The Path to Cure: Using Haploidentical (haplo) Donors and High-Dose Post-Transplant Cyclophosphamide (PTCy) for Treatment-Naïve and Refractory Severe Aplastic Anemia (SAA)

SAA is a life-threatening hematopoietic stem cell disorder that is often treated with bone marrow transplantation (BMT) to reconstitute hematopoiesis and eliminate clonality. Our group has shown that PTCy after related HLA-haplo BMT can facilitate engraftment and yield low rates of relapsed and refractory (R/R) SAA. Given the risk of relapse or secondary clonal disease following immunosuppressive therapy (IST) is > 50% at five years, we decided to implement this treatment paradigm in untreated SAA. Here, we review the haplo outcomes in SAA, with an update in R/R SAA patients and new results in treatment-naïve (TN) SAA patients using haplo donors and PTCy. Patients were eligible with SAA. Fanconi anemia and short telomere patients were excluded. R/R patients had ≥ one course of IST. The conditioning regimen included standard published haplo backbone of antithymocyte globulin, low dose CY, and total body irradiation (TBI). All R/R patients received 200cGy. The TBI dose for the TN cohort was modified after 3 graft failures (GF) in initial 7 patients treated at 200cGy; thus, the last 8 TN patients received 400cGy. After the marrow graft was infused on day 0, cyclophosphamide 50mg/kg/day IV on days +3,+4 post-transplant was administered. All received mycophenolate mofetil beginning day +5 through 35 and tacrolimus day +5 to 365. Engraftment definitions include: absolute neutrophil count >1.0 x10E9/L for three consecutive days; days from last red blood cell transfusion for hemoglobin and platelet count >50,000 for 7 days without transfusion. Thirty-five SAA patients received haplo BMT: 20 R/R and 15 TN. The median follow-up is 31 months (90% CI: 26.0, 45.4). The median age was 25 (range, 4-69) years, with 23 patients > age 20 and 57% were males. The median related haplo donor age was 34 years (range, 19-57), including three non-first degree relatives. Table 1 shows data by cohort. Median time to neutrophil recovery was 17 days (range 15-88), to red cell recovery 23 days (range 6-58) and to platelet recovery 28 days (range 15-108). At the time of BMT, 25 of 35 patients had evidence of clonality (mostly PNH clones). Four of 35 patients (11.4%) (95% CI: 3.2, 26.7%) experienced GF. There was one GF out of 20 patients in the R/R group (5%) (95% CI: 0.1, 24.9%) and 3 of 15 in the TN group 20% (95% CI: 4.3,48.1%, p= 0.20). OS for all patients (Figure 1) is 94% (90% CI: 88,100%) at one and two years, 100% in the R/R group and 86% (90% CI: 72, 100%) in the TN group. The cumulative incidence of grade II-IV aGVHD at day 100 is 9% (90% CI: 1, 17%). The cumulative incidence of chronic GVHD at 2 years is 9% (90% CI: 1,17%). All R/R patients are alive and well, and fully engrafted with 100% donor chimerism; patient with primary GF is 100% chimeric after 2nd transplant from different haplo donor. One patient has extensive cGVHD. Of the first 7 TN patients who received 200cGy TBI, 4 are fully engrafted and well; of the 3 with GF, 2 died from infection and one is now 100% chimeric using second haplo donor. After increasing the TBI dose to 400cGy, the subsequent 8 patients are alive with full donor chimerism. Nonmyeloablative haplo BMT with PTCy represents a potential cure in SAA, with all 20 R/R currently alive, disease-free (including eradication of clonal diseases), and no evidence of active GVHD. Extending this approach to TN patients was associated with higher GF rates. Perhaps this is not surprising given that the potential beneficial effect of front-line IST on engraftment is absent. The increase in TBI dose to 400cGy in TN patients appears to achieve more durable engraftment without early greater toxicity (infection, delayed engraftment, GVHD); more patients and longer follow up are required to understand rates of fertility and other survivorship issues. Alternative donor BMT (including haplo donors) should be offered to all SAA patients with R/R SAA who are fit enough to tolerate non-myeloablative conditioning. A potential advantage of haplo donors over unrelated donors is that the transplant center has full control and oversight of allograft quality, which can be especially important with the use of the preferred allograft source for SAA, bone marrow. Non-myeloablative haplo BMT in TN SAA could lead to a paradigm-shift in the field, such that essentially all children and fit adults can proceed quickly to a relatively safe, curative BMT. Disclosures DeZern: Astex Pharmaceuticals, Inc.: Consultancy; Celgene: Consultancy. Cooke:Jazz pharmaceuticals: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau.

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Post-Transplant Cyclophosphamide for Gvhd Prophylaxis in Matched Unrelated Donor Transplantation Compared to ATG-Based Prophylaxis

Blood ◽

10.1182/blood-2019-124849 ◽

2019 ◽

Vol 134 (Supplement_1) ◽

pp. 3285-3285

Author(s):

Rebeca Bailén ◽

Mi Kwon ◽

Maria Jesus Pascual-Cascon ◽

Anna Torrent ◽

Christelle M Ferra ◽

...

