Multicenter, Retrospective Evaluation of Therapeutic Efficacy of Ruxolitinib for Chronic Gvhd Treatment

Background Several agents have been investigated for beyond second-line treatment of chronic graft-versus-host disease (GVHD). Ruxolitinib has been recently approved for steroid-refractory acute GVHD, while a prospective randomized study is ongoing to examine its efficacy in steroid-resistant chronic GVHD (cGVHD). The present study evaluated the efficacy of Ruxolitinib in terms of 1) overall response rate (ORR), 2) clinical benefit (CB), 3) dose reduction of corticosteroid exposure, 4) failure-free survival (FFS) and 5) overall survival (OS), in patients heavily pretreated for steroid-resistant cGVHD. Patients and methods A total of 47 patients who developed cGVHD after HCT and treated with Ruxolitinib for cGVHD from March 2016 to April 2020, at three different sites (Princess Margaret Cancer Center, Canada; Vancouver General Hospital, Canada and Saint Vincent Hospital, Australia), were evaluated in the retrospective study. Patients and disease characteristics are as follows: median age 52 years; classical 35 (71%), overlap syndrome 14 (29%). Of note, 27 patients (57.4%) had a previous history of acute GVHD. The ORR and CB were assessed at months 3, 6 and 12, retrospectively. Responses were evaluated according to NIH scoring/staging/response assessment as part of standard clinical practice. CB was assessed considering clinical response as well as steroid dose reduction. For systemic steroid dose reduction, prednisone dose per kg per day was captured prior to Ruxolitinib start, at months 3, 6 and 12. Treatment failure was defined as 1) resistance requiring treatment switch, 2) non-relapse mortality (NRM), 3) relapse, 4) intolerance to treatment. FFS and OS were calculated from the day of starting Ruxolitinib therapy for cGVHD treatment. Results A total of 47 patients had moderate (11/47, 24.4%) to severe (33/47, 73.3%) cGVHD except one who had mild grade cGVHD with a high-risk feature (thrombocytopenia at the time of Ruxolitinib start). The median number of organ involvement was 3 (range 1-7). Over half of patients (63.8%) received Ruxolitinib as 4th line or beyond for cGVHD treatment, while median number of previous lines of therapy was 3 (range 1-9). All 47 patients (100%) had been previously treated with systemic steroids; other previous treatments included ECP therapy (53.2%), Imatinib (29.8%), Ibrutinib (23.4%), Rituximab (21.3%). Ruxolitinib was started at 10-15 mg daily as initial dose, then maintained at 20mg daily in two divided doses on months 3, 6 and 12.With a median follow-up duration of 12 months, ORR was attained in 35.7%, 36.0% and 35.0% at 3, 6 and 12 months, respectively (Figure A). Of note, ORR in patients with sclerotic changes was 56%, and 61.5% in those with lung involvement. Patients resistant to TKI (i.e. Imatinib or Ibrutinib) for cGVHD treatment showed similar ORR compared to those naïve to TKI therapy.The CB was observed in 53.5%, 66.7% and 72.2% at months 3, 6 and 12, respectively (Figure B). Patients resistant to TKI for cGVHD treatment did not show any difference in CB compared to those naïve to TKI therapy.In terms of prednisone dose reduction, by 12 months , half of patients (50.0%) could taper prednisone doses below 0.1mg/kg/day, while the proportion of patients on prednisone dose below 0.1mg/kg/day was 9.3%, 20.0%, 17.4%, and 50.0% at month 0, 3, 6 and 12, respectively (Figure C). The group who achieved CB at 3 months showed a significantly lower dose of prednisone at 12 months (0.078mg/kg/day) compared to those without clinical benefit at 3 months (0.197mg/kg/day; p=0.033; Figure D).Out of 37 patients evaluated, 11 failures (29.7%) were noted, including resistance requiring a switch to other therapy (n=7), NRM (n=2) and intolerance (n=2). The FFS rate at 1 year in the overall population was 68.5% (Figure E). The FFS at 1 year in those having CB at 3 months vs not was 86.5% vs 51.4% (p=0.025).The OS at 1 year was 90.9% (Figure F). The OS at 1 year in those having a CB at 3 months vs not was 100% vs 78.8% (p=0.053). Conclusion: This multicenter retrospective study revealed that Ruxolitinib is an effective treatment option for patients with cGVHD, with good ORR and CB. The achievement of CB in the first 3 months correlated well with steroid dose reduction. It suggests that Ruxolitinib is a feasible GVHD treatment option, even for patients who were heavily pretreated for cGVHD or failed previous TKI drug. Figure 1 Disclosures Hamad: Abbvie: Honoraria; Novartis: Honoraria. OffLabel Disclosure: Ruxolitinib treatment for steroid resistant chronic GVHD

