Hematopoietic Stem Cell Transplantation (SCT) for Hematologic Malignancy from Matched Related Donors (MRD) with a Myeloablative Once Daily IV Busulfan (Bu)/Fludarabine (Flu) Based Regimen (FLUBUP) with Thymoglobulin: Outcomes in 200 Patients with over One Year Follow-Up.

Abstract Earlier reports indicated that a myelablative protocol based on once daily IV Bu with Flu plus rabbit antithymocyte globulin appeared effective and relatively well tolerated. Since 1999 this has been our standard regimen for all pts with hematologic malignancy, including those who might otherwise be candidates for non-myeloablative regimens. Two hundred MRD SCT patients (pts) were treated between 05/99 and 07/05. Chemotherapy comprised fludarabine 50mg/m2 on days -6 to -2 and IV busulfan (Busulfex, PDL Pharma) 3.2 mg/kg daily days -5 to -2 inclusive. Forty-six acute leukemia pts had additional TBI 200cGy x 2 on day (D) -1 or 0. Prophylaxis for GVHD was cyclosporine A, methotrexate with folinic acid and Thymoglobulin (Genzyme) 4.5 mg/kg in divided doses over 3 consecutive days pretransplant finishing D0. Cell source was mobilized blood cells (BCT) in 172 and marrow (BMT) in 28. Median age was 46 (range 18–65) and follow-up of survivors was 13–87 months (median 42). As engraftment and GVHD did not differ significantly data for BMT and BCT were combined. Two pts had graft failure (1 with autologous recovery) and two died before D28. The remaining 196 evaluable pts engrafted granulocytes at median of 16 days (range 2–42). Platelets engrafted in 194 pts at a median of 18 days (0–101), 2 died before engraftment on days 29 & 72. Incidence of acute GVHD grade II-IV, acute GVHD grade III-IV and chronic GVHD was 14±2%, 3±1% and 54±4% respectively. Five pts died before D100 of GVHD (1), candidiasis (1), influenza B (1), veno-occlusive disease (1) and myocardial infarction (1), after D100 15 deaths were related to GVHD (11), pneumonia/ARDS (2), graft failure (1) and pulmonary embolus (1). One case of PTLD resolved with rituxan, there was no serious neurological toxicity. For low-risk (acute leukemia CR1/CR2, CML CP1) pts 3 year TRM was 4±3% for those ≤45 years old (n = 54) and 6±4% for those >45 (n = 31). Corresponding figures for all others (high risk) were 6±4% (n = 40) and 27±7% (18±5% at one year, n = 75) (p = 0.04). [table 1] We conclude that FLUBUP appears to be well-tolerated with little mortality attributable to the regimen itself. In partular, concerns about excessive immune suppression (partularly causing PTLD) and neurotoxicity have not been substantiated. Chronic GVHD is the major cause of non-relapse death. Control of early morbidity and mortality from GVHD may allow intensification of the regimen, for example by adding TBI. There is also evidence that the safety can be improved by monitoring Bu levels. The effect of age on TRM is only apparent in high-risk pts, the challenge is to reduce mortality from chronic GVHD in these individuals without sacrificing graft-vs.-malignancy. 3 year outcomes (%) for groups with >10 pts Disease/stage n survival TRM * p = 0.07 AML CR1/2 (no TBI) 32 66±8 9±5 AML CR1/2 (TBI)* 16 94±6 0 AML advanced (no TBI) 18 22±10 17±9 MDS 15 79±11 24±12 ALL CR1/2 15 73±11 8±7 CML CP1 22 100% 0 CLL/Richter’s (as primary indication) 14 68±13 16±10 Multiple Myeloma 13 54±14 8±7 NHL (low grade/mantle) 21 75±10 17±9 All pts 200 66±3 12±3

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Shortened Immunosuppression Following Peripheral Blood (PB) Haploidentical (haplo) Transplantation with Post-Transplant Cyclophosphamide (PTCy) Is Associated with Tolerable Rates of Graft-Vs-Host Disease (GVHD)

Blood ◽

10.1182/blood-2019-122762 ◽

2019 ◽

Vol 134 (Supplement_1) ◽

pp. 3320-3320

Author(s):

Amy E. DeZern ◽

Marianna Zahurak ◽

Javier Bolanos-Meade ◽

Richard J. Jones

Keyword(s):