Keyword(s):

Peripheral Blood ◽

Cumulative Incidence ◽

High Dose ◽

Unrelated Donor ◽

Matched Unrelated Donor ◽

Hematopoietic Stem ◽

Free Survival ◽

Post Transplant ◽

Gvhd Prophylaxis

Background: Post-transplant high dose cyclophosphamide (PT-CY) effectively prevents graft-versus-host disease (GVHD) after unmanipulated HLA-haploidentical hematopoietic stem cell transplantation (HSCT). The use of PT-CY in HLA-identical donor is less explored. In this study, we analyzed the results of PT-CY for GVHD prophylaxis in matched unrelated donor (MUD) HSCT and compared them with those obtained after prophylaxis with anti-thymocyte globulin (ATG), methotrexate (MTX) and cyclosporine (CsA). Methods: 132 matched unrelated donor HSCT from 4 Spanish centers have been analyzed: 60 performed between 2010 and 2018 using ATG-MTX-CsA and 72 performed between 2014 and 2018 using PT-CY. Results: Baseline characteristics and post-transplant complications are shown in Table 1. Peripheral blood was used as graft source in 92% of the patients in the ATG group and in 78% in the PT-CY group. GVHD prophylaxis consisted in rabbit ATG either 2mg/kg days -4 to -2 (41 patients, 68%) or 0.5mg/m2 on day -3 followed by 1mg/kg days -2 and -3 (19 patients, 32%), MTX days +1, +3, +6 and +11, and CsA from day -1 in the ATG group. The PT-CY group received cyclophosphamide 50 mg/kg/d on days +3 and +4, followed by either CsA or tacrolimus plus mycophenolate mofetil (MMF) from day +5 in 30 patients (42%), or cyclophosphamide on days +3 and +5 combined with CsA or tacrolimus in 42 patients (58%; 16 out of them also received sirolimus due to 9/10 HLA-match). Cumulative incidence of grade II-IV (67% vs 46%, p=0.008) and III-IV (34% vs 3%, p=0.003) acute GVHD, were significantly higher in the ATG group (Figure 1). There were no differences in the 2-year cumulative incidence of chronic moderate to severe GVHD (23% vs 24%, p=0.86). After a median follow-up of 78 months for the ATG group and 26 months for the PT-CY group, no differences were found in the 2-year overall survival (58% vs 60%, p=0.475), 2-year event-free survival (51% vs 50%, p=0.961) and the composite endpoint of GVHD-free and relapse-free survival (44% vs 40%, p=0.742). The 2-year cumulative incidence of relapse (22% vs 26%, p=0.67) and non-relapse mortality (NRM) (24% vs 22%, p=0.68) were also similar between both groups. However, NRM in the ATG group was due to GVHD in 9 out of 16 patients, while in the PT-CY group NRM was mostly due to infections and organ toxicity and only 3 out of 15 patients died due to GVHD. The incidence of sinusoidal obstruction syndrome was low in both groups (0% vs 4%, p=0.11). CMV reactivation rates were similar (40% vs 51%, p=0.191). However, both hemorrhagic cystitis and EBV reactivation were higher in the ATG group (56% vs 12%, p=0.00, and 5% vs 0%, p=0.05, respectively). Conclusions: In our experience, GVHD prophylaxis using PT-CY combined with additional immunosuppression after MUD HSCT, using mostly peripheral blood as graft source, resulted in lower incidence of aGVHD compared to prophylaxis based on ATG-MTX-CsA. Although no impact on non-relapse mortality was observed, GVHD associated mortality was higher in the ATG group as well as cystitis and EBV reactivations. Prospective studies with longer follow-up are needed to confirm these observations. Disclosures No relevant conflicts of interest to declare.

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Post-Transplant Cyclophosphamide Versus MTX-CSA As Gvhd Prophylaxis in HLA-Identical Sibling HSCT

Blood ◽

10.1182/blood-2018-99-110551 ◽

2018 ◽

Vol 132 (Supplement 1) ◽

pp. 3394-3394

Author(s):

Rebeca Bailén ◽

Maria-Jesús Pascual ◽

Pascual Balsalobre ◽

Anabel Gallardo-Morillo ◽

Abel García-Sola ◽

...

Keyword(s):

Cumulative Incidence ◽

Acute Gvhd ◽

Conflicts Of Interest ◽

Conditioning Regimen ◽

High Dose ◽

Hematopoietic Stem ◽

Free Survival ◽

Post Transplant ◽

Gvhd Prophylaxis

Abstract Background: Post-transplant high dose cyclophosphamide (PT-CY) effectively prevents graft-versus-host disease (GVHD) after HLA-haploidentical hematopoietic stem cell transplantation (HSCT). However, the use of PT-CY in HLA-identical HSCT is less explored. In this study, we analyzed the results of PT-CY as GVHD prophylaxis in HLA-identical sibling HSCT and compared them with those obtained after prophylaxis with methotrexate (MTX) plus cyclosporine (CsA). Methods: 107 HLA-identical sibling (10/10) HSCT from 2 Spanish centers have been analyzed: 50 performed consecutively between 2010 and 2015 using MTX-CsA as GVHD prophylaxis, and 57 performed consecutively between 2014 and 2018 using PT-CY. Results: Baseline characteristics and post-transplant complications are shown in Table 1. GVHD prophylaxis consisted in MTX days +1, +3, +6 and +11, and CsA from day -1 in the MTX-CsA group. The PT-CY group received cyclophosphamide 50 mg/kg/d on days +3 and +5 in 38 patients (65%), combined with CsA from day +5, and cyclophosphamide on days +3 and +4 in 19 patients (35%), followed by CsA and mycophenolate mofetil from day +5. Graft source was PBSC in 96% in the MTX-CsA group and 86% in the PT-CY group. Conditioning regimen was myeloablative in 64% and 40%, respectively. Neutrophil and platelet engraftment was significantly delayed in the PT-CY group (14.5 (11-27) vs 15.5 (13-37), p=0.02; 11.5 (8-180) vs 20.5 (10-43), p=0.02). After a median follow-up of 60 months for the MTX-CsA group and 15 months for the PT-CY group, 2-year overall survival (OS) was 56% (42-70) and 78% (67-90) (p=0.088), and event-free survival (EFS) was 48% (34-62) and 62.5% (42.5-82.5) (p=0.054), respectively. Cumulative incidence at 100 days of grade II-IV (52.2% vs. 22.6%, p=0.0015), and III-IV (24.4% vs. 8.8%, p=0.016) acute GVHD were significantly higher in the MTX-CsA group (Figure 1A). No differences were observed in the 2-year cumulative incidence of chronic moderate to severe GVHD (26% vs. 16.7% (p=0.306)). No differences were observed in the 2-years cumulative incidence of relapse (27% vs. 28% (p=0.47)). Non-relapse mortality (NRM) at 2-years showed a higher trend in the MTX-CsA cohort (24% vs. 8.8%, p=0.054). Finally, the composite endpoint of GVHD and relapse-free survival (GRFS) at 2-years was significantly better in the PT-CY group (48% vs. 24%, p=0.011) (Figure 1B). Conclusions: In our experience, GVHD prophylaxis using PT-CY combined with additional immunosuppression after HLA-identical sibling HSCT, using mostly peripheral blood as graft source, reduced the cumulative incidence of acute GVHD compared to standard prophylaxis with MTX-CsA, leading to an impact on GRFS. To our knowledge, this is the largest comparative retrospective cohort reported. Further prospective studies with longer follow-up are needed to confirm these observations. Disclosures No relevant conflicts of interest to declare.

