Prophylactic Rituximab after Reduced Intensity Conditioning Transplantation Results in Low Chronic Gvhd

Abstract Background: B cells are implicated in the pathophysiology of chronic GVHD. We hypothesize that prophylactic anti-B cell therapy delivered two months after reduced intensity conditioning (RIC) transplantation would prevent or reduce chronic GVHD incidence from the historical 50%. Chronic lymphocytic leukemia (CLL) and mantle cell lymphoma (MCL) were the target diseases as they are B cell malignancies with clear allogeneic GVL benefit. Methods: CLL and MCL patients were conditioned with total lymphoid irradiation (TLI) 80 cGy in 10 fractions, d-11 to d-1 and anti-thymocyte globulin (ATG) 1.5mg/kg/day, d-11 to d-7 (total 7.5mg/kg). PBPC were infused on day 0. Primary GVHD prophylaxis was cyclosporine (CSA) on d-3 with taper by 6 months, and MMF from day 0 until d28 for related donors, d100 for unrelated donors. Rituximab (375 mg/m2/week ×4) was infused on days 56, 63, 70, and 77 post-transplant. Results: 36 patients accrued to the study (median age 57, range 31–66 yrs), with 34 patients completing the 4 rituximab infusions. All 22 CLL patients were high risk (fludarabinerefractory, unmutated VH-IgG, or P53 deletion). The 14 MCL patients included 4 patients in PR and 10 patients in CR status at transplant. Median follow-up is 20 months. Twenty patients had sibling donors; 16, unrelated donors. Median CD34 cell dose was 7.5 CD34/kg. All patients had donor cell engraftment except for one patient who had graft failure with stable autologous recovery. Full donor chimerism (PB CD3>95%) was achieved in 14 out of 31 patients (45%) by day 90. However, all but 5 patients had achieved full donor chimerism at 1 year. The incidence of grade 2–4 acute GVHD was 6%. The incidence of chronic GVHD was 18%. Day 100 NRM was 0% and 1-year NRM was 3%. Ten relapses have occurred (5 CLL, 5 MCL). Estimated FFP and OS at 2 years for CLL patients is 82%(CI +/−16%) and 73% (CI +/−33%), respectively; for MCL patients, 64% and 68%, respectively Full donor chimerism was associated with persistent disease remission. Twelve of 19 VHIg mutated CLL patients have achieved minimal residual disease (MRD) by quantitative allele-specific oligonucleotide-IgH PCR (ASO-Q-PCR). DLI was given to 5 CLL patients and 1 MCL who had relapsed and had not achieved full donor chimerism.. There were no infusional toxicities with rituximab. Transient rituximab related neutropenia occurred in 10 patients d100–150. Post-transplant infections included influenza B, RSV, fungal sinusitis, pseudomonas, klebsiella infection, VZV reactivation, and one PTLD before day 56 rituximab. All recovered Of 22 patients at risk for CMV reactivation, 10 reactivated ( range 4 to 56 days post-HCT). Therefore, rituximab did not contribute to the CMV reactivation or increase infection incidence. Conclusion: Prophylactic rituximab infusion post RIC transplantation is well tolerated, provides safe donor B cell depletion without detrimental effect on engraftment or infection incidence, and is associated with a low incidence of chronic GVHD while maintaining GVL. A randomized trial of rituximab prophylaxis after allogeneic HCT is warranted.

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Tacrolimus and Sirolimus without Methotrexate as Acute GVHD Prophylaxis after Matched Related Donor Reduced Intensity Conditioning (RIC) Stem Cell Transplantation (SCT).

Blood ◽

10.1182/blood.v110.11.3046.3046 ◽

2007 ◽

Vol 110 (11) ◽

pp. 3046-3046 ◽

Cited By ~ 1

Author(s):

Vincent T. Ho ◽

Haesook Kim ◽

Shuli Li ◽

Corey Cutler ◽

John Koreth ◽

...

Keyword(s):

Cumulative Incidence ◽

Acute Gvhd ◽

Chronic Gvhd ◽

Reduced Intensity Conditioning ◽

Historical Cohort ◽

Post Transplant ◽

Donor Chimerism ◽

Gvhd Prophylaxis ◽

Grade Ii ◽

Reduced Intensity

Abstract We have previously shown that the combination of tacrolimus and sirolimus (TAC/SIR) without methotrexate (MTX) is a safe and effective regimen for GVHD prophylaxis after myeloablative SCT. However, TAC/SIR has not been investigated in the RIC setting. We hereby report a prospective phase II trial testing TAC/SIR as GVHD prophylaxis after RIC SCT from matched related donors (MRD). All patients received fludarabine (FLU) 30 mg/m2 IV and intravenous busulfan (BU) 0.8 mg/kg IV daily × 4 days (day -5 thru day -2) as conditioning, followed by transplantation of filgrastim mobilized peripheral blood stem cells. Filgrastim 5 mcg/kg SC QD was started on day +1 until neutrophil engraftment. Tacrolimus and sirolimus were started on day-3, and doses were adjusted to maintain target serum trough levels 5–10 ng/ml and 3–12 ng/ml, respectively. Twenty-six patients have been transplanted, with a median age of 52 years (range 29–64 yrs). Diagnoses include NHL (8), AML (6), HD (5), CLL/SLL (3), CML (2), MDS (1), MM (1). Median CD34+ cells infused was 8.06 × 106 cells/kg (range: 2.96–38.0 × 106 cells/kg). All patients had sustained hematologic engraftment. Only 4 (15%) patients developed neutropenia below ANC 500, and 6 (23%) had platelet counts below 20K. One patient had late graft failure at 7 months post transplant. Grade II-IV acute GVHD incidence was 20%, with grade III-IV incidence of 12%. No hepatic VOD or thrombotic microangiopathy was observed. Day +100 transplant related mortality (TRM) was 0%. The cumulative incidences of TRM and relapse at 1 year were 4% and 38%, respectively. The cumulative incidence of chronic GVHD at 1 year was 74%. A high level (>90%) of donor-derived hematopoiesis was achieved in 68% by 1 month post transplant. Median donor chimerism at between day 20–50 post transplant was 93.5% (range 32%-99%), and 94% (range 22%-100%) at day 85–115. With a median follow-up of 13.5 months among survivors (range 5.5–19 months), progression-free survival (PFS) and overall survival (OS) at 1 year were 58% and 79%, respectively. Compared to a historical cohort of 47 MRD transplant recipients treated with the same FLU/BU conditioning regimen and using TAC/SIR ± mini-MTX (5 mg/m2 IV day +1,3,6) as GVHD prophylaxis, there was no statistical difference between TAC/SIR vs. TAC/SIR/MTX in the incidence of grade II-IV acute GVHD (20% vs 11%, p= 0.48), cumulative incidence of relapse at year (38% vs. 57%, p= 0.25), 1-yr PFS (58% vs. 41%, p= 0.33), or 1-yr OS (79% vs. 73%, p= 0.79). These results demonstrate that omission of mini-MTX is permissible, and that the combination of TAC/SIR alone as GVHD prophylaxis following reduced intensity conditioning with FLU/BU is associated with low rates of acute GVHD, TRM, and high levels of donor chimerism after MRD SCT.

