed to be minimally toxic to the CNS. Methods: Between 2007 and January 2009, 20 patients with high risk IMD primarily affecting the CNS (13 ALD, 4 MLD, 3 other) were treated with a reduced intensity allogeneic HCT regimen at the University of Minnesota. All were conditioned with campath-1H (0.3mg/kg on days -12 through -8), clofarabine (40mg/m2 on days -7 through -3), melphalan (140mg/m2 on day -2) and total body irradiation (TBI 200cGy, n=14) or total lymphoid irradiation (TLI 500cGy, n=6) (day -1). Campath-1H blood levels were drawn on day -1. Cyclosporine and mycophenolate mofetil were used for graft versus host disease (GVHD) prophylaxis. All patients received standard antimicrobial prophylaxis and supportive care measures. Results: The median age at HCT was 8 years (range 0.1–44) with a median follow-up of 504 days (range 177-885). Graft sources consisted of matched sibling bone marrow (n=6) and unrelated donor umbilical cord blood (n=14; 5 single, 9 double). The median time to neutrophil engraftment was 18 days (range 10-26). Overall survival at 100 days was 100%. Fifteen patients achieved full (>80%, n=9) or mixed (10-80%, n=6) donor chimerism. There was a higher proportion of patients achieving full and mixed donor chimerism and less graft failure (GF) in those patients who received TBI as compared to TLI (12/14 [86%] vs. 3/6 [50%] and 2/14 [14%] vs. 3/6 [50%], respectively). Three patients with mixed chimerism have received donor lymphocyte infusions. Two patients (10%) developed steroid responsive GVHD, both after day 100. All five patients with graft failure (GF) had autologous recovery. Of those, 2 received a second HSCT and successfully engrafted. The median campath-1H area under the curve was 3.29 and was not different between those with successful engraftment and those with GF. Conclusions: Patients with advanced cerebral manifestations of lysosomal and peroxisomal disorders have limited therapeutic options. This reduced intensity transplant regimen designed to be minimally toxic to the CNS was very well tolerated with excellent overall survival. Donor engraftment appears to be better when TBI is utilized in the conditioning regimen. The incidence of GVHD is low, perhaps secondary to persistence of campath-1H. In summary, HCT with reduced intensity conditioning is feasible and should be considered for patients with high risk IMD. Disclosures: Off Label Use: Clofarabine is an antineoplastic agent approved for use in relapsed/refractory pediatric ALL, but was used in our patients as part of the pre-HCT conditioning regimen .

Defining The Optimal Dose Of Alemtuzumab In Unrelated Donor Reduced Intensity Allografts: A UK Retrospective Study

Blood ◽  
2013 ◽  
Vol 122 (21) ◽  
pp. 4540-4540
Author(s):  
Kile Green ◽  
Rob Sellar ◽  
Laura Jardine ◽  
Janice Ward ◽  
Paul Ferguson ◽  
...  
Keyword(s):  
Overall Survival ◽  
Retrospective Study ◽  
High Risk ◽  
Chronic Gvhd ◽  
Optimal Dose ◽  
Mixed Chimerism ◽  
Unrelated Donor ◽  
Post Transplant ◽  
Reduced Intensity ◽  
Grade Iii