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Engraftment Effects of Intra Bone Marrow Compared to Intravenous Transplantation of Allogeneic Hematopoietic Stem Cells Following a Reduced Intensity Conditioning in a DLA-Identical Canine Littermate Model

Blood ◽

10.1182/blood.v124.21.1089.1089 ◽

2014 ◽

Vol 124 (21) ◽

pp. 1089-1089

Author(s):

Juliane Werner ◽

Stephanie Schaefer ◽

Sandra Lange ◽

Christoph Machka ◽

Gudrun Knuebel ◽

...

Keyword(s):

Bone Marrow ◽

Conflicts Of Interest ◽

Control Group ◽

Reduced Intensity Conditioning ◽

Hematopoietic Stem ◽

Platelet Recovery ◽

Time Points ◽

Donor Chimerism ◽

Cell Counts ◽

Reduced Intensity

Abstract Introduction: Successful engraftment following hematopoietic stem cell transplantation (HSCT) depends on factors like immunosuppression, graft composition and number of infused HSC. Whereas the immunosuppression as well as the type and composition of the graft are influenceable low numbers of available HSCs i.e. “weak grafts” remain a clinical challenge. Weak grafts are accompanied by increased graft failure rates and longer cytopenias associated with increased morbidity. Intra bone marrow (IBM) infusion of HSC might be an approach to overcome these problems. Studies in rodents demonstrated faster engraftment with an IBM HSCT approach compared to intravenous (IV) HSCT following myeloablative conditioning. Studies of IBM HSCT following non-myeloablative or reduced intensity conditioning (RIC) are missing. Aims: Exploring the feasibility and efficiency of IBM allogeneic HSCT in comparison to IV HSCT in dog leukocyte antigen (DLA) identical canine littermates using a RIC regimen. Methods: DLA-identical siblings were used as donor/recipient pairs for HSCT. Recipient dogs were conditioned with 4.5 Gy total body irradiation before HSCT (d0) and received 15 mg/kg Cyclosporin A BID as pre- and postgrafting immunosuppression (d-1 to d+35). BM grafts were harvested at d0. In the control group (CON, n=7) unmodified BM was transplanted IV. In the IBM group (n=7) BM harvests were centrifuged and buffy coat of the BM was then transfused simultaneously into the recipient humeri and femura (50 ml, 10 min). 10 dogs are currently evaluable. Chimerism of the peripheral blood mononuclear cells (PBMC) and granulocytes (G) were tested weekly until week 8 and afterwards in larger intervals. Blood cell counts and clinical toxicities such as weight loss were monitored. Results: Infusion of BM directly into the bone was feasible. All animals engrafted. Median number of infused total nucleated cells was 4.0*108/kg (range 2.3-6.0*108/kg, IBM) and 3.3*108/kg (range 1.9-5.0*108/kg, CON, IBM vs CON: p=0.4). Median CD34+ numbers infused were 3.1*106/kg (range:1.2-10.0*106/kg, IBM) and 3.9*106/kg (range: 1.0-7.2*106/kg, CON; IBM vs CON: p= 0.8). Hematopoietic recovery in the IBM and CON groups were similar. Leukocytes recovery (>1.0*109/l) occurred at median d+11 (range: d+10 - d+16, IBM) and d+10 (range: d+9-d+12, CON; IBM vs CON: p=0.3). Median leukocytes nadirs amounted to 0.23*109/l (IBM) and 0.28*109/l (CON; IBM vs CON: p=0.3) and median duration of leukopenia (<1.0*109/l) were 6 days (range: 5.0–11.0, IBM) and 4 days (range: 3.0–6.0, CON; IBM vs CON: p=0.1). Median platelet nadir after IBMT was 10.0*109/l (range: 0.0 - 25.0*109/l) and 6.0*109/l (range: 3.0-15.0*109/l, CON; IBM vs CON: p=0.8). Period of thrombocytopenia (≤50.0*109/l) lasted for 12 days in both groups (p=0.7). Chimerism analyses showed an early and fast increase in donor chimerism in both groups. The PBMC donor chimerism at d+14, d+28 and d+56 were 46% (range: 30-53%), 57% (range: 40-73%), 64% (range: 60-83%) for IBM. Results in CON were 37% (range: 17-93%), 60% (range: 49-100%), 57% (range: 40-100%) (IBM vs CON, p=n.s. (all time points)). The G chimerism values at that specific points were 95% (range: 53-100%), 100% (range: 53-100%), 96% (range: 88-100%) for IBM and 100% (range: 93-100%), 99% (range: 92-100%), 98% (range: 93-100%) for CON (IBM vs CON, p=n.s. (all time points)). Primary goal of the study was the feasibility of the IBM approach. Ethics regulations did not allow to use weak grafts (≤2.0*106/kg) intentionally. However, 4 animals received weak grafts (CON n=2, 1.0 and 2.0*106/kg; IBM n=2, 1.2 and 1.3 *106/kg). Of interest, comparing data of these dogs showed that durations of leukopenia were similar (median 10 days, both groups), but duration of thrombocytopenia were different (median 8 days, IBM vs 22 days, CON). Additionally, long term donor chimerism was higher in the IBM (median 80% PBMC, 100% G) vs CON (median 61% PBMC, 42% G). Conclusion: First, IBM HSCT is a feasible and effective method to deliver HSC directly into the bone marrow following RIC in a canine HSCT model. Second, our preliminary data suggest that IBM HSCT reveals advantageous engraftment differences in regards to platelet recovery and donor chimerism kinetics compared to the IV HSCT when grafts with low HSC numbers were infused. Follow up data of this study and future studies will have to clarify these observations further. Disclosures No relevant conflicts of interest to declare.