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Alternative-Donor Hematopoietic Stem Cell Transplantation for Sickle Cell Disease in Pediatric Patients: A Systematic Review and Meta-Analysis

Blood ◽

10.1182/blood-2018-99-119287 ◽

2018 ◽

Vol 132 (Supplement 1) ◽

pp. 5875-5875

Author(s):

Eman M. Elsabbagh ◽

Osama Abunar ◽

Ammar Habbal ◽

Mohammad Tanbour ◽

Ahmed Mansour ◽

...

Keyword(s):

Stem Cell ◽

Meta Analysis ◽

Chronic Gvhd ◽

Reduced Intensity Conditioning ◽

Post Transplant ◽

Cell Counts ◽

Significant Difference ◽

Unrelated Donors ◽

Alternative Donor ◽

Reduced Intensity

Abstract Background Allogeneic hematopoietic stem cell transplantation (HSCT) from HLA-matched sibling donor for patients with sickle cell disease (SCD) provides excellent curative potential with acceptable rates of graft rejection and other common post transplant complications. However, in the United States, only 18% of patients with SCD have an HLA-matched sibling donor. Hence, multiple studies adopted various strategies to figure out alternative donors with favorable outcomes. Poor engraftment, graft versus host disease (GVHD) and regimen related toxicities are the main obstacles following alternative-donor transplant. To overcome these complications, different modalities had been experimented targeting the source of the stem cell, CD34 and TNC cell counts, pre-transplant conditioning regimens and adding immunosuppressive drugs pre/post transplant. However, so far there is no worldwide consensus about robust strategy for alternative donor HSCT. Aim The aim of this review is to systematically evaluate the outcomes of alternative-donor HSCT in patients with SCD in pediatric population, and correlate the outcomes with experimented interventional regimens. Methods We searched PubMed, SCOPUS, Embase, Cochrane and Clinical trials.gov from 2000 till February 2018. We utilized the Systematic Reviews and Meta-Analyses guidelines for Preferred Reporting Results (PRISMA). Two reviewers independently screened titles/abstracts, assessed full-text articles, extracted data from included articles, and assessed their quality. Risk of bias in the included studies was assessed using ROBINS-I tool. Data of platelet/neutrophil recovery, acute/chronic GvHD incidence and overall survival were pooled in a single-arm meta-analysis approach. Results Of the 2886 records examined, 19 met predefined criteria. 16 studies were included in the meta-analysis. 12 clinical trials, 5 cohort observational studies and 2 case reports. All studies had a sample size <50. The pooled times of platelet and neutrophil recovery were 31.55 and 20.15 days, respectively. The pooled incidences of acute and chronic GvHD were 36.1% and 21.7, respectively (Figure 1). The pooled one-year overall survival was 90.3% and two-years was 88.3%. Neutrophil engraftment was earlier and more sustained after using Reduced Intensity Conditioning, 16 days (7-32) compared to 23 days (12-42) after Myelo-ablative Conditioning, (P=0.013). Platelet engraftment was earlier and more sustained after using Reduced Intensity Conditioning, 29 days (15-204) in comparison to 62 days (18-123) after Myelo-ablative Conditioning, (P=0.026). The median duration of neutrophil engraftment after mismatched related donors was 14 days (14-17), after unrelated donors was 14 days (9-25) , after haplo-identical transplantation was 14 days (12-16), after umbilical cord blood transplantation (UCBT) was 23 days (7-42), (P=0.001). The median duration of platelet engraftment after haplo-identical and mismatched related transplantation was 19 days, after matched unrelated donors was 19 days (18-24), after mismatched unrelated donors was 22 day (19-37) and after UCBT was 47 days (15-204), (P=.001). There was no significant difference in acute/chronic GvHD between different types of alternative donors but acute GvHD was significantly less in Myelo-ablative Conditioning compared to Reduced Intensity Conditioning (P=.036) Conclusion Our systematic review showed better outcomes with using Myelo-ablative Conditioning and post transplant cyclophosphamide in haplo-identical transplantation compared to using Reduced Intensity Conditioning. Adding pre-transplant immunosuppressive drugs in haplo-identical transplantation didn't significantly improve the outcomes. In unrelated donor no significant difference between Myelo-ablative Conditioning and Reduced Intensity Conditioning but adding Mesenchymal Stem Cell to the reduced intensity regimen improved the outcomes. In UCBT and mismatched related donors, Reduced Intensity Conditioning had better outcomes especially with high doses of TNC and CD34 cell counts and with applying Mesenchymal Stem Cell or adequate dose of Alemtuzumab. Randomized controlled trials are mandated to generate standardized regimen in the setting of alternative-donor HSCT. Figure 1. Figure 1. Disclosures No relevant conflicts of interest to declare.