Acute and chronic graft versus host disease (GVHD) represent major causes of morbidity and mortality following reduced intensity unrelated donor allografts, particularly in older patients. Alemtuzumab (AL, humanised anti-CD52 antibody) is highly effective at reducing the incidence of both forms of GVHD. There are a number of reported schedules used in this setting, with doses of between 50-100mg AL administered over 2-5 days. The timing of AL administration relative to stem cell return is also likely to have a significant impact on the depletion of donor T cells, but comparative data for unrelated donor transplants are lacking and the optimal dose and schedule remain unknown. In this three-centre retrospective study, we compared the post-transplant outcomes of patients receiving the same chemotherapeutic backbone of fludarabine 150mg/m2 and melphalan 140mg/m2 (flu-mel) along with the originally described AL regimen (100mg administered as 20mg/day, day -7 to -3, n=79), with those of patients receiving flu-mel and one of two alternative AL schedules: 60mg administered as 30mg/day, day -4 and -2, n=72; or 50mg administered as 10mg/day, day -7 to -3, n=107. In keeping with prior pharmacokinetic studies of de-escalating schedules in sibling donor cohorts, the day 1 serum AL levels in the 60mg cohort (median 4.7 mcg/ml, range 1.75-8.02 mcg/ml, n=14), did not differ significantly from historical data for the 100mg schedule. Donor lymphocyte infusions were given for mixed chimerism in all centres according to similar schedules starting at 6 months post transplantation. Median age at transplantation differed significantly between cohorts at 52, 45 and 56 years for the 100mg, 60mg and 50mg cohorts respectively (p = 0.005). Other statistically significant differences between cohorts were CMV status (p = 0.006) and disease indication (p = 0.0005); with AML patients constituting a majority in the 50mg cohort and lymphoproliferative disorder patients a majority in the 100mg cohort. No significant differences were detected between cohorts for HLA matching status (mismatched in 21/79 [27%], 12/72 [17%] and 33/107 [31%] respectively, p = 0.11), graft type (p = 0.06), or disease status at transplantation (p = 0.09). The incidences of acute grade II-IV GVHD were 35%, 32%, and 38% (p = 0.6) for the 100mg, 60mg and 50mg cohorts respectively, whilst those for grade III-IV GVHD were 4%, 6%, and 15% (p = 0.02). The corresponding incidences of chronic GVHD at 2 years were 29%, 28% and 39% respectively (p = 0.38). A trend towards a higher incidence of chronic GVHD in the 50mg cohort was confirmed by comparison with the combined data for the other 2 cohorts (29% vs 39%, p = 0.17). In the high-risk CMV cohort (seropositive recipient), reactivation requiring anti-viral therapy occurred in 97%, 77% and 76% respectively (p = 0.02). The incidences of full donor T-cell chimerism (>97% donor according to assay sensitivity) at day 100 were 56%, 29% and 44% respectively (p = 0.02). There were no significant differences with respect to non-relapse-related mortality at two years post-transplant (28%, 27% and 29% respectively, p = 0.57). Although univariate analyses of relapse rates and overall survival were confounded by the differences in patient characteristics between cohorts, no significant differences were observed (relapse rate at 3 years 20%, 20%, and 26%, p = 0.39; overall survival at 3 years 59%, 64% and 37%, p = 0.05). In conclusion, this study represents the first attempt to define an optimal dosing schedule for AL in unrelated donor allograft recipients, and suggests that significant reduction in AL dose is achievable for patients receiving flu-mel conditioning with unrelated donor grafts. There was evidence of more acute grade III-IV GVHD with the 10mg/day x5 schedule, and a trend towards a higher incidence of chronic GVHD, whilst the 30mg/day x2 schedule delivered similar results to the 20mg/day x5 schedule, perhaps in keeping with the comparable day 1 serum AL levels. Lower alemtuzumab doses were associated with a modest reduction in the risk of CMV reactivation in high-risk patients. Whilst the usual caveats associated with retrospective cross-institutional comparative studies apply, the data suggest that reduction to 30mg/day x2 is not associated with any significant detrimental impact and may be preferable on economic grounds. Disclosures: No relevant conflicts of interest to declare.

scholarly journals Allogenic Stem Cell Transplantation for Secondary CNS Lymphoma: A Retrospective Review of 21 Patients

Blood ◽  
2019 ◽  
Vol 134 (Supplement_1) ◽  
pp. 3342-3342 ◽  
Author(s):  
Cole Sterling ◽  
Nina D. Wagner-Johnston ◽  
Douglas E Gladstone ◽  
Richard F. Ambinder ◽  
Lode J. Swinnen ◽  
...  
Keyword(s):  
Overall Survival ◽  
Board Of Directors ◽  
Residual Disease ◽  
Cns Lymphoma ◽  
P Value ◽  
Myeloablative Conditioning ◽  
Advisory Committees ◽  
Term Survival ◽  
Cns Disease ◽  
Post Transplant