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Addition of Bortezomib (Velcade™) to High Dose Melphalan (Vel-Mel) as an Effective Conditioning Regimen with Autologous Stem Cell Support in Multiple Myeloma (MM).

Blood ◽

10.1182/blood.v104.11.929.929 ◽

2004 ◽

Vol 104 (11) ◽

pp. 929-929 ◽

Cited By ~ 9

Author(s):

Klaus Hollmig ◽

Julie Stover ◽

Giampalamo Talamo ◽

Maurizio Zangari ◽

Raymond Thertulien ◽

...

Keyword(s):

Multiple Myeloma ◽

Bone Marrow ◽

High Risk ◽

Conditioning Regimen ◽

High Risk Population ◽

High Dose ◽

Complete Disappearance ◽

Care Hospital ◽

Platelet Recovery

Abstract Velcade has shown promising activity alone and, more recently, in combination with other anti-myeloma agents (dexamethasone, thalidomide, doxil, standard dose melphalan) for relapsed or refractory multiple myeloma. We have now explored the efficacy and safety of Velcade™ 1.0 or 1.3mg/m2 administered on days -4 and -1 prior to Melphalan, which was given in two fractionated doses for a total of 100–250 mg/m2 on days -4 and -1 or as single dosing on day -1 supported on day 0 by PBSC infusion. Follow-up is now 1–5 months; detailed follow-up data will be available at presentation. Of 37 patients currently evaluable for toxicity, 27 are also evaluable for response. Patient characteristics are outlined in Table 1, depicting a high risk population. The treatment was administered in the out-patient setting in 37 patients, 27 of whom were entirely managed through ambulatory care. Hospital admission was required for pneumonia in 4, sepsis in 3, nausea and vomiting in 2 and ileus in 1 patient. In 37 evaluable patients, hematopoetic recovery depended upon the timing of PBSC collection (prior to the first, second or the Vel-Mel transplant). Neutrophil recovery to > 1,000/μL occurred at a median of 13 days and platelet recovery to 50,000/μl at a median of 17 days. Non-hematologic toxicities included ≥ grade III mucositis in 5, diarrhea in 11, febrile neutropenia in 5, pneumonia/sepsis in 14, and fatigue in 22 patients. No fatal complications were seen. Of 27 evaluable patients, partial response (≥ 75% of serum M protein reduction, ≥ 75% of urinary M excretion) was obtained in 9 (39%) including 6 (26%) who showed a complete disappearance of serum M and urine M. Bone marrow follow-up examinations were available in 17 patients and revealed a median reduction in plasmacytosis of 75% including 2 patients achieving a normal bone marrow plasmocytosis Our results are promising and demonstrate that Vel can be safely added to Mel at doses as high as 250 mg/m2 in fractionated dosing with a high response rate also in high-risk, advanced disease. This approach will be formally evaluated in a randomized trial comparing tandem transplants with Mel 200 mg/m2 alone versus added Vel 1.0 mg/m2 on days 1 and 4 followed on each day by Mel 140 (total 280 mg/m2). Velcade 1.0 mg/m² Velcade 1.3 mg/m² Parameter Mel 250 Mel 220–240 Mel 200 Mel 100–150 Mel 250 Mel 200 Mel 100–150 N 4 4 12 10 4 2 1 % AGE ≥ 65 0 25 33 30 0 0 100 %Abn Cytogen 75 0 8 30 50 50 0 % Prior Autotx 75 25 33 40 75 0 100 % Prior VTD 50 25 25 30 75 50 100

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Sustained Effect of First Line Sequential Therapy with Intensive Consolidation Chemotherapy and Allogeneic Hematopoietic Stem Cell Transplantation (ASCT) after Reduced Intensity Conditioning (RIC) for Patients with Acute Myeloblastic Leukemia (AML) in First Complete Remission (CR1).

Blood ◽

10.1182/blood.v108.11.3000.3000 ◽

2006 ◽

Vol 108 (11) ◽

pp. 3000-3000

Author(s):

Didier Blaise ◽

R. Tabrizi ◽

C. Faucher ◽

Mohamad Mohty ◽

J.O. Bay ◽

...

Keyword(s):