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Cytomegalovirus Reactivation and Relapse Following Allogeneic Stem Cell Transplantation Using a Reduced Intensity Conditioning Regimen.

Blood ◽

10.1182/blood.v104.11.5104.5104 ◽

2004 ◽

Vol 104 (11) ◽

pp. 5104-5104

Author(s):

Revati Rao ◽

Kevin Chin ◽

Geoff Chan ◽

Kellie Sprague ◽

Andreas Klein ◽

...

Keyword(s):

Stem Cell ◽

High Risk ◽

Stem Cell Transplantation ◽

Antiviral Therapy ◽

Allogeneic Stem Cell Transplantation ◽

Chronic Gvhd ◽

Attributable Mortality ◽

Reduced Intensity Conditioning ◽

Cmv Reactivation ◽

Reduced Intensity

Abstract Background: Recent studies have reported CMV reactivation rates of 42% to 65% in patients treated with allogeneic stem cell transplantation using reduced intensity conditioning regimens (RIT). However, published data on RIT patients who experience CMV reactivation, are treated successfully with antiviral therapy to eliminate detection, and who subsequently develop CMV relapse, is sparse. Methods: We performed a retrospective cohort analysis of 106 patients who underwent RIT at Tufts-New England Medical Center using a preparative regimen of pentostatin, extracorporeal photophoresis, and reduced total body irradiation, from 1997–2003. All patients received identical graft-versus-host disease (GVHD) prophylaxis, which consisted of IV cyclosporine and PO methotrexate. CMV serostatus was determined on all patients prior to transplant. All patients were screened weekly by CMV antigen capture assay after day +14. Patients did not receive CMV prophylaxis. CMV reactivation was defined as 2 consecutive positive (>2.1 pg/mL) CMV DNA measurements. CMV reactivation was treated with either Ganciclovir 5mg/kg IV daily or Valganciclovir 450mg PO BID until whole blood CMV DNA levels were no longer detectable. Patients were treated with antiviral therapy until a documented negative CMV DNA assay. Those found to have detectable CMV DNA after adequate therapy were then defined as having CMV relapse. Patients were also assessed for incidence of GVHD and mortality. Attributable mortality was defined as mortality in patients who had CMV relapse compared to those who had CMV reactivation without relapse. Fisher’s exact test was used to compare proportions, Kruskal-Wallis was used to compare means, and survival and time to reactivation and relapse were analyzed by Kaplan-Meier Results: Of 106 patients, 49 (46.2%) were CMV seropositive prior to transplant. Twenty -five (51%) of forty-nine CMV positive patients developed CMV reactivation at a median of 43 days (range 26 – 312 days) after receiving stem cells. Among patients with CMV reactivation, 36 were MRD and 13 were MUD. Nine (36%) of 25 patients with CMV reactivation developed CMV relapse. CMV relapse occurred at a median of 16 days (range 4 – 77 days) after CMV reactivation. CMV reactivation occurred earlier among those who relapsed (median 34 days, range 26 – 70 days) compared to those who did not relapse (median 55.5 days, 27 – 312 days, p=.03). Peak viral load was significantly higher in CMV relapsers (median 55.3 pg/mL, range 14.5 to 486.8) compared to non–relapse patients (median 4.4 pg/mL, range 2.1 – 58.2, p=. 0007). There was no difference in acute GVHD in the groups (100% vs. 75%, p=.26). However, those who did relapse had a higher incidence of chronic GVHD than those who did not (89% vs. 38%, p=.03). There was no difference in median survival between non-relapse and relapse patients (13 months vs. 16 months, p=. 99). The attributable mortality rate due to CMV relapse was 23%. Conclusions: Our results suggest there is a subgroup of patients who are at high risk for CMV relapse in the post RIT setting. Risks for CMV relapse include early reactivation and higher peak CMV viral loads. In addition, there was a higher risk of chronic GVHD in CMV relapse patients. We have identified a high- risk subset of patients who reactivate CMV for whom additional therapeutic strategies may be warranted.

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Transplant Outcome of Unrelated Hematopoietic Stem Cell Transplantation (HSCT) after Myelo-Ablative or Reduced Intensity Conditioning (RIC) for Chronic Lymphocytic Leukemia(CLL). A Study of EBMT Registry.

Blood ◽

10.1182/blood.v106.11.561.561 ◽

2005 ◽

Vol 106 (11) ◽

pp. 561-561 ◽

Cited By ~ 2

Author(s):

Mauricette Michallet ◽

Thomas Prebet ◽

Quoc-Hung Le ◽

Anne-Sophie Michallet ◽

Anja Van Biezen ◽

...

Keyword(s):