Graft Failure ◽

Acute Gvhd ◽

Risk Index ◽

Chronic Gvhd ◽

Prospective Trial ◽

Stopping Rules ◽

High Dose ◽

Gvhd Prophylaxis ◽

Grade 3

With PTCy as GVHD prophylaxis, nonmyeloablative (NMA) HLA- haplo and HLA-matched blood or marrow (BMT) have comparable outcomes. Previous reports showed that discontinuation of immunosuppression (IST) as early as day 60 after infusion of bone marrow (BM) haplo allograft with PTCy is feasible. However, there are certain diseases in which PB may be favored over BM grafts to augment engraftment rates; however, given the higher rates of GVHD with PB, excessive GVHD becomes a concern with early discontinuation of IST. We present a completed, prospective single-center trial of stopping IST at days 90 and 60 after NMA haplo PB. (NCT02556931) From 12/2015-7/2018, 117 evaluable patients (pts) with hematologic malignancies associated with higher rates of graft failure with PTCy (MDS, MPN, overlap syndromes, 2o AML, AML with MRD, MM, and CLL) received NMA PB allografts on trial. Haplo donors were preferred, but in patients lacking suitable haplo relatives, unrelated donors were employed with 6 in each IST cohort. The primary objective was to evaluate the safety and feasibility of reduced‐duration IST (from Day 5 through Day 90 in cohort 1 and through Day 60 in cohort 2.) Transplant inclusion criteria were standard and the conditioning included Cy (14.5 mg/kg IV D -6 and -5), fludarabine (D -6 to -2), TBI (200 cGy D -1) and T-cell replete PB. GVHD prophylaxis consisted of high-dose PTCy (50 mg/kg IV D 3 and 4), mycophenolate mofetil (D 5-35) and IST (tacrolimus/sirolimus) from D 5 forward. Priot to transplantation, pts were assigned to stop IST early if eligible, as defined by having ≥ 5% donor T cells at ~D 56 onward, no relapse, and no grade 2-4 acute or significant chronic GVHD. If ineligible to discontinue IST early, it continued through D 180. Monitoring rules declared reduced IST feasible if ≥ 33% of pts stopped IST early as planned. Safety stopping rules for early IST cessation were based on ≥ 5% graft failure, ≥ 5% NRM, ≥ 50% relapse, and ≥ 10% combined grade 3-4 acute GVHD and severe chronic GVHD, measured from the IST stop date to ~D 180. Historical data from 55 haplo transplants for MDS, CLL, and MPNs at our center using the same regimen and PB grafts informed safety calculations. Of the 117 pts (median age 64 years, range 24-78), the most common diagnoses were MDS (33%), AML (with MRD or arising from antecedent disorder) (31%), MPNs (21%) myeloma (10%), and CLL (6%). By refined Disease Risk Index, 13% were low risk, 69% intermediate and 18% high. Shortened IST was feasible in 75 pts (64%) overall. Ineligibility for shortened IST was due most commonly to GVHD (17 pts), followed by early relapse (11 pts), NRM (7 pts), patient/ physician preference (4 pts) or graft failure (3 pts). Of the 57 patients in the D90 cohort (median follow up 35 mos), 33 (58%) stopped IST early as planned. Of the 60 patients in the D60 cohort (median follow up 20 mos), 42 (70%) stopped IST early as planned. The graft failure rate was 2.6%. NRM was very similar in the two arms, 12% at both 12 and 18 months in the D90 cohort and 10% and 13% at 12 and 18 months in the D60 cohort. Relapse in D90 cohort is 40% at 18 months compared to 33% at 18 months in the D60 cohort. Figure 1 shows cumulative incidence (CI) of acute grade 2-4 and grade 3-4 GVHD. Although the CI of grade 1-2 GVHD may be slightly higher in day 60 cohort, it is only 40% at D180. Severe chronic GVHD was 12% (D90) and 11% (D60) at 540 days. One year OS is 75% and 78% for the D90 and D60 cohorts, respectively. At 12 months PFS is 54% in the D90 group and 67% in the D60. At 12 months, the GRFS is 33% in the D90 group, and 38% in the D60 group. (Figure 2) These data suggest that reduced-duration IST in pts receiving NMA haplo PB with PTCy is feasible and carries an acceptable safety profile. Risks of acute GVHD, chronic GVHD, graft failure and NRM appear similar to historical outcomes with IST until D180 and between the two cohorts. When comparing the D90 and D60 arms, grade 3-4, severe chronic GVHD, GRFS, OS and PFS were similar. Although a larger, prospective trial would be needed to uncover potential small differences in outcomes based on IST duration, these data show that similar to our findings with BM, many PB pts (64% in this trial) can discontinue IST as early as D60 without undue toxicity. The favorable toxicity profile of the PTCy platform, coupled with the feasibility and safety of early IST cessation, provides an ideal setting to incorporate novel post-transplantation approaches for relapse reduction. Figure 1 Disclosures DeZern: Astex Pharmaceuticals, Inc.: Consultancy; Celgene: Consultancy. Bolanos-Meade:Incyte Corporation: Other: DSMB fees.

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Phase II Trial Of Medium-Dose VP-16, Cyclophosphamide and Total-Body Irradiation Conditioning Regimen Before Allogeneic Stem Cell Transplantation For Acute Lymphoblastic Leukemia In Adults

Blood ◽

10.1182/blood.v122.21.544.544 ◽

2013 ◽

Vol 122 (21) ◽

pp. 544-544

Author(s):

Tatsunori Goto ◽

Akio Shigematsu ◽

Makoto Onizuka ◽

Shin Fujisawa ◽

Ritsuro Suzuki ◽

...

Keyword(s):

Stem Cell ◽

High Risk ◽

Lymphoblastic Leukemia ◽

Conditioning Regimen ◽

Once Daily ◽

High Risk Disease ◽

Total Body ◽

One Year ◽

Medium Dose

Abstract Background The prognosis of adult patients (pts) with acute lymphoblastic leukemia (ALL) is dismal, and allogeneic stem cell transplantation (allo-SCT) is performed in most pts. However, even for pts treated with allo-SCT using the standard regimen of cyclophosphamide with total body irradiation (CY/TBI), the prognosis is not satisfactory due to a high rate of relapse. We previously reported excellent outcomes in adult pts with ALL undergoing allo-SCT conditioned with medium-dose VP-16, CY and TBI (medium-dose VP/CY/TBI). We therefore conducted a prospective nationwide multicenter phase II trial (UMIN trial number 000001672) to evaluate the efficacy of this conditioning regimen. Methods The eligibility criteria of this study were as follows: (1) diagnosis of ALL or acute biphenotypic leukemia (ABL), (2) aged 15-49 years, (3) in CR, (4) first SCT, (5) PS (ECOG) 0-2, (6) intact organ function, and (7) HLA-serologically 6/6 matched donor. Pts with Burkitt leukemia were ineligible for this study. Conditioning regimen consisted of medium-dose VP (15 mg/kg once daily i.v. for two days) and CY (60 mg/kg once daily i.v. for two days) combined with fractionated TBI (total dose: 12 Gy). Stem cell source was limited to bone marrow (BM) or peripheral blood stem cell (PBSC). The primary endpoint of this study was event-free survival (EFS) at one year after SCT, and the events were defined as death or relapse. The expected 1-year EFS was estimated to be 75%, and the threshold 1-year EFS was estimated to be 55%, on the basis of our previous observations. Results Between February 2009 and August 2011, 52 pts were enrolled, and 50 pts met the criteria. Among 50 eligible pts, the median age was 33.5 years (range, 17-49 years), and 15 pts (30%) were over 40. Twenty-three (46%) pts were female. Forty-eight (96%) pts had ALL and 2 (4%) had ABL. Nineteen (38%) pts were Philadelphia chromosome (Ph)-positive. Forty-seven (94%) pts were in first CR at SCT, and 3 (6%) in second CR. Among pts with ALL in first CR (n=45), 38 (84%) had high-risk disease. Twenty-six (52%) pts underwent SCT from a related donor and 24 (48%) from an unrelated donor. Forty (80%) pts received BM and 10 (20%) received PBSC. All pts achieved neutrophil engraftment. The incidence of grade II-IV and III-IV acute graft-versus-host disease (GVHD) was 38% and 8%, respectively, and that of chronic GVHD was 54%. After 1-year follow-up of the final enrollment (range, 379-1218 days), the 1-year EFS was 76% (95% confidence interval (CI): 62-86%, Figure). One-year overall survival was 80% (95% CI: 66-89%). No pts died within 100 days after SCT and 1-year non-relapse mortality (NRM) was 14% (95% CI: 6-25%). No secondary malignancies were observed during the-follow-up period. The 100-day and 1-year relapse rate was 2% (95% CI: 0-9%) and 10% (95% CI: 4-20%), respectively. The 1-year EFS for pts with high-risk and standard-risk disease was 76% (95% CI: 59-87%) and 71% (95% CI: 26-92%), Ph-positive and negative pts was 79% (95% CI: 53-92%) and 76% (95% CI: 56-88%), and pts over 40 years and under 40 years was 73% (95% CI: 44-89%) and 77% (95% CI: 59-88%), respectively. In univariate analysis, high-risk disease, Ph-positivity and higher age were not significant risk factors for EFS. Conclusions The results demonstrate that the conditioning regimen of medium dose VP/CY/TBI for allo-HCT in adult pts with ALL enable good disease control without increase in NRM, even for relatively high age pts and pts with high-risk disease. A phase III trial comparing this regimen with standard CY/TBI regimen for adult pts with ALL is warranted. Disclosures: No relevant conflicts of interest to declare.