INTRODUCTION: Allogeneic blood or marrow transplant (alloBMT) is widely used in relapsed/refractory systemic non-Hodgkin lymphoma. The graft-versus-tumor effect has been thought to be blunted by the immune privilege of the central nervous system (CNS). Communication between the CNS and the systemic immune system suggests that CNS disease could benefit from the graft versus lymphoma (GVL) effect provided by alloBMT. METHODS: The charts of all patients who received post-transplant cyclophosphamide (PTCy)-based graft-versus-host disease (GVHD) prophylaxis between January 2004 and October 2018 were reviewed. Survival statistics were calculated using the Kaplan-Meier method. Differences in time to death between groups were estimated using Cox proportional hazards models. RESULTS: Twenty-one patients with systemic lymphoma involving the CNS were identified. The median age was 59 years (range 24-73); 7 were over the age of 60 and 13 were male. Histology types included diffuse large B cell (71%), Burkitt (10%), T cell (10%), follicular (5%), and anaplastic large cell (5%). Prior to transplant, 12 patients were in complete remission, 9 had residual disease, and 5 had residual CNS disease by imaging. Induction therapy included CNS radiation therapy in 11 of 21 patients (52%) and high-dose methotrexate (HD-MTX) in 10 (48%). Only 1 patient was in first remission, with the remaining 20 in second or later remission. All but 1 patient received non-myeloablative conditioning using fludarabine, cyclophosphamide, and total-body irradiation; the other patient received busulfan and cyclophosphamide. Fifteen patients (71%) had haploidentical donors. Graft source was bone marrow in 18 patients and G-CSF-stimulated peripheral blood in 3. Median overall survival (OS) for the entire cohort was 1375 days (95% confidence interval [CI] 184-NR) and median progression free survival (PFS) was 1375 days (95% CI 112-NR). Three-year overall survival was 51% (95% CI 27-71%). The cumulative incidence of relapse was 29% (95% CI 9-49%) at 3 years, and non-relapse mortality was 20% (95% CI 2-38%) at 1 year. Of the 6 patients who relapsed, 2 were CNS only, 2 were systemic only, and 2 were combined CNS / systemic. There were 2 cases of grade III-IV acute GVHD and 1 case of chronic GVHD involving the mouth. Univariable analysis revealed no predictors of survival in our small data set: age > 60 (hazard ratio [HR] 1.48, 95% CI 0.42-5.29, p-value 0.54), haploidentical donor (HR 4.2, 95% CI 0.53-33.66, p-value 0.17), residual disease (HR 1.3, CI 0.37-4.52, p-value 0.68), and prior CNS radiation (HR 1.5, 95% CI 0.42-5.31, p-value 0.53). DISCUSSION: Allogeneic BMT with non-myeloablative conditioning is potentially curative in patients with secondary CNS lymphoma. Post-transplant cyclophosphamide is well tolerated in this older group. Myeloablative conditioning directed at the CNS is not required for long-term survival. Given its biologic plausibility and potential as a viable treatment option in certain patient populations, the role of alloBMT in CNS lymphoma deserves further investigation. Figure Disclosures Wagner-Johnston: ADC Therapeutics: Membership on an entity's Board of Directors or advisory committees; Jannsen: Membership on an entity's Board of Directors or advisory committees; Gilead: Membership on an entity's Board of Directors or advisory committees; Bayer: Membership on an entity's Board of Directors or advisory committees. Swinnen:Pharmacyclics: Consultancy; AbbVie: Consultancy.

scholarly journals Hypomethylating Agent Maintenance Therapy after Allogeneic Stem Cell Transplant Improves Transplant Outcome in High Risk Acute Myelogenous Leukemia