Chronic Gvhd ◽

Hla Matching ◽

Reduced Intensity Conditioning ◽

Hematopoietic Stem ◽

Allogeneic Hsct ◽

Significant Difference ◽

Unrelated Donors ◽

Global Population ◽

Reduced Intensity ◽

Grade Iii

Abstract Place of allogeneic HSCT in the therapeutical strategy of CLL remains still controversial and unrelated allogeneic transplantation has to be better explored. This retrospective analysis concerned 214 patients (164 males and 50 females) who underwent allogeneic HSCT for CLL from unrelated donors (150 males and 64 females) and who were reported on EBMT registry. The median age was 49 years. Fifty two patients received bone marrow (BM) and 162 peripheral blood stem cells (PBSC) from 48 HLA mismatched and 166 HLA matched unrelated donors. Sex mismatch and ABO incompatibility were found in 33% and 52% of cases respectively. On 194 evaluated patients for conditioning, 80 received a myelo-ablative regimen, 114 a reduced intensity conditioning and a Total Boby Irradiation was performed in 70 cases. After transplant, 72 patients (37%) developed an acute GVHD grade II-IV (36% in BM patients and 37% in PBSC patients; 49% in myelo-ablative group and 28% in RIC group). On evaluated patients, a chronic GVHD was present in 61% of the patients (50% in BM patients and 67% in PBSC patients, 66% in myelo-ablative group and 63% in RIC group). With a median follow-up of 20 months, we found no significant difference for 3-year probability of Overall Survival between myelo-ablative group (59%, 46–76) and RIC group (48%, 37–63). No significant difference was observed when comparing BM and PBSC patients whatever the conditioning they received. OS was significantly better in HLA matched compared to HLA mismatched patients in RIC population (51% vs 36%, p=0.01) but not in myelo-ablative population. In multivariate analysis (table 1) studying pre and post transplantation factors, a significant impact of 2 variables, age and aGVHD (grade III-IV vs 0-I), was shown on OS for the global population, myelo-ablative and RIC groups. Other variables influenced also significantly the OS: HLA matching (global and RIC populations), sex matching (myelo-ablative and RIC), TBI (myelo-ablative group). Concerning BM and PBSC groups, we demonstrated the influence of age and aGVHD. In conclusion, besides the known influence of severe aGVHD on survival, this study points out the importance of age and HLA matching in allogeneic unrelated HSCT transplantation setting for CLL. No difference was found regarding conditioning regimen and further studies are needed to determine the most adequate regimen for this disease. Multivariate analyses Variables OS (HR) p Global population Age 1.04 (1-1.07) 0.05 HLA matching: yes vs no 0.44 (0.22-0.89) 0.02 aGVHD grade III-IV vs 0-I 1.37 (1.1-1.74) 0.01 Myelo-ablative group Age 1.07 (1-1.13) 0.04 Sex Mismatch: F to M vs F to F 6.26 (1.53-25.6) 0.01 TBI: yes vs no 16.3 (3.26-80.2) 0.0006 aGVHD grade III-IV vs 0-I 1.9 (1.18-3.06) 0.008 RIC group Age 1.05 (1-1.1) 0.05 HLA matching: yes vs no 0.28 (0.1-0.76) 0.01 Sex Mismatch M to F vs F to F 0.63 (0.42-0.96) 0.03 aGVHD grade III-IV vs 0-I 1.66 (1.16-2.39) 0.005 BM group Age 1.12 (1-1.24) 0.03 aGVHD grade III-IV vs 0-I 1.88 (1-1.36) 0.05 PBSC group aGVHD grade III-IV vs 0-I 1.38 (1.02-1.86) 0.03

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High Rates of Early Donor Chimerism and Low Risk of Chronic GVHD Can Be Achieved in Poor Risk Patients Undergoing Unrelated Donor Stem Cell Transplantation Using a Reduced Intensity Conditioning Regimen Incorporating Fludarabine, Busulfan, and Rabbit ATG.

Blood ◽

10.1182/blood.v110.11.5080.5080 ◽

2007 ◽

Vol 110 (11) ◽

pp. 5080-5080

Author(s):

Mehdi Hamadani ◽

Patrick Elder ◽

Farrukh Awan ◽

David Krugh ◽

William Blum ◽

...

Keyword(s):

Stem Cell ◽

Stem Cell Transplantation ◽

Cell Transplantation ◽

Chronic Gvhd ◽

Unrelated Donor ◽

Reduced Intensity Conditioning ◽

Post Transplant ◽

Ebv Reactivation ◽

Risk Patients ◽

Reduced Intensity

Abstract Reduced intensity conditioning (RIC) regimens are increasingly used for allogeneic stem cell transplantation (allo-SCT) in patient groups with relative contraindications for transplantation since they promote effective engraftment of donor cells with minimal regimen related toxicity. However, following unrelated donor (URD) transplantation, high rates of acute and extensive chronic GVHD have mitigated the overall benefits of this approach. We pursued a strategy designed to enhance early full donor hematopoietic chimerism while potentially reducing the risk of severe acute and extensive chronic GVHD using an RIC regimen containing fludarabine (F), busulfan (B), rabbit antithymocyte globulin (A) (FBA) followed by URD SCT in 30 consecutive high risk patients (pts). Criteria for selection included advanced age (>55yrs), prior autograft, and/or high co-morbidity index (median 2, range 0–4). There were 24 male and 6 female pts with a median age of 53 years (range 22–66yrs). Diagnoses included AML (N=10), NHL (N=7), Hodgkin’s lymphoma (N=6), advanced CML (N=4), and advanced CLL (N=4). Nine pts had previously undergone autologous SCT. 43% had a Karnofsky performance status of 70 or 80% at the time of transplant. 80% were matched with their donor at HLA-A, B, C, and DRB1 by high-resolution DNA typing, while 3 were mismatched at 1 antigen and 3 mismatched at 1 or 2 alleles. All pts were conditioned with F (30 mg/m2/day, days −7 to −3), B (0.8 mg/kg/dose IV x 8 doses) and A (2.5 mg/kg/day, days −4 to −2) followed by micro-dose methotrexate and tacrolimus. Stem cell source included peripheral blood (n=26) or bone marrow (n=4). All pts engrafted neutrophils and platelets promptly (median 15 and 16 days, respectively). There were no primary graft failures. Rates of grade II-IV and III-IV acute GVHD were 43% (n=13) and 23% (n=7) respectively. Nine pts (30%) developed chronic GVHD but extensive chronic GVHD was seen in only 10% (n=3). Day 100 TRM was 10% (n=3). Causes of death included disease progression=2, post-transplant lymphoproliferative disorder (PTLD) =1 and sepsis=1. CMV and EBV reactivation occurred in 30% (n=9) and 20% (n=6) respectively. 2 pts developed PTLD requiring rituximab. Three pts had BK-virus associated hemorrhagic cystitis. Lineage-specific chimerism analysis showed 100% donor CD33+ at all time points (days 30, 60, 100) and median donor CD3+ chimerism of 94% at day +30 and 100% at day +100. One patient had secondary graft failure. 23 pts (76%) were in CR after SCT. The median follow-up of surviving patients is 6 months (range 1–32 months). Kaplan-Meier estimates of overall survival (OS) and progression free survival (PFS) at 1year are 62% and 43% respectively. Using the Log-Rank test, OS (P=0.95) and PFS (P=0.65) was not statistically significant between recipients of matched and mismatched grafts. In conclusion, this approach using FBA and a tacrolimus based GVHD prophylaxis achieved rapid donor chimerism and a favorably low incidence of TRM, acute, and chronic GVHD despite being tested in a poor risk group of pts. Although rates of infectious complications were within expected ranges, the rate of both EBV reactivation and disease relapse warrant further exploration of this approach using lower doses of ATG (e.g. 5–6mg/kg total dose) combined with post transplant immunomodulation.