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Outpatient Haploidentical Peripheral Blood Stem-Cell Transplantation with Post-Transplant Cyclophosphamide in Children and Adolescents

Blood ◽

10.1182/blood.v126.23.4389.4389 ◽

2015 ◽

Vol 126 (23) ◽

pp. 4389-4389

Author(s):

Oscar Gonzalez-Llano ◽

Elias Eugenio Gonzalez-Lopez ◽

Ana Carolina Ramirez-Cazares ◽

Edson Rene Marcos-Ramirez ◽

Guillermo J. Ruiz-Arguelles ◽

...

Keyword(s):

Stem Cell ◽

T Cell ◽

High Risk ◽

Children And Adolescents ◽

Hematological Malignancies ◽

Acute Gvhd ◽

Chronic Gvhd ◽

High Dose ◽

Post Transplant

Abstract Patients with high-risk hematological malignancies have a poor prognosis without a hematopoietic stem cell transplant. An HLA- haploidentical donor is available in 95% of the cases, and post-transplant cyclophosphamide permits the use of T-cell replete grafts in settings were ex-vivo manipulation is not available. The experience with HLA-haploidentical HSCT with PBSC and post-tranplant Cy in the pediatric and adolescent population is limited; we report the following experience. We retrospectively collected data on 25 patients (0 to 21 years old) with hematological malignancies, who underwent ambulatory haploidentical HSCT with post-transplant Cy from November 2011 to November 2014. The different conditioning regimens are described in Table 1. All patients received high-dose Cy(50mg/kg) on days +3 and +4. Cyclosporine A (CYA; 6mg/kg/d per os) and mycophenolate mofetil (MMF; 15mg/kg two times daily per os) were started on day +5. MMF was discontinued on day +35 and tapering of cyclosporin started day +90 in the absence of GVHD. All patients received anti-microbial prophylaxis for bacteria, fungal, herpes infection and Pneumocystis jiroveci according to institutional practices. First chimerism was performed at day +30, and second chimerism at day +100. Primary graft failure was defined when neutrophil counts did not exceed 0.5 x 109/L by day +30. Acute and chronic GVHD were graded according to NIH criteria. Patient, donor and stem-cell harvest characteristics are described in Table 1. All patients had high risk hematological malignancies. There were 5 patients who underwent their first transplant on 1st CR, 4 with ALL with high risk cytogenetics and 1 with AML. All other patients were defined as high risk because they were refractory/relapsed. Twenty-three patients (92%) had neutrophil engraftment after a median 17 (7-24) days. Platelet engraftment was observed in 20 (80%) patients after a median of 14.5 (11-23) days, 3 (12%) patients did not have platelet counts below 20,000/mcL. One patient was catalogued as a primary failure for not achieving neutrophil and platelet engraftment by day +30. One patient died before engraftment at day +10 of septic shock. Four patients (16%) died before day +30. The only patient that did not have a complete chimerism, had a diagnosis of AML and 30% of donor cells by day +30, by day +45 relapse of disease was documented. After a median follow-up of 157 days, 13 patients (52%) remain alive, with an estimated 1-year OS of 52% (95%CI: 30.4 - 65.6%).Nine patients (36%) died of complications (mainly infectious) not related to relapse at a median time of 66 days (10-579 days) from stem cell infusion. Nine patients (36%) relapsed in a median time of 105 days (45-288 days); three of those patients died at days +150, +113 and + 370 from transplant. Estimated 1 year event-free survival is 40.2% (95%CI: 41.3 - 75.8%) (Figures 1 and 2). Patients transplanted on 1st CR had a median follow-up of 664 days with an OS and EFS of 80% (4 patients), which was statistically different from the rest of the population (p=0.03) (Figure 3). Among those who engrafted (n=21), 9 cases (42.9%) had grade 2-4 acute GVHD and 4 cases (19%) of grade 3-4 acute GVHD. Three patients (14.3%) developed chronic GVHD, two had mild skin or liver cGVHD. One patient had severe (NIH stage 3) skin cGVHD, she was alive and with a grade 2 cGVHD until last follow up at day +893. Outpatient procedure, HLA-haploidentical HSCT including PBSC as a stem cell source, and post-transplant T-cell in vivo depletion using high-dose cyclophosphamide is feasible in children and adolescents, with acceptable rates of response and GVHD. Table 1. Patient, donor and harvest characteristics Variable N=25 Age, median(range in years) 10 (1-21) Gender, n(%) Male Female 17 (68%) 8 (32%) Diagnosis, n(%) ALL-B ALL-T AML CML 16 (64%) 2 (8%) 5 (20%) 2 (8%) Time from diagnosis to transplant (months) 17.2 (1.9-153.5) Conditioning regimen, n(%) Cy 1500mg/m2 + Flu 75mg/m2 + Bu 9.6mg/kg (IV) Cy 1050mg/m2 + Flu 75mg/m2 + Bu 12 mg/kg (oral) Cy/VP-16/RT Cy/Flu/Mel 16 (64%) 6 (24%) 2 (8%) 1 (4%) Donor, n(%) Mother Father Sister 20 (80%) 3 (12%) 2 (8%) Donor age, median(range in years) 38 (17-49) Infused CD34+ x 106/kg, median(range) 11 (3.2-20) Disclosures No relevant conflicts of interest to declare.

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Shortened-Duration Tacrolimus after Nonmyeloablative HLA-Haploidentical (NMA haplo) BMT with High-Dose Posttransplantation Cyclophosphamide (PTCy) Facilitates Strategies for Relapse Reduction

Blood ◽

10.1182/blood.v128.22.831.831 ◽

2016 ◽

Vol 128 (22) ◽

pp. 831-831 ◽

Cited By ~ 1

Author(s):

Yvette L. Kasamon ◽

Ephraim J. Fuchs ◽

Marianna Zahurak ◽

Gary L. Rosner ◽

Heather J. Symons ◽

...