High Risk ◽

Cumulative Incidence ◽

Sequential Therapy ◽

High Dose ◽

Intensive Chemotherapy ◽

Consolidation Chemotherapy ◽

Hematopoietic Stem ◽

Cell Counts ◽

To Receive

Abstract We recently reported our experience using RIC prior to ASCT in pts with AML in CR1 (Blaise, Cancer, 2005). We have shown that RIC-based ASCT can be safely used in this setting after intensive consolidation chemotherapy. With a median follow-up of 18 months, disease control was high and was not related to a selection bias (Mohty, Leukemia, 2005). In the present analysis, we investigated if this control was maintained after a longer follow-up. Thirty-seven pts (age: 51 (range, 26–60)) with high risk clinical characteristics (n=26; 70%) (Age ≥ 50 (N=22, 59%); Associated severe comorbidity (N=10; 30%)) and/or poor risk leukemic features (n=24; 65%) (Poor Cytogenetics (N=13, 35%); failure of first induction course (N= 10, 27%); secondary leukemia (N= 4; 11%), High white blood cell counts(N= 5; 14%) or partial remission (N=1, 3%)) were included in this analysis. After CR1, all pts received a low dose cytarabine consolidation chemotherapy followed one month later by one course of high dose cytarabine (24 g/m²) and anthracycline (HIDAC). Pts were then scheduled to receive ASCT prepared with RIC (fludarabine (180 mg/m²), busulfan (8 mg/kg), Thymoglobulin (2.5 to 10 mg/kg)) followed with BMT (N=10 (28%) or PBSC (N=26 (72%)). However after treating the first pts, it becomes evident that this schedule was not associated prohibitory toxicity. All following pts were, thus, proposed to receive one month after HIDAC, one course of melphalan (140 mg/m²) (HDMEL) with auto-SCT followed after recovery by the allo-SCT. Overall, 21 pts received HIDAC only and 16 HIDAC and HDMEL. Median follow-up at time of abstract is 3 years (16 months–70 months). 15 pts experienced aGVHD (Grade 1: 7; Grade 2: 4; Grade 3–4: 4). The cumulative incidence of grade 2–4 aGVHD was 22% (9–35). 33 pts (90%) were evaluable for cGVHD: 10 and 14 pts presented a limited and extensive form respectively. The cumulative incidence of cGVHD was 65 % (50–80). Three deaths were attributed to non-relapse causes (AGVHD: 1; CGVHD: 2° (cumulative incidence of non-relapse death (NRD): 8% (95% CI: 0–17). In all, 8 pts relapsed at 5 months (2–19) (cumulative incidence: 22% (95% CI, 9–35). Relapse was clearly associated with the absence of cGVHD (cGVHD: 4 (4–12), no cGVHD 44% (12–76), p=.02) and at a lesser extent with the intensity of consolidation chemotherapy (HIDAC: 33% (13–53); HIDAC + AUTO; 6% (0–19%), p=.06). Twenty-six pts are still alive in CR1 for overall survival and leukemia-free survival (LFS) probability estimates at 4 years of 67 % (95%CI, 49–81%) and 68% (95%CI, 50–81%) respectively. When restricting the analysis to the 33 pts evaluable for cGVHD, cGVHD remained the only independent risk factor positively influencing LFS (cGVHD: 83% (59–74); no cGVHD (56% (27–81), p=.03). We conclude that RIC Allo-SCT preceded by adequate prior intensive chemotherapy might offer a relatively low NRD while exerting a sustained leukemia control even in high risk pts. The intensity of intensive chemotherapy needed for optimal will be assessed prospectively.

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Prognostic Effect of ASXL1 Mutations in Patients with MDS and Secondary AML Following MDS After Allogeneic Hematopoietic Stem Cell Transplantation

Blood ◽

10.1182/blood.v118.21.1709.1709 ◽

2011 ◽

Vol 118 (21) ◽

pp. 1709-1709 ◽

Cited By ~ 1

Author(s):

Christian Koenecke ◽

Felicitas Thol ◽

Patrick Löffeld ◽

Stefanie Buchholz ◽

Michael Stadler ◽

...

Keyword(s):

Bone Marrow ◽

High Risk ◽

Cumulative Incidence ◽

Unrelated Donor ◽

Donor Age ◽

Hematopoietic Stem ◽

Frameshift Mutations ◽

Gvhd Prophylaxis ◽

Related Donor

Abstract Abstract 1709 Introduction: Allogeneic hematopoietic stem cell transplantation (HSCT) is the only curative therapy for patients with myelodysplastic syndromes (MDS), but it is associated with high mortality and morbidity. Predictors for treatment outcome after HSCT are limited. Recently, mutations in ASXL1 have been described as an independent adverse prognostic marker for MDS patients not undergoing HSCT. The aim of this study was to investigate the prognostic impact of ASXL1 in a large cohort of patients with high risk MDS or secondary AML following MDS (sAML) undergoing HSCT. Patients and Methods: Patients (n=105) with a diagnosis of MDS (34.3%) or sAML (65.7%) who received an allogeneic HSCT at Hannover Medical School between 1996 and 2010 and for whom genomic DNA was available from a time when the disease was active, were evaluated for the presence of ASXL1 mutations by direct sequencing. Patients gave their informed consent in accordance with the Declaration of Helsinki, and the study was approved by the institutional review board of Hannover Medical School. Overall survival (OS) and cumulative incidence of non-relapse mortality endpoints, measured from HSCT, were death (failure) and alive at last follow-up (censored). A Cox proportional hazards model was constructed for multivariate analysis and the two-sided level of significance was set at P <.05. Results: Median follow up from time of transplantation was 3.67 years. Median patient age at time of HSCT was 58 years (range 22–72) and the median donor age was 39 years (range 0–71). Twenty-seven patients (26.0%) were in complete remission and 78 patients (74%) had active disease before transplantation. In MDS, 9, 21, and 6 patients had intermediate-1, intermediate-2, or high risk IPSS, respectively. Low, intermediate, and high risk cytogenetics according to IPSS were found in 40, 21, and 44 patients, respectively. Related donor HSCT was performed in 24 patients (23%), and unrelated donor HSCT in 81 patients (77%). Six patients received bone marrow (6%), two cord blood (2%), and 97 (92%) received peripheral blood stem cells. Myeloablative preparative regimens were used in 17 patients (16%), and a non-myeloablative regimen was given to 88 patients (84%). Mutations in ASXL1 were detected in 21 (20%) patients with 17 (16.2%) mutations being frameshift mutations. Previously, we showed that only frameshift mutations are prognostically relevant in MDS patients and therefore considered only those for further analysis. ASXL1 frameshift mutations were not correlated with clinical parameters (age, sex, MDS vs. sAML, cytogenetics, bone marrow blasts, blood group, CMV status of patient, type of previous treatment, and remission status prior to transplantation). ASXL1 frameshift mutated patients had received a graft from a related donor (41 vs. 19%, respectively, P=.05) and from bone marrow (17.6 vs. 3.4%, respectively, P=.03) more often compared to wildtype patients, however, there were no differences regarding other transplant-related characteristics (reduced intensity vs. standard conditioning, GvHD prophylaxis, donor age, donor sex, and CMV compatibility between recipient and donor). The presence of ASXL1 frameshift mutations was associated by trend with a shorter overall survival (5-year OS 31 vs. 47%, HR 1.87; 95%CI 0.96–3.64; p=.06). In multivariate analysis, when considering variables with P<.1 in univariate analysis (karyotype, stage [MDS vs. sAML], CMV serostatus of patient, donor type [related vs. unrelated], donor sex, donor age, and GvHD prophylaxis), ASXL1 frameshift mutations were an independent prognostic marker for OS (HR 2.63; 95%CI 1.29–5.38; P=.008) besides karyotype, stage, donor type, and GvHD prophylaxis. The cumulative incidence of relapse was similar between ASXL1 mutated and wildtype patients (P=.47). However, the cumulative incidence of non-relapse mortality was significantly higher in mutated compared to wildtype patients in univariate (61 vs. 34%, P=.01) and multivariate (P=.03) analysis. Grade III-IV acute GvHD was more frequent in ASXL1 mutated patients (37.5 vs. 7.4%, P=.002), while no extensive chronic GvHD was noted in these patients (0 vs. 20%, P=.14). Summary: ASXL1 frameshift mutations independently predicted worse patient outcome after allogeneic HSCT in MDS and sAML patients in our study. The high rate of non-relapse mortality in ASXL1 mutated patients warrants further investigation. *equal contribution Disclosures: No relevant conflicts of interest to declare.