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No Influence of Peripheral Blood CD34+ and CD3+ Graft Cell Counts on Outcomes after Reduced-Intensity Conditioning Transplantation Using Post-Transplant Cyclophosphamide

Blood ◽

10.1182/blood-2018-99-112453 ◽

2018 ◽

Vol 132 (Supplement 1) ◽

pp. 4577-4577

Author(s):

Alice Garnier ◽

Thierry Guillaume ◽

Pierre Peterlin ◽

Amandine Le Bourgeois ◽

Alix Duquesne ◽

...

Keyword(s):

Board Of Directors ◽

Acute Gvhd ◽

Chronic Gvhd ◽

Reduced Intensity Conditioning ◽

Advisory Committees ◽

Cell Content ◽

Post Transplant ◽

Cell Counts ◽

Gvhd Prophylaxis ◽

Reduced Intensity

Abstract Introduction Although associated with a higher incidence of acute GVHD, peripheral blood stem cells (PBSC) are increasingly used for haploidentical allogeneic transplantation with post-transplant cyclophosphamide (PTCY). Data reporting whether or not the composition of the PBSC graft impacts outcomes of patients receiving PTCY are still scarce. Materials and Methods This retrospective study included all adults allografted in our department who received a PBSC allotransplant after reduced-intensity conditioning (RIC) with PTCY. Grafts originated from a matched or haploidentical donor and recipients received a Baltimore-based or a Clo-Baltimore (where fludarabine is replaced by clofarabine)-based RIC regimen. All patients received cyclosporine + mycophenolate mofetyl and PTCY as GVHD prophylaxis. CD34+ and CD3+ graft cell contents were considered to study their potential impact on the following outcomes: OS, DFS, GRFS, acute grade 2-4 and 3-4 GHVD and chronic GVHD, early immune reconstitution (IR, lymphocytes and monocytes counts at days+30 and +100 post-transplant, CD4+, CD8+, NK and B cells at day+100 post-transplant). Results Between November 2013 and May 2017, 77 patients met the inclusion criteria. There were 48 males and 29 females with a median age of 58 years (range: 22-71) and a median follow-up for alive patients of 29.2 months (range: 8.4-53.2). Initial diagnoses were mainly acute myeloid (n=21) or lymphoid (n=6) leukemia, lymphoma (n=13), myelodysplastic syndrome (SMD, n=12), myelofibrosis (n=9). Thirty-eight patients were in complete remission at time of transplant (CR1 n=23; CR2 n=12, CR3 n=3) while 22 had active disease and 17 were in partial remission. Donors were sibling in 6 cases, matched unrelated (MUD) in 14, 9/10 mismatched unrelated in 1 and haploidentical in 56. Forty patients received a Baltimore RIC regimen and 37 a Clo-Baltimore RIC regimen. Analyses were performed in July 2018. Median infused CD34+ and CD3+ graft cell counts, based on recipients' weight, were 7.8 106/Kg (range: 1.45-14.24) and 22.23 107/kg (range: 1.95-66.75), respectively. All patients but three engrafted, the latter being 1 patient transplanted with a haplodonor, 1 with a MUD and 1 who died of infection during induction. Two-year OS, DFS and GRFS were 62.6% (52-74), 51.5% (40-63) and 36.6% (27-49), respectively. The incidences of grade 2-4 and 3-4 acute GVHD were 46.7% and 14.2%, respectively, while the incidence of moderate + severe chronic GVHD was 14%. Relapse occurred in 26 patients and non-relapse mortality (NRM) was 15.5%. Baltimore vs Clo-Baltimore patients shared similar median infused CD34+ and CD3+ graft cell counts and outcomes. The same was observed for patients allografted with a haplodonor or not, except for the incidence of grade 2-4 acute GVHD which was significantly higher for the haplo group at 57.1% vs 19% (p=0.006). This difference was first attributed to the higher CD3+ cell content infused in this group (median: 24.05 vs 18.85 107/kg, p=0.04). However, using the median of CD3+ cell graft content as threshold, the incidence of acute grade 2-4 GVHD was not different between low vs high groups when considering haplo patients. This suggests that it was rather the type of donor that did influence acute GVHD occurrence and that PTCY is of particular interest for GVHD prophylaxis when using matched donors. Partitioning the patients according to the median level of CD34+ cells, there was no difference in terms of 2-year OS (57.1% vs 60.7%, p=0.53), DFS (44.5% vs 55.6%, p=0.47) , GRFS (31.7% vs 44.3%, p=0.32), acute grade 2-4 (59% vs 39%, p=0.13) and 3-4 GVHD (17% vs 6.4%, p=0.29), and moderate + severe chronic GVHD (19.5% vs 20%, p=0.57). Similarly, partitioning patients according to median graft CD3+ cell content, outcomes were similar for 2-year OS (64.8% vs 55.8%,p=0.45), DFS (46.3% vs 55.8%, p=0.62), GRFS (36.3% vs 40.4%, p=0.63), acute grade 2-4 (44.7% vs 56.4%, p=0.42) and 3-4 GVHD (10.5% vs 15.3%, p=0.76), and moderate + severe chronic GVHD (14% vs 17.6%, p=0.91). Finally, early IR was not influenced by CD34+ and CD3+ graft cell contents. Conclusion: PBSC CD34+ and CD3+ graft cell contents have no impact on survivals, GVHD incidence nor early IR after a RIC allotransplant using PTCY as GVHD prophylaxis. As a consequence, there is no need to manipulate the graft nor cap the stem cells dose to be infused. These data have to be confirmed prospectively on a larger cohort of patients. Disclosures Gastinne: Millennium/Takeda: Honoraria. Moreau:Janssen: Honoraria, Membership on an entity's Board of Directors or advisory committees; Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees; Amgen: Honoraria, Membership on an entity's Board of Directors or advisory committees; Takeda: Honoraria, Membership on an entity's Board of Directors or advisory committees; Abbvie: Honoraria, Membership on an entity's Board of Directors or advisory committees.