Keyword(s):

Graft Failure ◽

Acute Gvhd ◽

Risk Index ◽

Chronic Gvhd ◽

Stopping Rules ◽

High Dose ◽

Stopping Criteria ◽

Gvhd Prophylaxis ◽

Grade 3

Abstract Background: With PTCy as GVHD prophylaxis, outcomes of NMA haplo and matched BMT are similar, and relapse rather than toxicity is the leading cause of treatment failure. Early discontinuation of IS may augment a graft-versus-tumor effect and permit early implementation of strategies to reduce relapse, but may increase GVHD. We present a completed, prospective single-center trial of stopping tacrolimus (tacro) 3 or 4 months earlier than our Day (D) 180 standard after NMA haplo BMT (ClinicalTrials.gov: NCT01342289). Methods: From 8/2011-11/2015,105 evaluable patients (pts) with hematologic malignancies received NMA haplo BMT on this trial. The primary objective was to evaluate the feasibility and safety of reduced-duration tacro, stopping tacro without taper before D 180.Transplant criteria included age ≤ 75, ECOG PS ≤ 2, LVEF ≥ 35%, FEV1 and FVC ≥ 40% predicted, transaminases < 5 x ULN and no prior allogeneic BMT. All received Cy (14.5 mg/kg IV D -6 and -5), fludarabine (D -6 to -2), TBI (200 cGy D -1) and T-cell replete bone marrow. GVHD prophylaxis consisted of high-dose PTCy (50 mg/kg IV D 3 and 4), mycophenolate mofetil (D 5-35) and tacro from D 5. Pretransplantation, pts were assigned to stop tacro early if eligible, contingent on having ≥ 5% donor T cells at ~D 56 onward, no relapse and no grade 2-4 acute or significant chronic GVHD. Tacro was first planned through D 90 (n=47), then through D 60 (n=55). A D 120 cohort (n=3) enrolled while D 90 safety data were maturing. For pts ineligible for planned early tacro cessation, IS was individualized and continued to at least D 180. Monitoring rules declared reduced IS feasible if ≥ 33% of pts stopped tacro early as planned. Safety stopping rules for early tacro cessation were based on ≥ 65% probability of a ≥ 20% incidence of grade 3-4 acute plus severe chronic GVHD, ≥ 10% nonrelapse mortality (NRM) or ≥ 5% graft failure, measured from the tacro stop date to ~D 180. Historical data from 212 haplo transplants at our center using the same regimen but tacro until D 180 informed safety risk calculations. Results: Of the 105 pts (median age 61, range 13-74), the most common diagnoses were acute leukemia (50%), MDS (17%), NHL (16%) and HL (8%). By refined Disease Risk Index, 11% were low risk, 70% intermediate and 19% high. Shortened IS was feasible in 63 pts (60%) overall. Ineligibility for shortened IS was due most commonly to GVHD, followed by low donor chimerism or graft failure and early relapse. Of the 47 pts in the D 90 cohort (median follow-up 44 months), 23 (49%) stopped tacro early as planned. Safety stopping criteria were not met. Of these 23 pts, 16 (70%) had no safety events before D 180, 5 (22%) developed grade 2 acute GVHD (1 complicated by severe chronic GVHD) and 2 (9%) developed grade 3-4 acute GVHD. Of the 55 pts in the D 60 cohort (median follow-up 14 months), 38 (69%) stopped tacro early as planned, and safety stopping criteria were likewise not met. Of these 38 pts, 25 (66%) had no safety events before D 180, 1 developed graft failure, 9 (24%) developed grade 2 acute GVHD and 3 (8%) developed grade 3-4 acute GVHD. GVHD outcomes by cohort relative to historical outcomes are shown in Figures A and B. In both cohorts, the D 180 CuI of grade 2-4 acute GVHD was < 40% and was < 10% for grade 3-4 acute GVHD and NRM. The 1-year CuI of any chronic GVHD was 11% for the D 90 arm and 13% for the D 60 arm (12% historically). The 1-year probabilities of PFS, OS and GVHD-free relapse-free survival (GRFS, Figure C) were 40%, 59% and 27% respectively for the D 90 arm and 63%, 77% and 53% respectively for the D 60 arm. Conclusion: These data suggest that reduced-duration tacro is feasible and carries an acceptable safety profile in pts receiving NMA haplo BMT with PTCy. Risks of acute GVHD, chronic GVHD, graft failure and NRM appear similar to historical outcomes with tacro until D 180. A larger prospective study is needed to define the optimal duration of IS that balances GVHD risk and relapse risk. However, these data show that many pts (60% in this trial) can discontinue tacro without taper well before D 180. There is even a suggestion of improved PFS and GRFS in the D 60 arm compared to the D 90 arm, although the trial was not powered for these endpoints. The favorable toxicity profile of the PTCy platform, coupled with the feasibility and safety of early tacro cessation, provides an ideal setting to incorporate novel posttransplantation approaches for relapse reduction. Disclosures No relevant conflicts of interest to declare.

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HLA-Haploidentical Hematopoietic Cell Transplantation after TCR-Αβ and CD45RA+ Depletion Following Reduced Intensity Conditioning in Adults and Children with Hematological Malignancies- Two-Year Follow-up of Multicenter Study in Singapore

Blood ◽

10.1182/blood-2019-128014 ◽

2019 ◽

Vol 134 (Supplement_1) ◽

pp. 2039-2039 ◽

Cited By ~ 1

Author(s):

Li Mei Poon ◽

Yeh Ching Linn ◽

Poh Lin Tan ◽

Ziyi LIM ◽

Balamurugan Vellayappan ◽

...

Keyword(s):