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Pilot Study: Favorable Outcomes with Addition of Topotecan to Busulfan/Melphalan As High-Dose Myeloablative Therapy Followed by Autologous Hematopoietic Cell Transplantation

Blood ◽

10.1182/blood.v120.21.4553.4553 ◽

2012 ◽

Vol 120 (21) ◽

pp. 4553-4553

Author(s):

Joseph Rosenthal ◽

Anna Pawlowska ◽

Jerry Cheng ◽

Steven Kechichian ◽

Debbie Hitt ◽

...

Keyword(s):

Cell Transplantation ◽

Hematopoietic Cell Transplantation ◽

Conflicts Of Interest ◽

Complete Response ◽

Disease Recurrence ◽

Electrolyte Imbalance ◽

High Dose ◽

Hematopoietic Stem ◽

Platelet Recovery ◽

Post Transplant

Abstract Abstract 4553 High dose (HD) therapy followed by autologous hematopoietic stem cell transplantation (AHCT) has been the mainstay of treatment in patients diagnosed with advanced neuroblastoma (NBL). Busulfan and Melphalan (Bu/Mel) was demonstrated to be superior to other HD regimens and is widely considered as standard treatment. (Ladenstein, Bone Marrow Transplant. 2008 Jun;41 Suppl 2:S118-27), Topotecan (Topo) with or without cyclophosphamide has demonstrated efficacy in treatment of advanced NBL (Kushner, Cancer 116: 3054, 2010). We hypothesize that adding Topo to Bu/Mel as HD therapy followed by AHCT is well tolerated and will result in favorable outcomes. Patients and Methods: Patients with NBL, stage III or IV were eligible and consented to participate in the study. Seven patients were enrolled, the median age was 2.65 yrs (range 2.3 – 4.x yrs), and there were 4 males (57%). All patients were initially treated on COG protocols and in all cases a complete response was documented prior to proceeding with AHCT. Autologous hematopoietic cells were collected, following mobilization with G-CSF, after 2 (n=6) or 3 (n=1) cycles of chemotherapy. All patients were given post transplant radiation therapy to the primary tumor bed and cis-retinoic acid, 3 patients were also given monoclonal antibodies. Data on engraftment, toxicities, event free survival (EFS) and overall survival (OS) were analyzed. Results: The median cell dose was 6.62 × 106 CD34+/kg (5.57×106−7.33 × 107). Engraftment occurred promptly in all patients. Myeloid and platelet recovery occurred at a median of 12 (8–17 days) and 22 (17–41 days), respectively. The treatment was well tolerated with no grade 4 or higher toxicities. Grade 3 toxicities included; mucositis (n=7, 100%), electrolyte imbalance (n=3), diarrhea (n=3), autoimmune hemolysis (n=1) and epistaxis (n=1). Three patients suffered disease recurrence, 156, 821 and 899 days post AHCT. One patient is dead and two continue salvage therapy 55 and 52 months, post transplant, respectively. The 4-year OS and EFS were 87% to 57%, respectively. Conclusion: This novel regimen of Topo/Bu/Mel appears to be well tolerated with low TRM and promising EFS and OS. Further and larger studies are required to establish its role as HD therapy prior to AHCT in patients with advanced NBL. Disclosures: No relevant conflicts of interest to declare.

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Association of Increased Ring Ssideroblasts with Inferior Survival in Patients with Myelodysplastic Syndrome with Multi-Lineage Dysplasia

Blood ◽

10.1182/blood.v128.22.5530.5530 ◽

2016 ◽

Vol 128 (22) ◽

pp. 5530-5530

Author(s):

Hiroshi Kawabata ◽

Kaoru Tohyama ◽

Akira Matsuda ◽

Kayano Araseki ◽

Tomoko Hata ◽

...