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Outcome of Sibling Reduced-Intensity Conditioning Allogeneic Stem Cell Transplantations in Low-Grade B Cell Lymphoproliferative Disorders. A Single Centre Experience.

Blood ◽

10.1182/blood.v110.11.5059.5059 ◽

2007 ◽

Vol 110 (11) ◽

pp. 5059-5059

Author(s):

Ronan Desmond ◽

Marianna David ◽

Eibhlin Conneally ◽

Paul Browne ◽

Mairead Ni Conghaile ◽

...

Keyword(s):

Stem Cell ◽

B Cell ◽

Chronic Gvhd ◽

Autologous Transplantation ◽

Conditioning Regimen ◽

Lymphoproliferative Disorders ◽

Mixed Chimerism ◽

Low Grade ◽

Reduced Intensity Conditioning ◽

Reduced Intensity

Abstract Reduced intensity conditioning allogeneic stem cell transplantations (allo-SCT) have been developed to exploit graft-versus-malignancy effect while reducing the toxicity of allo-SCT. We report the outcome of 21 patients with low-grade B cell lymphoproliferative disorders transplanted in a single center. The mean age of the patients was 54 years (range 32–66) with 11 males, 10 females. Follicular lymphoma was the diagnosis in 10 patients, CLL in 5, mantle cell lymphoma in 4, MALT lymphoma in 1 and lymphoplasmocytoid lymphoma in 1 patient. The median number of prior treatment lines was 2. All patients received peripheral blood stem cell transplants from sibling donors and no patients had undergone a prior autologous SCT. 12/21 patients (57%) received a ATG based conditioning regimen while the remainder, 9/21 (42%) received a Campath containing conditioning regimen. Full donor chimerism was confirmed in 17/19 (89%) patients. Acute graft versus host disease (GVHD) developed in 5/21 (23%) of the patients. Chronic GVHD occurred in 7/21 (33%) with 5/21 occuring post donor lymphocyte infusion (DLI). DLI has been administered in 11/21 patients (52%), 2 for progressive disease and 9 for re-emerging mixed chimerism. Non-relapse mortality (NRM) at 100 days and 1 year were 5% and 12.5% respectively. With a median follow up of 21 months (range 3–54) the overall survival rates (OS) at 1 year and 2 years were 72% and 58% respectively. Progression free survival (PFS) at 1 year and 2 years were 66% and 50%. We have shown that reduced intensity conditioning allogeneic stem cell transplantation is associated with a low TRM comparible to that of autologous transplantation and allows long term control of low grade B-cell lymphoproliferative disorders.

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Influence of Donor Type (sibling vs matched-unrelated donor vs haplo-identical donor vs cord blood) on Outcomes after Clofarabine-Based Reduced-Intensity Conditioning Allograft for Myeloid Malignancies

Blood ◽

10.1182/blood-2018-99-112369 ◽

2018 ◽

Vol 132 (Supplement 1) ◽

pp. 3451-3451

Author(s):

Louise Bouard ◽

Thierry Guillaume ◽

Pierre Peterlin ◽

Alice Garnier ◽

Amandine Le Bourgeois ◽

...

Keyword(s):