T Cells ◽

High Risk ◽

Acute Gvhd ◽

Hematopoietic Cell Transplantation ◽

Chronic Gvhd ◽

Hla Antibodies ◽

Day Range ◽

Haploidentical Hematopoietic Cell Transplantation ◽

Matched Donor

Background: Haploidentical hematopoietic cell transplantation (HCT) provides an alternative option for patients without HLA-matched donor. GVHD, engraftment failure, and infectious complications continue to be the main causes of non-relapse mortality (NRM). We hypothesized that selective depletion of TCRαβ+ and CD45RA+ naïve T cells subset will permit hematopoietic engraftment, while effectively reducing GVHD, and provide improved donor immune reconstitution through adoptive transfer of donor's mature NK cells, γδ T cells and CD45RO+ memory T cells. Methods: Mobilized PBSC product were divided into two fractions in 9:1 ratio, and depleted using CliniMACS device after labeling with TCRαβ and CD45RA reagents (Miltenyi Biotec, Bergish-Gladbach, Germany), respectively. The conditioning regimen consisted of fludarabine 160 mg/m2 divided daily over 4 days, thiotepa 10 mg/kg divided twice daily for 1 day and melphalan 70-140 mg/m2 for 1 day, in combination with total lymphoid irradiation 6 Gy (n=23), or 7.5 Gy (n=12) over 3 equal fractions, or total body irradiation of 2 Gy (n=2). Short term GVHD prophylaxis for 30 days was given to 1 patient using MMF, 25 patients using tacrolimus and 2 patients using sirolimus. Results: We transplanted 37 patients, including 32 adults (median age 47 years, range 20 - 69) and 5 children (median age 13 years, range 7-15 years) with high risk AML (n=17), ALL (n=11), MDS (n=5), myeloma (n=1), mast cell leukemia (n=1), acute undifferentiated leukemia (n=1) or NK/T lymphoma (n=1). The patients were infused with TCRαβ and CD45RA depleted graft containing a median of 8.65 x 106 (range, 3.54 - 20.78) CD34+ cells/kg, 0.00 x 104 (range 0 - 0.97) CD45RA+CD3+ cells/kg, and 2.4 x 106 (range, 0.15 - 11.67) CD45RO+CD3+ cells/kg. The TCRαβ depleted graft fraction contained a median of 0.19 x 104 (range 0 - 8.53) TCRαβ+ cells/kg, and 8.76 x 106 (range 1.73 - 30.00) TCRγδ+ cells/kg. Only 1 patient experienced primary graft failure. All others had engraftment of ANC > 500 cells/µL at a median of 10 day (range, 8 - 22) and PLT > 20,000 cells/µL at a median of 12 day (range, 7 - 19). There was no secondary graft failure. Four patients with high titers of donor-specific HLA antibodies (DSA) engrafted successfully after effective desensitisation with plasma exchange, rituximab and immunoglobulin. Fourteen patients (38%) developed acute GVHD of grade II-IV (Gd II n=9 ; Gd III n=4 ; Gd IV n=1 ). Only one patient experienced chronic GVHD, giving 2 year cumulative incidence (CI) of chronic GVHD of 3.9 %. Day 180 CI of NRM and relapse were 22.7 % (95% 10.5-37.7%) and 12.0 % (95% CI 3.7-25.7%), respectively. NRM was attributed to aGVHD in 3 of the 13 deaths. Viral reactivation included CMV (n=13), HHV6 (n=4), EBV (n=3) and adenovirus (n=4), with no fatal viral infection occurred within 180 days. Seven patients died of infection, including 3 patients who had fatal blood stream infection (bacteria n=2; fusarium n=1) within 180 days. With a median follow up of 436 days (range 20- 916 days) in surviving patients, the 6 month and 2 year overall survival (OS) were 77.2% (95% CI 59.4-87.9%) and 57.7 % (95% CI 37.6-73.4%), respectively (Figure 1). The 2-year OS for patients with intermediate risk and high/very high risk disease risk index (DRI) were 60% and 24%, respectively (p=0.07) (Figure 2). Conclusions: Our preliminary results suggest that RIC haplo-HCT with TCRαβ and CD45RA+ depleted grafts allows successful allograft in high-risk patients lacking a suitable matched donor, including patients with high level of donor-specific HLA antibodies. Acute GVHD was generally abortive, leading to chronic GVHD in <5% of the patients. Fatal viral infection was not observed. Further efforts are needed to lower the risk of death due to bacterial infection, and also relapse in patients with high risk DRI, such as antibiotic prophylaxis or repeated doses of memory-cell DLI. Disclosures Leung: Miltenyi Biotec: Employment.

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Busulfan (Bu) in Combination with Double Nucleoside Analogues Fludarabine (Flu) and Clofarabine (Clo) Plus Vorinostat As a Novel Reduced Toxicity Conditioning Regimen for Allogeneic Hematopoietic Cell Transplantation (HCT) in Patients (pts) with Acute Leukemia

Blood ◽

10.1182/blood.v128.22.64.64 ◽

2016 ◽

Vol 128 (22) ◽

pp. 64-64

Author(s):

Partow Kebriaei ◽

Wei Wei ◽

Peter F Thall ◽

Celina Ledesma ◽

Benigno C. Valdez ◽

...

Keyword(s):

High Risk ◽

Acute Leukemia ◽

Disease Control ◽

Median Time ◽

Acute Gvhd ◽

Conditioning Regimen ◽

Nucleoside Analogues ◽

Unrelated Donor ◽

Equity Ownership

Abstract The combination of IV Bu and Flu is an effective and well-tolerated HCT conditioning regimen for patients with advanced acute leukemia. However, relapse remains the main reason for treatment failure. We combined two nucleoside analogues Flu and Clo, and showed cytotoxic synergy when combined with Bu, first in pre-clinical models, and subsequently in a randomized clinical study (Andersson BBMT 2011). We selected the optimized regimen from Andersson et al, and combined with escalating doses of the histone deacetylase inhibitor vorinostat in attempts to augment disease control without increasing toxicity. Herein, we describe our initial experience with this novel regimen for patients with advanced acute leukemia or MDS undergoing allogeneic HCT. Methods: Vorinostat (200mg to 1200mg) was escalated in cohorts of 3 patients, and administered 1 hour prior to the fixed regimen of Flu 10 mg/m2 followed by Clo 40 mg/m2 followed by Bu. The nucleoside analogs were infused over 1 hour once daily for 4 days, followed on each day by Bu, infused over 3 hours to a pharmacokinetically targeted daily area under the curve (AUC) of 5500 μMol-min ± 5%. Dilantin was given for seizure prophylaxis. GVHD prophylaxis was based on tacrolimus andmini-MTX, with the addition of rabbit anti-thymocyte globulin (4 mg/kg total dose) for unrelated donor transplants. The presence of minimal residual disease (MRD) was determined by multiparameter flow cytometry. Results: 21 patients (7 AML, 14 ALL) with median age 43 years (range 19-60) received an allogeneic matched sibling (n=10) or unrelated donor (n=11) HCT in CR1 (n=13), CR2 (n=1), primary induction failure (n=5), or relapse (n=2). Twelve patients had MRD or overt disease present at time of HCT. Ten patients had high-risk karyotype defined by t(9;22) (n=3), t(4;11) (n=2), complex (n=2), or del 5 or 7 (n=3). Median time from diagnosis to HCT was 5 months (range 3-48). Median time to ANC > 0.5 x 109/L and platelets > 20 x 109/L were 11 (range 10-15) and 12 days (5-30), respectively. Excluding grade 1 toxicities, the most commonly reported toxicities were nausea with maximum grade 2 (71%), followed by grade 2 or 3 mucositis (64%). Grade 2 or 3 reversible elevation of liver function tests was noted in 54% of pts, including 1 case of reversible VOD. No renal toxicities were noted. Two patients with prior systemic treatment for acute GVHD died of infections (disseminated adenovirus and E.coli sepsis). Ten patients achieved CR and clearance of MRD by day +30 after HCT; one patient had progressive disease and on patient died before disease restaging. Eighteen patients achieved 100% donor chimerism at 30 days following HCT, 2 patients remain with mixed chimerism by 100 day assessment following HCT, and 1 patient died before assessment. The incidence of grades II-IV acute GVHD is 43% and chronic extensive GVHD among 18 evaluable patients is 24%. With a median follow-up of 10 months among surviving patients (1-22), overall and progression-free survival at 6 months is 95% and 71%, respectively. Early results suggest excellent disease control in MRD negative patients (Figure). Conclusion: The Vorinostat-Flu-Clo-Bu combination is well-tolerated and did not add appreciable toxicity in these patients with high-risk leukemia. Longer follow-up is needed to better assess disease control. Figure Figure. Disclosures Ciurea: Spectrum Pharmaceuticals: Other: Advisory Board; Cyto-Sen Therapeutics: Equity Ownership. Patel:Ziopharm Oncology: Equity Ownership, Patents & Royalties; Intrexon: Equity Ownership, Patents & Royalties.