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Single Centre, Retrospective Study to Evaluate Treatment Outcomes Following Tyrosine Kinase Inhibitor for Chronic Gvhd Treatment Including Ruxolitinib, Ibrutinib and Imatinib

Blood ◽

10.1182/blood-2020-142182 ◽

2020 ◽

Vol 136 (Supplement 1) ◽

pp. 17-18

Author(s):

Swe Mar Linn ◽

Omar Abduljalil ◽

Igor Nicolas Novitzky-Basso ◽

RAM V Nampoothiri ◽

Ivan Pasic ◽

...

Keyword(s):

Retrospective Study ◽

Tyrosine Kinase ◽

Tyrosine Kinase Inhibitor ◽

Dose Reduction ◽

Research Funding ◽

Kinase Inhibitor ◽

Single Centre ◽

Prednisone Dose ◽

Steroid Dose ◽

Heavily Pretreated

Background Chronic graft-versus-host-disease (cGVHD) is one of the main causes of morbidity and mortality after allogeneic hematopoietic stem cell transplantation (HCT). Tyrosine kinase inhibitor such as Ruxolitinib, Ibrutinib and Imatinib showed a promising efficacy in cGVHD treatment. Ruxolitinib is a JAK-STAT inhibitor, reducing inflammation and immune pathway. Ibrutinib is a BTK inhibitor, blocking B cell-activating factor (BAFF), while Imatinib inhibits the platelet-derived growth factor receptor pathway activated by cGvHD-induced antibodies. The present retrospective study evaluated the efficacy of 3 TKIs for cGVHD at a single-centre in terms of 1) overall response rate (ORR), 2) clinical benefit (CB), 3) dose reduction of steroid, 4) failure-free survival (FFS) and 5) overall survival (OS). Patients and Methods A total of 43 patients who developed cGVHD after HCT and treated with TKI therapy for cGVHD at Princess Margaret Cancer Centre, Canada from August 2014 to April 2020 were evaluated in this retrospective study. 16 patients were treated with more than one TKI drug. A total of 62 lines of TKI therapy was evaluated, including Ruxolinitib (n=18), Ibrutinib (n=13) and Imatinib (n=31). The ORRs and CBs were assessed at months 3, 6 and 12, retrospectively. Responses were evaluated according to NIH scoring/staging/response assessment as part of standard clinical practice. CB was assessed considering clinical response as well as steroid dose reduction. For systemic steroid dose reduction, prednisone dose per kg per day was captured prior to Ruxolitinib start, at months 3, 6 and 12. Treatment failure was defined as 1) resistance requiring treatment switch, 2) non-relapse mortality (NRM), 3) relapse, 4) intolerance requiring treatment discontinuation. FFS and OS were calculated from the day of starting TKI therapy for cGVHD treatment. Results The patients and disease characteristics are summarized as follow: median age was 54 years (range 16 -70); 33 patients (53%) presented with classical cGVHD, while 29 patients (47%) with overlap syndrome; 14 (23%) presented with moderate and 48 (77%) with severe grade cGVHD. There was no difference in cGVHD subtype among 3 TKI subgroups (p= 0.478). The median number of organ involvement was 3 (range 1-5), and number of previous lines of therapy was 5 (range 3-9), implying that most of the patients were heavily pretreated for cGVHD. The mean (±S.E.) dosage of TKI treatment was as follows: Ruxolitinib was started at 15±1.1mg as initial dose and 20±0.7, 19±1.5, 22±4.4 mg per day in two divided doses on months 3, 6 and 12, respectively. Ibrutinib dose was 226±37, 