Blood ◽  
2019 ◽  
Vol 134 (Supplement_1) ◽  
pp. 3297-3297 ◽  
Author(s):  
Amany R. Keruakous ◽  
Jennifer Holter Chakrabarty ◽  
Sarah Ann Schmidt ◽  
Mohamad O. Khawandanah ◽  
George Selby ◽  
...  
Keyword(s):  
Overall Survival ◽  
Stem Cell ◽  
High Risk ◽  
Stem Cell Transplant ◽  
Control Group ◽  
P Value ◽  
Cell Transplant ◽  
Allogeneic Stem Cell Transplant ◽  
Allogeneic Hsct ◽  
Post Transplant

Background: Allogeneic hematopoietic stem cell transplant (HSCT) is the only potential curative modality for high risk acute myelogenous leukemia (AML). However, relapse disease remains to be the main reason of failure of allogeneic HSCT. Salvage therapy for relapse AML after allogeneic HSCT is limited and rarely successful. Prognosis is poor with a 2-year survival rate of less than 20%. As majority of relapses occur within first 6 months after transplant, effective preventive intervention given early post allogeneic HSCT may be crucial. An ideal drug for pharmacologic maintenance is difficult to achieve as it should have activity against the disease without excessive myelosuppression or eradication of donor cells, and has minimal or low risk of exacerbation of graft-versus-host disease or additional toxicity. Azacitidine and decitabine are hypomethylating agents (HMAs), which work epigenetically to modulate various genes, including tumor suppressor genes. They have been shown to have benefits in improvement of event free survival and overall survival in relapse AML. Similar benefits have also been reported when low dose azacitadine was given after allogeneic stem cell transplant as a maintenance therapy. Method: This is a single institutional study carried out at the Bone Marrow Transplant Program at the University of Oklahoma Health Science Center. It was started as a case control study in June 2014 when post-transplant azacitadine protocol was initiated, and continues on as a prospective study. Subjects over 18 years old with high risk AML based on cytogenetic and molecular mutation undergoing allogeneic HSCT were enrolled from September 2013 to July 2018. The study is to compare outcome in patients received post-transplant low dose azacitidine at 32mg/m2 on days 1-5 every 28 days for 4 cycles initiating between 6-8 weeks post-transplant versus post-transplant observation. Multivariable cox proportional hazards model was derived to adjust for covariates that differ between the two treatment arms and was used to analyze time to relapse and overall survival in both arms; then our results were graphed using Kaplan Meier Plot. Results: This study included 49 patients undergoing allogeneic HSCT for high risk AML. They were divided into 2 groups with 31 patients received post-transplant azacitidine, and 18 patients did not (prior to initiation of post-transplant azacitadine protocol, control). Our Analysis concluded a greater proportion of deaths among the control group (88.89%) compared to the azacitidine group (25.81%). Majority of deaths in the control group was due to relapse (12 of 16 deaths). Relapse rate was higher in the control group (66.67%) as compared to azacitidine group (25.81%) with statistically significant improvement in time to relapse in the azacitidine group (not reach (NR)) versus 4.1 months in the control arm (log-rank p-value <0.0001) which was described in Figure (1). Median Overall survival was 7.6 months in control arm versus 27.4 months in the 8 patients who relapsed in azacitidine arm (log-rank p-value<0.0001). (Figure 2) Among the 29 subjects from both arms who were relapse-free, overall survival differed between the two treatment groups (log-rank p-value 0.003). Median survival time among those in the control group was 9.8 months. For the azacitidine arm, only 2 events occurred among the 23 relapse-free subjects while the remaining 21 subjects were censored (Figure 3). Among other transplant-related factors, disease status was not differed among the two groups (p=0.411), but conditioning regimen was (p=0.019) with a greater proportion of reduced intensity conditioning (RIC) in the control group (55.56%) than azacitadine group (22.58) (Table 1). After adjusting for conditioning regimen, hazard of relapse was 5.26 (1.99,13.93) times greater (p value<0.001) and death was 5.41 (1.99,13.93) times greater (p value<0.001) in the control group than azacitadine group. In our analysis, cause of death was not statistically significantly different among the two arms (p-value 0.325). Use of azacitidine post-HSCT did not increase the risk of GVHD or infections (table 2). Implications: Low dose azacitidine maintenance therapy after allogeneic stem cell transplant in high risk acute myelogenous leukemia decreases relapse rate, time to relapse and improved overall survival without increasing adverse events and no increased risk of graft-versus-host disease or infections. Disclosures No relevant conflicts of interest to declare.