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HLA-Haploidentical Hematopoietic Cell Transplantation after TCR-Αβ and CD45RA+ Depletion Following Reduced Intensity Conditioning in Adults and Children with Hematological Malignancies: Three-Year Follow-up of Multicenter Study in Singapore

Blood ◽

10.1182/blood-2020-138638 ◽

2020 ◽

Vol 136 (Supplement 1) ◽

pp. 8-9

Author(s):

Yang Liang Boo ◽

Yeh Ching Linn ◽

Rajat Bhattacharyya ◽

Michelle Li Mei Poon ◽

Zi Yi Lim ◽

...

Keyword(s):

T Cells ◽

High Risk ◽

Acute Gvhd ◽

Hematopoietic Cell Transplantation ◽

Blood Stream Infection ◽

Chronic Gvhd ◽

Blood Stream ◽

Haploidentical Hematopoietic Cell Transplantation ◽

Matched Donor

Background: Haploidentical hematopoietic cell transplantation (HCT) provides an alternative option for patients without HLA-matched donor. Graft-versus-host disease (GVHD), engraftment failure, and infectious complications continue to be the main causes of non-relapse mortality (NRM). We hypothesized that selective depletion of TCRαβ+ and CD45RA+ naïve T-cells subset will permit hematopoietic engraftment, while effectively reducing GVHD, and provide improved donor immune reconstitution through adoptive transfer of donor's mature NK-cells, γδ T-cells, and CD45RO+ memory T-cells. Methods: Mobilized PBSC products were divided into two fractions in 9:1 ratio and depleted using CliniMACS device after labeling with TCRαβ and CD45RA reagents (Miltenyi Biotec, Bergish-Gladbach, Germany), respectively. The conditioning regimen consisted of fludarabine 160mg/m2 divided daily over 4 days, thiotepa 10mg/kg divided twice daily for 1 day, and melphalan 70-140mg/m2 for 1 day, in combination with total lymphoid irradiation 6Gy (n=35) or 7.5Gy (n=12) over 3 equal fractions, total body irradiation of 2Gy (n=13) or antithymocyte globuline (n=2). Short term GVHD prophylaxis for 30 days was given to 1 patient using MMF, 50 patients using tacrolimus, and 2 patients using sirolimus. Results: We transplanted 62 patients, including 55 adults (median age, 47 years; range 20-69) and 7 children (median age, 13 years, range 7-17) with high risk AML (n=34), ALL (n=15), MDS (n=7), plasma cell neoplasm (n=2), mast cell leukemia (n=1), acute undifferentiated leukemia (n=1), and NK/T-cell lymphoma (n=1). The patients were infused with TCRαβ and CD45RA depleted graft containing a median of 6.79 x 106 (range 3.54-20.78) CD34+ cells/kg, 0.00 x 104 (range 0-0.97) CD45RA+CD3+ cells/kg, and 1.09 x 106 (range 0.15-11.67) CD45RO+CD3+ cells/kg. The TCRαβ depleted graft fraction contained a median of 0.20 x 104 (range 0-11.30) TCRαβ+ cells/kg, and 8.52 x 106 (range 0.62-30.00) TCRγδ+ cells/kg. Only 1 patient experienced primary graft failure. All others had engraftment of ANC > 500 cells/µL at a median of 10 days (range 8-22) and platelet > 20,000 cells/µL at a median of 12 days (range 8-22). There was no secondary graft failure. Six patients with high titers of donor-specific HLA antibodies (DSA) engrafted successfully after effective desensitisation with plasma exchange, rituximab, and immunoglobulin. Twenty-two patients (35%) developed acute GVHD of grade II - IV (Gd II, n=15; Gd III, n=5; Gd IV, n=2). Three patients experienced chronic GVHD, giving 2-year cumulative incidence of 7 %. Day 180 cumulative incidence of NRM and relapse were 24.8% (95% CI 14.3-36.8%) and 14.9% (95% CI 6.3-27.0%), respectively. Four of the 16 NRM were attributed to aGVHD. Viral reactivation included CMV (n=25), HHV-6 (n=14), EBV (n=11), and adenovirus (n=7). Fourteen patients died of infection, including 5 patients who had fatal blood stream infection (bacteria, n=3; candidemia, n=2) and 1 patient from disseminated adenovirus infection within 180 days. With a median follow-up of 298 days (range 21-1298) in surviving patients, the 2-year overall (OS), event-free (EFS), and GVHD-free/relapse-free (GRFS) survival were 58% (95% CI 37.6-73.4%), 43% (95% CI 27-57%), and 39% (95% CI 24-54%), respectively (Figure 1). In multivariable analysis, only HCT-comorbidity index (HCT-CI) showed significant impact on OS (HR 6.24; 95% CI 2.05-19.05; p=0.0013), EFS (HR 4.80; 95% CI 1.73-13.35; p=0.0027), and RRM (HR 6.49; 95% CI 1.44-29.25; p=0.015), whereas disease risk index (DRI) impacts risk of relapse (HR 4.50; 95% CI 1.39-14.52; p=0.012). The 2-year OS, EFS, and GRFS for the subset of 30 patients (adults, n=25; children, n=5) with HCT-CI score of 0 and low/intermediate risk DRI were 68%, 68%, and 60%, respectively (Figure 2). Conclusions: Our preliminary results suggest that RIC haplo-HCT with TCRαβ and CD45RA+ depleted grafts allowed successful allograft in high-risk patients lacking a suitable matched donor, including patients with high level of DSA. Acute GVHD was generally abortive, leading to low incidence of chronic GVHD. The best outcome is seen in patients with favorable HCT-CI and DRI. Further efforts are needed to lower the risk of death due to blood stream infection, and relapse in patients with high risk DRI, such as optimisation of anti-microbial prophylaxis or repeated doses of memory-cell donor lymphocyte infusion (DLI). Disclosures No relevant conflicts of interest to declare.