Stem Cells ◽

Cord Blood ◽

Board Of Directors ◽

Peripheral Blood ◽

Chronic Gvhd ◽

Reduced Intensity Conditioning ◽

Advisory Committees ◽

Post Transplant ◽

Donor Type ◽

Reduced Intensity

Abstract Background: Recently, we have reported the good results of a clofarabine-based reduced-intensity conditioning (RIC) regimen for peripheral blood stem cell (PBSC) allografts, using either matched (Le Bourgeois, ASH 2017) or haploidentical (haplo) donors (Chevallier, ASH 2017). However, the influence of donor type in this setting is unknown. Patients and Methods: We conducted a retrospective study including all adults (≥18 yo) allografted in our department with a clofarabine-based RIC regimen for a myeloid malignancy. All types of donors were accepted, and patients received allogeneic peripheral blood stem cells (PBSC) or cord blood (CB) transplants. The aim of this study was to assess whether or not the donor type (sibling, matched unrelated (MUD), haplo or CB) impacted outcomes. Results: Between October 2009 and February 2018, 122 patients met the inclusion criteria. Donors were sibling in 36 cases, "MUD" in 55 (including one 9/10 mismatched donor), haplo in 27 and CB in 4. The sibling+MUD patients received a CloB2A1/A2 RIC regimen consisting of clofarabine 30 mg/m²/day 4 to 5 days (Clo), busulfan 3.2 mg/kg/day 2 days (B2) and 2.5mg/kg/day of rabbit anti-thymocyte globulin 1 or 2 days (A1 or A2). Haplo and CB recipients were conditioned by a Baltimore-like RIC regimen and a Minneapolis-like regimen, respectively, where fludarabine were replaced by clofarabine. All patients received cyclosporine (CsA) + mycophenolate mofetyl as GVHD prophylaxis, except sibling recipients who were given CsA alone. Haplo recipients received also 2 days of post-transplant cyclophosphamide. All non-CB patients received PBSC as source of graft. The median age of the whole cohort was 61,5 years old (range: 18-73) and the median follow-up 31 months (range: 4,5-106). All patients engrafted except 1 CB patient and 1 haplo recipient who died of infection before engraftment. All CB cases died at 1, 8, 9 and 11,5 months post-transplant, respectively (infection n=1, relapse n=2, chronic GVHD n=1). As a consequence, we thereafter compared outcomes only between the three other donor groups. There were no significant differences between sibling, MUD or haplo recipient groups in terms of gender, median age, type of disease, ELN 2010 classification for AML, status at transplant (complete remission vs active), disease risk index, donor/recipient CMV status or median graft quantity of CD34+ stem cells. The only differences were the partition of ABO compatibility, less frequent in the MUD group (42% vs sibling 69% vs haplo 67%, p=0,02) and a history of previous allograft (haplo n=7, sibling n=0, MUD n=6, p=0,005). Neutrophils (>0,5 Giga/L) and platelets (50 Giga/L) recoveries were significantly delayed in the haplo-group (19 days, vs sibling 15 vs MUD 15, p=0.0003; and 31 days vs 11 vs 12, p<0.0001). Acute grade 2-4 or 3-4 graft versus host disease (GVHD) incidences were similar between the three groups at 50% and 22% for sibling, 34,5% and 14,5% for MUD and 48% and 11% for haplo (p=0,18 for grade 2-4 and p=0,45 for grade 3-4) as well as moderate+severe chronic GVHD incidences (sibling 14%, MUD 16%, haplo 15% p=0,94). Follow-ups were similar at 34.2 (6-74), 33.7 (4.5-106) and 21.4 (7-53) months respectively for sibling, MUD or haplo donors. This was associated with similar 2-year overall survivals (OS) at 64,7% (50-83), 73,9% (62-87) and 60,2% (43-83) respectively (p=0.4) and 2-year disease-free survivals (DFS) at 57,7% (43-76), 70,9% (59-84) and 53,6% (37-77) respectively (p=0.1). Two-year GVHD-relapse free survival (GRFS) was also similar at respectively 37,9% (24-57), 54,3% (41-70) and 38,9% (23-63) (p=0.2) as well as 2-year non-relapse mortality (NRM) at 14%, 11% and 18,5% (p=0,63). When considering only AML patients, again similar 2-year survivals were observed between the three groups. OS was 71.4% (54-93) for sibling (n=21), 75.1% (62-90) for MUD (n=40) and 66.6% (46-95) for haplo (n=15, p=0.65) and DFS respectively 66,6% (49-90), 70,8% (57-87) and 66,6% (46-95 p=0.47). The same was observed for GRFS at 38% (22-65), 56% (41-75) and 40% (21-74, p=0.14) and NRM at 14%, 7,5% and 7%, p=0.34). In multivariate analysis, donor type remained independent of outcomes in this series. Conclusion: These data confirm that since no difference was observed in terms of outcomes, haplodonors represent a valid alternative for patients receiving a clofarabine-based RIC PBSC allograft for myeloid malignancies who lack a matched sibling donor. Disclosures Gastinne: Millennium/Takeda: Honoraria. Moreau:Abbvie: Honoraria, Membership on an entity's Board of Directors or advisory committees; Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees; Takeda: Honoraria, Membership on an entity's Board of Directors or advisory committees; Janssen: Honoraria, Membership on an entity's Board of Directors or advisory committees; Amgen: Honoraria, Membership on an entity's Board of Directors or advisory committees.

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CD34+ Donor Chimerism and Wilms Tumor Gene 1 (WT1) Expression Provide an Early Indication of Relapse in Patients with Acute Leukemias and MDS after Hematopoietic Cell Transplantation (HCT) with Reduced-Intensity Conditioning.

Blood ◽

10.1182/blood.v108.11.548.548 ◽

2006 ◽

Vol 108 (11) ◽

pp. 548-548 ◽

Cited By ~ 1

Author(s):

Max Hubmann ◽

Ralph Burkhardt ◽

Georg Franke ◽

Michael Cross ◽

Markus Scholz ◽

...

Keyword(s):