scholarly journals A Phase II Study of Decitabine Followed By Allogeneic Hematopoietic Stem Cell Transplantation in High-Risk Patients with Myeloid Malignancies

Blood ◽  
2018 ◽  
Vol 132 (Supplement 1) ◽  
pp. 2107-2107
Author(s):  
Christopher R. D'Angelo ◽  
Aric C. Hall ◽  
Kyungmann Kim ◽  
Ryan J. Mattison ◽  
Walter L. Longo ◽  
...  
Keyword(s):  
Stem Cell ◽  
High Risk ◽  
Hematopoietic Stem Cell Transplantation ◽  
Stem Cell Transplantation ◽  
Chronic Gvhd ◽  
Infectious Complications ◽  
Myeloablative Conditioning ◽  
Hematopoietic Stem ◽  
Post Transplant ◽  
Risk Patients

Abstract Introduction: Allogeneic hematopoietic stem cell transplantation (allo-HSCT) is the only curative therapy for myelodysplastic syndrome (MDS) and high-risk acute myeloid leukemia (AML). Patients with high-risk disease have a markedly increased risk of relapse and death following transplant (Armand et al, Blood, 2014). Those who remain disease-free are at risk of severe morbidity from graft-versus- host-disease (GvHD). These issues highlight the importance of improved allo-HSCT platforms designed to reduce relapse rate without increasing risk of GvHD. Decitabine has minimal non-hematologic toxicity and proven efficacy in myeloid diseases (Blum et al, PNAS, 2010). Use of post-transplant cyclophosphamide has demonstrated improved rates of GvHD following allo-HSCT using haplo-identical donors (Bashey et al, JCO, 2013). No studies have reported on outcomes in patients undergoing decitabine immediately prior to transplantation followed by post-transplant cyclophosphamide (PTCy). We hypothesized that the combination of decitabine induction prior to transplant and PTCy would be safe and result in improved disease control with low rates of GVHD, translating into improved survival in a high-risk transplant cohort. Methods In this single-arm, single institution trial, eligible patients received 10 days of IV decitabine at 20mg/m2 no sooner than 24 days and no later than 17 days prior to conditioning. Myeloablative conditioning included fludarabine (50mg/m2 day-5-2), busulfan (IV 3.2mg/kg/day -5-2), and 4 Gy total body irradiation on day -1. Patients above age 65 received a 25% busulfan dose reduction. Patients received a fully or partially matched related bone marrow graft on day 0. GvHD prophylaxis included 50mg/kg of IV cyclophosphamide on day +3-4. Patients with fully matched donors received only PTCy while those with partially matched donors also received mycophenolate mofetil through day +35 and tacrolimus through day +180. Results We enrolled 20 patients, fifteen patients with AML and 5 with MDS. The cohort had a median age of 64 (29-73) and was predominantly male (14/20, 70%). Eight (40%) patients scored as high risk by the HSCT comorbidity index. Eighteen patients (90%) had a high or very high-risk score by the refined disease risk index. All patients received decitabine and 18/20 (90%) underwent transplantation; 2 patients did not receive a transplant due to infectious complications. The majority of patients received a haplo-identical graft (13/18, 72%), and the remaining 5 received a matched related graft. Outcomes are reported in table 2 and figure 1. There were no engraftment failures. Five patients, 3 MDS and 2 AML, are long-term survivors with median follow-up over 3 years. One patient developed donor derived MDS and required a second transplant. Most transplanted patients (13/18, 72%) survived to day 100 with a median post-transplant survival of 138 days. There were 15 deaths on study with the majority due to underlying disease. Six patients (6/20, 30%) died of infectious complications or did not receive a transplant due to infection. Incidence of grade 3-4 acute GvHD was low among those surviving at least 40 days from transplant (3/17, 17%). There were also low rates of chronic GvHD among the 12 patients alive without ongoing GvHD at day 100 (2/12, 17%). Conclusions Decitabine induction followed by myeloablative conditioning in this high-risk population resulted in a high treatment related mortality of 40%. Still, outcomes fell into an expected range for high-risk myeloid disease in an elderly and comorbid population. Based on expected outcomes for high-risk patients from the literature (Armand et al, Blood, 2014), decitabine did not markedly improve overall survival outcomes, recognizing that no direct comparisons are available in our limited study population. Decitabine may increase the risk of peri-transplant infections by contributing to a cumulative immunologic insult combined with disease-related immunosuppression and transplant-related toxicity, highlighting the importance of strict vigilance for infections within this setting. Diligent monitoring may improve infectious outcomes as shown in the second half of the cohort; only two out of the latter 10 patients on protocol died of treatment related complications. There were no cases of engraftment failure. Rates of acute and chronic GvHD using a PTCy platform were low and support other studies reporting this benefit. Disclosures No relevant conflicts of interest to declare.