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Reduced-Intensity Conditioning (RIC) with Busulfan, Fludarabine and Campath-1H Is Complicated by a High Rate of Graft Failure and Severe Viral Complications in Patients with CLL.

Blood ◽

10.1182/blood.v104.11.5080.5080 ◽

2004 ◽

Vol 104 (11) ◽

pp. 5080-5080 ◽

Cited By ~ 1

Author(s):

Johannes Schetelig ◽

Martin Bornhaeuser ◽

Christian Thiede ◽

Brigitte Mohr ◽

Uta Oelschlaegel ◽

...

Keyword(s):

T Cell ◽

Graft Failure ◽

Acute Gvhd ◽

Chronic Gvhd ◽

Cell Depletion ◽

Unknown Etiology ◽

T Cell Depletion ◽

Hematopoietic Stem ◽

One Year

Abstract Recently we demonstrated that RIC with busulfan, fludarabine and ATG followed by allogeneic hematopoietic stem cell transplantation (HSCT) induced molecular remissions in patients (pts) with advanced CLL. However, this approach was hampered by severe GVHD. In an attempt to lower the rate of severe GVHD we replaced ATG by campath in a new study protocol. Patients and Methods: 20 pts with a median age of 54 years (range, 43 to 64) and advanced CLL were included. A median of 3 prior chemotherapy regimens had been given before HSCT, including fludarabine-containing regimens in all but two pts with autoimmune hemolysis. High risk cytogenetic features (17p−, 11q−, +12) were present in 9 pts. After conditioning with busulfan (8 mg/kg), fludarabine (150 mg/m2) and campath (75 mg) on days −9 to −5 peripheral blood stem cells from matched related (n=4) or unrelated donors (n=16) were transplanted. GVHD prophylaxis consisted of CSA monotherapy. Campath levels were analysed in frozen serum samples by BioAnaLab, Oxford, UK. Results: Two pts had no detectable campath level at the day of HSCT, while four pts had levels between 0.5 to 1.8 microgram/mL. Regeneration of neutrophils (>0.5/nl) and platelets (>20/nl) required a median of 17 (range, 14–25) and 10 (range, 0–27) days, respectively. Incomplete T-cell chimerism (<50%) was observed in 7 pts and subsequently 3 pts experienced secondary graft failure on days 134, 152 and 324. Six pts received donor lymphocyte infusions (DLI) for the conversion of incomplete T-cell chimerism (N=4) or progressive disease (N=2). Sponaneous acute GVHD II° to IV° occurred in 9/20 pts. After DLI four additional pts developed acute GVHD II° to IV°. Limited chronic GVHD occurred in 9 and extensive disease in 2 pts. In CMV seropositive pts the day 100 probability of CMV infection was 74% (95% CI, 44% to 100%). Severe encephalitis (HHV6, EBV and JC virus as suspected agents) was observed in 5 pts. Two pts recovered without sequelae, 2 pts are cognitively handicaped and one pt died. Hemorrhagic cystitis (CTC 2/3) occurred in 2 pts. After a median follow-up of 13 months (range, 6 – 26 months), 15 pts are alive. Four pts died from treatment related complications. Causes of death were pneumonia of unknown etiology (N=2), encephalitis (N=1) and GVHD grade IV (N=1). One pt died from severe acute GVHD subsequent to the treatment of relapse with DLI. One-year overall and progression-free survival was 75% (95% CI, 55% to 95%) and 50% (95% CI, 25% to 75%), respectively. The one-year probability of non-relapse mortality was 20% (95% CI, 2% to 38%). The number of binding sites for campath is highly variable in pts with progressive CLL resulting in interindividually highly variable pharmacokinetics. Differences in the extent of in vivo T-cell depletion might therefore explain the individually varying T-cell engraftment pattern. In addition, the high incidence of severe viral infections reflects impaired immunoreconstitution. Including pts after DLI we observed a substantial rate of severe GVHD. Based on these data we decided to skip the strategy of in vivo T-cell depletion with campath in patients with CLL.

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Hematopoietic Stem Cell Transplantation (SCT) for Hematologic Malignancy from 10/10 Matched Unrelated Donors (MUD) with a Myeloablative Once Daily IV Fludarabine (Flu)/Busulfan Based Regimen (FLUBUP) with Thymoglobulin: Outcomes According to Stem Cell Source.

Blood ◽

10.1182/blood.v108.11.3140.3140 ◽

2006 ◽

Vol 108 (11) ◽

pp. 3140-3140

Author(s):

James A. Russell ◽

M. Ahsan Chaudhry ◽

Michelle Geddes ◽

Nizar J. Bahlis ◽

Mary Lynn Savoie ◽

...

Keyword(s):