Keyword(s):

Bone Marrow ◽

Stem Cell ◽

Myelodysplastic Syndrome ◽

Cumulative Incidence ◽

Research Funding ◽

Who Classification ◽

Pharmaceutical Research ◽

Ethics Committee ◽

Hematopoietic Stem

Abstract Myelodysplastic syndrome (MDS) is a heterogeneous group of hematopoietic stem cell disorders characterized by ineffective hematopoiesis and a high propensity to transform into acute myeloid leukemia (AML). Although hematopoietic stem cell transplantation can cure some MDS patients, most patients are not eligible to undergo the treatment because of advanced age or comorbidities. In order to choose the optimal treatments, predicting prognosis is crucial. Chromosomal karyotype, bone marrow (BM) blast percentage, and cytopenia are well-known prognostic factors for MDS patients. These factors are incorporated into the international prognostic scoring system and its revised version (IPSS-R). However, the impact of morphological abnormalities has not been fully determined. Thus, to elucidate this, we examined the influence of the number of dysplastic lineages and the presence of increased ring sideroblasts (RS) on the survival of MDS patients whose BM blast percentages were <5%. Since 2006, the National Research Group on Idiopathic Bone Marrow Failure Syndromes, Japan, has been conducting the Prospective Registration, Central Review and Follow-up Study for Aplastic Anemia and Myelodysplastic Syndrome. Patients with BM blasts of <5% were subjected to our central review system for final diagnosis, and their medical records were collected every 6 months after their registration. By using this depository database, we retrospectively analyzed overall survival (OS) and cumulative incidence of progression to AML. This study was performed in accordance with the Declaration of Helsinki, and the study protocol was approved by the Ethics Committee of Kyoto University Graduate School and Faculty of Medicine and by the ethics committee of each participating institution. Either t test or Mann-Whitney U test was used as appropriate for analyzing the differences in variables between the groups. The Kaplan-Meier method and log-rank test were used for analyzing differences in OS between the groups. The Cox proportional hazards model was used for analyzing risk factors for OS, and Grayfs test was used for analyzing differences in cumulative incidence of progression to AML. P values of <0.05 was considered statistically significant. By May 2016, 351 cases had been registered to the depository. After central review, 216 cases were diagnosed as MDS according to definition by the French-American-British Cooperative Group. Cases that were not registered within 1 year after the time of institutional diagnosis and cases with follow-up periods of <4 weeks were excluded from this study. In the 2008 WHO classification, 30 cases were RCUD (MDS-SLD in the 2016 WHO classification) and 78 were RCMD (MDS-MLD in the 2016 WHO classification). The median ages of patients with RCUD and RCMD were 67.5 and 71.5 years, respectively (P = 0.11). The male-to-female ratios were 1.14 and 2.25, respectively (P = 0.18), and the median follow-up times of the survivors were 45 and 24 months, respectively (Table 1). Among patients with RCMD, 22 showed >15% RS in erythroblasts. The mean BM blast percentage was significantly lower in patients with RCUD than in those with RCMD, consistent with the result of our pervious study that used a different cohort where the BM blast percentages in patients with RA according to the 2008 WHO classification were significantly lower than those in patients with RCMD (Matsuda A, et al. Eur J Haematol. 2013;90:79-80). The 2-year OS of patients with RCUD was significantly higher than that of patients with RCMD (84% vs 76%, P = 0.014; Fig. 1a), which is consistent with the results of a German study (Maassen A, et al. Leuk Res. 2013;37:64-70). The cumulative incidence of progression to AML tended to be higher in RCMD than in RCUD, although the difference was not statistically significant (P = 0.0656, Fig. 1b). Among patients with RCMD, those with increased number of RSs showed significantly lower hemoglobin levels and higher cytogenetic scores according to the IPSS-R definition than those without increased RS (Table 2). The 2-year OS of the former was significantly inferior to that of the latter in our cohort (58% vs 87%, P = 0.009; Fig. 1c). Increased number of RSs is known to be associated with SF3B1 mutations, which in turn have been shown to be associated with favorable prognosis. However, the results of the present study indicate that in RCMD, an increase in the number of RSs may be an unfavorable indicator of patient survival. Disclosures Ozawa: Celgene Japan: Consultancy; Sumitomo Dainippon Pharma Co. Ltd: Research Funding; JCR Pharmaceutical Inc: Consultancy; Takara Bio Inc: Research Funding. Takaori-Kondo:Pfizer: Research Funding; Eisai: Research Funding; Takeda Pharmaceutical: Research Funding; Astellas Pharma: Research Funding; Kyowa Kirin: Research Funding; Cognano: Research Funding; Toyama Chemical: Research Funding; Mochida Pharmaceutical: Research Funding; Shionogi: Research Funding; Alexion Pharmaceuticals: Research Funding; Chugai Pharmaceutical: Research Funding; Janssen Pharmaceuticals: Speakers Bureau; Merck Sharp and Dohme: Speakers Bureau; Bristol-Myers Squibb: Speakers Bureau.

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High-dose cyclophosphamide for severe aplastic anemia: long-term follow-up

Blood ◽

10.1182/blood-2009-06-225375 ◽

2010 ◽

Vol 115 (11) ◽

pp. 2136-2141 ◽

Cited By ~ 77

Author(s):

Robert A. Brodsky ◽

Allen R. Chen ◽

Donna Dorr ◽

Ephraim J. Fuchs ◽

Carol Ann Huff ◽

...