Odds Ratio ◽

Wilms Tumor ◽

Reduced Intensity Conditioning ◽

Acute Leukemias ◽

Wilms Tumor Gene ◽

Post Transplant ◽

Donor Chimerism ◽

Tumor Gene ◽

Disease Specific ◽

Reduced Intensity

Abstract HCT following reduced intensity conditioning (RIC) relies mainly on immunological effects for disease control. The early detection and quantification of minimal residual disease and the timely adjustment of immune suppression are therefore particularly important in this setting. Since appropriate disease-specific gene markers are available only in a minority of patients with acute leukemias or MDS, the potential of both donor chimerism and Wilms Tumor gene 1 (WT1) expression to provide quantification of MRD was investigated. Patients and Methods: Ninety-five consecutive patients with AML (n=68), ALL (n=7) and intermediate/high-risk MDS (n=20) were analyzed. Patients were 60 (median; range 21–74) years old and in CR1 (n=45), CR2 (n=25), or more advanced disease status (n=25). Grafts were obtained either from related (n=24) or unrelated (n=71) donors. Conditioning regimens consisted of fludarabine 30mg/kg BW day -4 to -2 (n=90) and total body irradiation with 2 Gy at day 0 (n=95), and post-transplant immunosuppression employed cyclosporin A and mycophenolate mofetil. Total donor chimerism (TDC, n=93 patients, 236 samples), CD34+− chimerism (n=89, 219 samples) and disease-specific molecular markers detected by FISH (DSM, n=39, 77 samples) were all determined prospectively from bone marrow (BM) samples at baseline and on days +28, +56 and +84 post-transplant. WT1 expression was analyzed retrospectively by RT-PCR from stored peripheral blood (PB) samples (n=95, 321) from the same time points. Results: With a median follow-up of 11.7 (range 2–61) months, 34 (36%) patients relapsed (defined by BM blasts >5%). Since complete results from all techniques were available up to day 84, we analyzed the diagnostic power of all methods to predict hematological relapse one month in advance up until the fourth month after HCT (n=21 patients, 22%). First, we estimated the value of the three different prospective MRD techniques (DSM, TDC and CD34+ chimerism) using Receiver Operating Curves (ROC). Relapse was predicted 1 month in advance by CD34+−chimerism [p= 0.001, area under the curve (AUC) = 0.875], but not by TDC or DSM, (n=30). The cut-off value of 5% decrease in CD34+ chimerism in a one month period achieved a sensitivity of 71% and specificity of 91%. In comparison, WT1 expression was similarly associated with a pending relapse (p< 0.0001, AUC = 0.861). The optimal cut-off value of 24 WT-1 copies per 10000 ABL copies was assessed by ROC and resulted in a sensitivity of 79% and specificity of 91%. In a logistic regression model, we estimated the ratios of the odds of relapsing within the next month. WT1 achieved a higher odds ratio (36/1) than CD34+ chimerism (25/1). Combining both techniques yielded a specificity of 98% and an odds ratio of 72/1 Conclusion: WT1 expression in PB and CD34+ chimerism in BM are superior to full donor chimerism and disease-specific markers determined by FISH in predicting relapse in all patients with acute leukemia and MDS. Both markers are suitable to develop effective post-transplant treatment strategies to further decrease the relapse rate using immunological or cytotoxic approaches.

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Donor Lymphocyte Infusion for Mixed Chimerism or Residual Disease after Reduced-Intensity T Cell Depleted Stem Cell Transplantation Results in Conversion to Full Donor Chimerism Combined with Graft Versus Tumor Responses and Limited GVHD.

Blood ◽

10.1182/blood.v110.11.1652.1652 ◽

2007 ◽

Vol 110 (11) ◽

pp. 1652-1652 ◽

Cited By ~ 1

Author(s):

Peter A. von dem Borne ◽

Ingrid Starrenburg ◽

Erik W.A. Marijt ◽

Stijn Halkes ◽

J.H. Frederik Falkenburg ◽

...

Keyword(s):

Bone Marrow ◽

Stem Cell ◽

T Cell ◽

Chronic Gvhd ◽

Bone Marrow Involvement ◽

Mixed Chimerism ◽

Donor Chimerism ◽

Measurable Disease ◽

Unrelated Donors ◽

Reduced Intensity

Abstract We perform reduced intensity allogeneic stem cell transplantation (SCT) with HLA identical sibling and matched unrelated donors using a conditioning regimen consisting of fludarabine, busulphan and ATG combined with alemtuzumab added to the stem cell graft for extensive donor T cell depletion. With this regimen hardly any acute and chronic graft versus host disease (GVHD) are observed after SCT and mixed chimerism is induced in most patients (Barge et al, Exp Hematol 2003). In patients transplanted for malignant disease, donor lymphocytes (DLI) are administered in escalating doses from 6 to 9 months to convert mixed into complete donor chimerism and to induce graft versus tumor (GVT) responses. We report results of chimerism analysis, clinical antitumor response and GVHD after DLI. 41 patients (median age 54 years, range 37–65) transplanted with stem cells from sibling donors (29) or matched unrelated donors (12) for various malignancies received DLI with a median dose of 5 × 106 CD3+ cells/kg (range 1–5) at a median time point of 7 months after SCT (range 5.1–15). After DLI administration 35 of 38 evaluable patients (92%) developed an immune response as defined as a major decrease in patient chimerism. In 26 patients full donor chimerism was achieved, in 9 patients a low patient signal remained present (1–2%). Patient chimerism decreased from median 12% (range 1 to 86%) to 0% (range 0–2%). In most patients conversion occurred after the first DLI, in 4 patients after the second and in 1 patient after the third DLI. In 31 of 38 patients measurable disease was present before DLI. In 22 of these patients conversion from mixed to full donor chimerism coincided with clinical GVT responses. Seven patients with active myeloid disease all achieved complete remission (4 AML/MDS patients with 8–65% blasts, 2 patients with progressive CML and 1 with active CMMOL). All these patients are still in CR after a median time of 22 months. In 8 myeloma patients with measurable disease 5 complete and 1 partial response were observed. However, most responding myeloma patients subsequently developed bone or extramedullary relapses without evidence of bone marrow involvement. In 13 patients with lymphoid disease 9 responses were observed. One patient with an immunocytoma and one with T-PLL achieved CR. In 7 CLL patients 3 CR and 1 PR were observed, notably two CR occurred in patients with massive bone marrow involvement. Two of four patients with aggressive NHL showed a CR to DLI in combination with rituximab and one patient a PR to DLI. Although no regression of tumor was observed in three patients with renal cell carcinoma after DLI, disease progression was halted for several years. Grade 3–4 acute GVHD developed in 22% of patients, grade 1–2 in 39%. Limited or extensive chronic GVHD was observed in 30 and 23% of patients, respectively. GVHD responded to therapy in most patients, only in 9% of patients chronic GVHD did not resolve. Mortality due to acute and chronic GVHD was 10%. In conclusion, after T cell depleted reduced intensity SCT a state of mixed chimerism is induced in most patients, which can be converted into full donor chimerism with DLI in more than 90% of patients. Conversion to full donor chimerism is accompanied with clinical GVT responses in a high percentage of patients with acceptable GVHD.

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