Stem Cell ◽

High Risk ◽

Acute Gvhd ◽

Hematologic Malignancy ◽

Multiorgan Failure ◽

Chronic Gvhd ◽

Low Risk ◽

Hematopoietic Stem ◽

Platelet Recovery ◽

Unrelated Donors

Abstract Since 1999 we have used FLUBUP for all patients (pts) with hematologic malignancy including those who might be considered candidates for nonmyelablative SCT. Eighty-four pts were transplanted with marrow (BMT) or blood (BCT) from unrelated donors matched for HLA-A, -B, C, DR and DQ between 05/99 and 07/05. Chemotherapy comprised Flu 50mg/m2 on days -6 to -2 and IV Bu (Busulfex, PDL Pharma) 3.2 mg/kg daily days -5 to -2 inclusive. Thirty-four pts had additional TBI 200cGy x 2 on day -1 or 0. Prophylaxis for GVHD was cyclosporine A, methotrexate with folinic acid and Thymoglobulin (Genzyme) 4.5 mg/kg in divided doses over 3 consecutive days pretransplant finishing day (D) 0. Follow-up of survivors was 12–82 months (median 33). Two BMT pts were unevaluable for engraftment (died before D28), one relapsed before AGC engraftment and 2 had graft failure (GF). Two additional pts died of relapse and one of transplant-related causes without platelet engraftment. Granulocytes engrafted in all BCT recipients, 2 died before D28 and 2 later of relapse without platelet engraftment. Details of Recipients, SCT and Outcomes BMT BCT Number 49 35 Patient age median (range) 40 (16–60) 41 (19–61) ns Donor age median (range) 32 (19–51) 29 (20–57) ns Low risk (Acute leukemia (AL) CR1/2, CML CP1) 23 (47%) (AML 8 CR1, 4 CR2, ALL 5 CR1, 1 CR2, 5 CML CP1) 22 (62%) (AML 10 CR1, 8 CR2, ALL 2 CR1, 3 CR 2, AUL 1 CR1) ns High risk 26 (53%) ( 11 active AL, 2 CML AP, 3 CLL, 1 CMML, 4 MDS, 1 MF, 3 NHL) 13 (38%) (5 active AL, 1 CML AP, 1 MM/MDS, 2 MDS,1 MF, 1 HD/CLL, 1 HD, 1 CLL) ns CMV+ve Recipient or Donor D 35 (71%) 23 (66%) ns Female to male SCT 13 (27%) 3 (9%) 0.05 Male pt 29 (59%) 18 (51%) ns TBI (not TRM risk factor) 11 (22%) 23 (66%) 0.0001 CD34+ cell dose x 10e6/kg median (range) 2.7 (0.44–18.32) 7.47 (1.36–23.87) <0.0001 Median AGC recovery (D) (range) 19 (13–113) 15 (10–46) <0.0001 Median platelet recovery (D) (range) 28 (15–120) 18 (5–67) <0.0001 Acute GVHD II–IV 19±2% 21±7% ns Acute GVHD III–IV 9±4% 12±6% ns Chronic GVHD 77±8% 53±10% ns Low risk TRM (3 years) 22±9% 0 0.03 High risk TRM 43±12% 39±14% ns Primary cause of non-relapse death <D100 PTLD (1), sudden death cause unknown (1), HUS (1), aspiration pneumonia (1) Pneumonia (1), multiorgan failure (2), PTLD (1) Primary cause of non-relapse death >D100 GVHD related (5), primary GF (2), infection (2) Secondary GF (1) Low risk survival 70±10% 81±9% ns High risk survival 33±10% 54±14% ns In low-risk pts FLUBUP appears to be relatively well-tolerated and TRM is lower after BCT. Infection and PTLD contribute as much as GVHD to TRM so there may be little to gain by changing ATG dose or timing. Engraftment is faster after BCT as expected but there is no difference in acute or chronic GVHD. In general therefore, BCT seems preferable to BMT for MUD SCT with this protocol.

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Hematopoietic Cell Transplantation After Reduced Intensity Conditioning for Severe Paroxysmal Nocturnal Hemoglobinuria:

Blood ◽

10.1182/blood.v118.21.2047.2047 ◽

2011 ◽

Vol 118 (21) ◽

pp. 2047-2047 ◽

Cited By ~ 1

Author(s):

Rafic Farah ◽

Georg Franke ◽

Tara B. Gregory ◽

Mark W. Brunvand ◽

Thoralf Lange ◽

...

Keyword(s):

High Risk ◽

Graft Failure ◽

Paroxysmal Nocturnal Hemoglobinuria ◽

Hematopoietic Cell Transplantation ◽

Chronic Gvhd ◽

Reduced Intensity Conditioning ◽

Graft Versus Host ◽

Pnh Clone ◽

Reduced Intensity

Abstract Abstract 2047 Objectives: Paroxysmal Nocturnal Hemoglobinuria (PNH) is a rare acquired clonal hematopoietic stem cell disease. Patients may present with intermittent hemolysis, thrombotic events or cytopenias. The manifestations can be life threatening. Hematopoietic Cell Transplantation (HCT) is still the only curative therapy. Hegenbart et al reported early results in 7 patients with PNH with high risk features who received transplants from matched related (n=2) or unrelated donors (n=5) after conditioning with a fludarabine / total body irradiation (TBI) based regimen (Biol Blood Marrow Transplant 2003; 9: 689–697). Here we update the data and report outcomes in 12 additional patients. Patients: Nineteen patients diagnosed with severe PNH underwent allogeneic HCT after a reduced intensity conditioning (RIC) regimen. Patients were treated at 9 centers. Eighteen patients had at least 1 high-risk feature (Table), 1 patient had none but underwent transplant because of severe hemolysis prior to the era of eculizumab. Conditioning consisted of fludarabine (30 mg/m2/d) on days −4 to −2 before HCT and 2 Gy (n=16) or 4 Gy (n=3) of TBI on day 0 (n=16) followed by treatment with mycophenolate mofetil and cyclosporine or tacrolimus. All patients received peripheral blood stem cells (PBSC). Donors were HLA-matched related (n=3), HLA-matched unrelated (n=12) or HLA-mismatched unrelated (n=4). Results: The follow-up period ranges between 2 months and almost 10 years (median 27.5 months) after HCT. Neutropenia (absolute neutrophil count<500/μl) developed in 15 of 19 patients after transplantation. The median time to neutrophil recovery in patients who engrafted was 16 days (range 0–29) with a median duration of neutropenia of 12 days (range 0–17, n=12). The median duration of thrombocytopenia (platelet count <20,000/μl) was 3 days (range, 0 to 10 days, n=12). All but 2 patients (89.5%) had a sustained engraftment. One patient experienced primary graft failure and remained neutropenic. He received a second nonmyeloablative HLA-matched unrelated PBSC transplant, 47 days after the first transplant, from a different donor, with 3 Gy TBI and 90mg/m2 fludarabine, and had sustained engraftment. The second patient experienced after engraftment, late graft failure 6 months after HCT. She underwent, 7 months after the first transplant, a second nonmyeloablative, HLA- matched unrelated PBSC transplant, from a different donor, with 4 Gy TBI and 150mg/m2 fludarabine, and had sustained engraftment. Eighteen patients were assessable for acute graft-versus-host disease (GvHD). The incidence of grades 2, 3, and 4 acute GvHD were 22% (4/18), 17% (3/18), and 5% (1/18), respectively. Chronic GvHD developed in 78% (14/18) of evaluable patients. Fifteen patients (78.9%) are alive at the time of last follow-up (Fig.). None of the 15 patients still alive has any evidence of relapse, clinically nor by flow cytometry. Four patients died (21.1%) of complications (necrotizing pancreatitis of unknown cause, pseudomonas infection during treatment of chronic GvHD, hemorrhage after liver biopsy with subacute/chronic liver GvHD, intracerebral bleed). All 15 surviving patients have an ECOG performance status of 0 or 1. Conclusion: The RIC regimen reported here is well tolerated and leads to a high rate of successful engraftment. The graft-versus-host effect seems to be sufficient to eradicate the PNH clone. This regimen may be equally effective in medically fit PNH patients to eradicate the PNH clone while reducing treatment related complications of higher intensity conditioning regimens. Note: 1st 3 authors contributed equally. Disclosures: No relevant conflicts of interest to declare.

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