Keyword(s):

Bone Marrow ◽

Aplastic Anemia ◽

Severe Aplastic Anemia ◽

High Dose ◽

Actuarial Survival ◽

Free Survival ◽

Long Term Follow Up ◽

Treatment Naïve

Abstract Severe aplastic anemia (SAA) is a life-threatening bone marrow failure disorder that can be treated with bone marrow transplantation, immunosuppressive therapy, and high-dose cyclophosphamide. Here, we report long-term follow-up on 67 SAA patients (44 treatment-naive and 23 refractory) treated with high-dose cyclophosphamide. At 10 years, the overall actuarial survival was 88%, the response rate was 71% with the majority being complete, and the actuarial event-free survival was 58% in 44 treatment-naive SAA patients. Patients with refractory SAA fared less well after high-dose cyclophosphamide therapy; at 10 years, overall actuarial survival, response, and actuarial event-free survival rates were 62%, 48%, and 27%, respectively. High-dose cyclophosphamide is highly effective therapy for severe aplastic anemia. Large randomized controlled trials will be necessary to establish how results of high-dose cyclophosphamide compare with either bone marrow transplantation or standard immunosuppressive regimens, such as antithymocyte globulin and cyclosporine.

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Antibody Drug Conjugates Targeted to CD45 or CD117 Enable Allogeneic Hematopoietic Stem Cell Transplantation in Animal Models

Blood ◽

10.1182/blood-2018-99-119432 ◽

2018 ◽

Vol 132 (Supplement 1) ◽

pp. 3324-3324

Author(s):

Rahul Palchaudhuri ◽

Sharon L. Hyzy ◽

Jennifer L Proctor ◽

Hillary L Adams ◽

Bradley R Pearse ◽

...

Keyword(s):

Bone Marrow ◽

Stem Cell ◽

Employment Equity ◽

Hematopoietic Stem ◽

Antibody Drug Conjugates ◽

Post Transplant ◽

Donor Chimerism ◽

Drug Conjugates ◽

Equity Ownership ◽

Antibody Drug

Abstract Introduction Targeted antibody drug conjugates (ADCs) to mouse CD45 or mouse CD117 have recently been shown to effectively prepare immunocompetent mice for whole bone marrow transplants (Palchaudhuri et al. Nature Biotech 2016 34:738-745; and Czechowicz et al. Blood 2016 128:493). This new targeted approach to conditioning using ADCs has the potential to expand the utility of transplantation if it can be successfully translated to humans. The anti-CD45 or anti-CD117 antibodies used previously were coupled to saporin (SAP), a ribosome-inhibiting protein, which once internalized elicits cytotoxicity in a cell cycle-independent manner. Both anti-CD45-saporin (CD45-SAP) and anti-CD117-saporin (CD117-SAP) ADCs have been shown to effectively deplete bone marrow hematopoietic stem cells (HSCs) as single dosed agents, creating vacancies that enable efficient autologous HSC engraftment (>95% long-term donor chimerism). Results To further investigate and develop the utility of these tool ADCs in murine transplant models, we explored CD45-SAP (1.9 mg/kg, iv) and CD117-SAP (1 mg/kg, iv) in an allogeneic minor mismatch transplant model (Balb/c donor into DBA/2 recipients). The ADCs were used alone or in combination with an additional immune depleting agent, clone 30F11 (25 mg/kg, IP), a naked anti-CD45 antibody that mimics ATG by relying on effector function to enable potent peripheral B- and T -cell depletion. In addition to the lymphodepleting antibody, we included post-transplant Cytoxan (200 mg/kg, IP) to prevent GvHD. To compare the CD45-SAP and CD117-SAP to conventional conditioning methods, we investigated sub-lethal total body irradiation (TBI, 2Gy) or pre-transplant Cytoxan (200 mg/kg, IP) in combination with the immunosuppressants. Conditioned mice were transplanted with 2x107 whole bone marrow cells, and chimerism assessed over 12 weeks. CD45-SAP or CD117-SAP in combination with immunosuppressants (30F11 and post-transplant Cytoxan) enabled >85% peripheral donor chimerism at 12 weeks post-transplantation. Multilineage reconstitution was observed in the T-, B- and myeloid cell compartments with >80%, >90% and >90% donor chimerism respectively in both CD45-SAP and CD117-SAP groups. In contrast, 2Gy TBI in combination with immunosuppressants (30F11 and post-transplant Cytoxan) resulted in only 5% donor engraftment. Multi-dosing with 30F11 (QDx3) plus 2Gy TBI and post-transplant Cytoxan increased the peripheral donor chimerism to 40%. Pre-transplant Cytoxan plus 30F11 (QDx3) and post-transplant Cytoxan yielded 20% donor chimerism. For all groups, stem cell chimerism in the bone marrow matched the peripheral chimerism. Conclusion These results indicate anti-CD45 or anti-CD117 ADCs may be used in combination with immunosuppression to enable highly efficient allogeneic transplants in a minor mismatch model (>85% donor chimerism). CD45-SAP and CD117-SAP were more effective at conditioning versus 2Gy TBI or pre-transplant Cytoxan. Future experiments will investigate anti-CD45 and anti-CD117 ADCs in additional allogeneic models. Disclosures Palchaudhuri: Magenta Therapeutics: Employment, Equity Ownership, Patents & Royalties; Harvard University: Patents & Royalties. Hyzy:Magenta Therapeutics: Employment, Equity Ownership. Proctor:Magenta Therapeutics: Employment, Equity Ownership. Adams:Magenta Therapeutics: Employment, Equity Ownership. Pearse:Magenta Therapeutics: Employment, Equity Ownership, Patents & Royalties. Sarma:Magenta Therapeutics: Employment, Equity Ownership. Aslanian:Magenta Therapeutics: Employment, Equity Ownership. Gillard:Magenta Therapeutics: Employment, Equity Ownership. Lamothe:Magenta Therapeutics: Employment, Equity Ownership. Burenkova:Magenta Therapeutics: Employment, Equity Ownership. Brooks:Magenta Therapeutics: Employment, Equity Ownership. Gabros:Magenta Therapeutics: Employment, Equity Ownership. McDonagh:Magenta Therapeutics: Employment, Equity Ownership, Patents & Royalties. Boitano:Magenta Therapeutics: Employment, Equity Ownership, Patents & Royalties. Cooke:Magenta Therapeutics: Employment, Equity Ownership, Patents & Royalties.

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