HLA Haploidentical versus Matched Unrelated Donor Transplants with Post-Transplant Cyclophosphamide based prophylaxis

Blood ◽  
2021 ◽  
Author(s):  
Mahasweta Gooptu ◽  
Rizwan Romee ◽  
Andrew St. Martin ◽  
Mukta Arora ◽  
Monzr M. Al Malki ◽  
...  
Keyword(s):  
Overall Survival ◽  
Graft Failure ◽  
Unrelated Donor ◽  
Matched Unrelated Donor ◽  
Post Transplant ◽  
Gvhd Prophylaxis ◽  
Conditioning Regimens ◽  
Disease Free ◽  
Reduced Intensity ◽  
Grade Iii

Post transplant cyclophosphamide (PTCy) graft-versus-host disease (GVHD) prophylaxis has allowed haploidentical (Haplo) transplantation to be performed with results similar to that after matched unrelated donor (MUD) transplantation with traditional prophylaxis. The relative value of transplantation with MUD versus Haplo donors when both groups receive PTCy/calcineurin inhibitor/mycophenolate containing GVHD prophylaxis is not known. We compared outcomes after 2036 Haplo and 284 MUD transplantations with PTCy GVHD prophylaxis for acute leukemia or myelodysplastic syndrome in adults between 2011 and 2018. Cox regression models were built to compare outcomes between donor types. Recipients of myeloablative and reduced intensity regimens were analyzed separately. Among recipients of reduced intensity regimens, 2-year graft failure (3% versus 11%), acute grade II-IV GVHD (HR 0.70, p=0.022), acute grade III-IV GVHD (HR 0.41, p=0.016) and non-relapse mortality (HR 0.43, p=0.0008) were lower after MUD compared to Haplo transplantation. Consequently, disease-free (HR 0.74, p=0.008; 55% versus 41%) and overall survival (HR 0.65, p=0.001; 67% versus 54%) were higher after MUD compared to Haplo transplants. Among recipients of myeloablative regimens, day-100 platelet recovery (95% versus 88%) was higher and grade III-IV acute (HR 0.39, p=0.07) and chronic GVHD (HR 0.66, p=0.05) were lower after MUD compared to Haplo transplantation. There were no differences in graft failure, relapse, non-relapse mortality, disease-free and overall survival between donor types with myeloablative conditioning regimens. These data extend and confirm the importance of donor-recipient HLA matching for allogeneic transplantation. A MUD is the preferred donor, especially for transplantations with reduced intensity conditioning regimens.

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