256±37, 308±40 and 370±33 mg per day, while Imatinib dose was 106±6, 189±18, 196±16 and 190±19 mg per day prior to TKI starts, at months 3, 6 and 12, respectively. With a median follow up duration of 12 months, 19 (31%), 20 (32%), and 17 patients (27%) responded to TKI therapy at 3, 6, and 12 months without any difference of ORR among the TKIs (p=0.126, 0.554, 0.721 at 3/6/12 months; Figure A). The CBs were achieved in 47 (76%), 34 (55%), and 23 patients (37%) at 3, 6 and 12 months without any difference of CBs among the TKIs (p=0.187, 0.499, 0.750 at 3/6/12 months; Figure B). Prednisone dose (mg/kg/day) was 0.238±0.03 prior to TKI initiation, 0.177±0.03, 0.173 ± 0.03 and 0.110 ± 0.02 at 3, 6, and 12 months, respectively. No difference was noted in steroid dose among the 3 TKIs at each time point. However, the Ibrutinib group tends to require higher prednisone dose over time than other 2 groups. The FFS at 12 months was higher in Imatinib (71%) or Ruxolitinib groups (67%) than Ibrutinib group (46%; Figure C). The OS rate at 12 months was similar: 100 % in Ruxolitinib and Ibrutinib, and 96% in Imatinib group (Figure D). With regard to those patients treated with TKI for sclerotic GVHD (n= 39), the ORR were 11 (28%), 15 (38%) and 13 (33%) for 3, 6 and 12 months, while CB was noted in 32 (82%), 25 (64%) and 16 patients (41%) at 3, 6 and 12 months respectively. Of interest, Ruxolitinib was as effective as Imatinib in improving PROM score of sclerotic GVHD, while no significant improvement of PROM score was observed in the patients treated with Ibrutinib. Conclusion This retrospective study evaluated the efficacy of TKI drugs for cGVHD treatment in heavily pretreated patients. Ruxolitinib seems as effective as Imatinib to treat sclerotic GVHD. No difference was observed in OS at 12 months; while FFS appears better with Ruxolitinib and Imatinib over Ibrutinib. Figure Disclosures Lipton: Ariad: Consultancy, Research Funding; Pfizer: Consultancy, Honoraria, Research Funding; Takeda: Consultancy, Honoraria, Research Funding; Bristol-Myers Squibb: Honoraria; Novartis: Consultancy, Research Funding; BMS: Consultancy, Research Funding.

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Mesenchymal Stem Cells for Treatment of Refractory Chronic Graft-Versus-Host Disease.

Blood ◽

10.1182/blood.v110.11.4968.4968 ◽

2007 ◽

Vol 110 (11) ◽

pp. 4968-4968

Author(s):

Weng Jianyu ◽

Xin Du ◽

Xiang Peng ◽

Zhang Xiumin ◽

Suijin Wu ◽

...

Keyword(s):

Stem Cells ◽

Mesenchymal Stem Cells ◽

Graft Versus Host Disease ◽

Acute Gvhd ◽

Chronic Gvhd ◽

Immunosuppressive Agents ◽

Steroid Resistant ◽

Host Disease ◽

Graft Versus Host

Abstract Refractory extensive chronic graft-versus-host disease (GVHD) after allogeneic stem-cell transplantation (SCT) is associated with high mortality [Margolis J., SeminOncol 2000].However, conventional therapies including steroids are often unsuccessful in those patients with multiorgan involvement and are associated with significant therapy-related complications and poorly life quality. Mesenchymal stem cells (MSCs) have immunomodulatory effects [Tse WT et al., Transplantation 2003; Spees JI et al.,Proc Natl Acad Sci USA 2003]. Recently MSCs have been given intravenously to treat seven steroid resistant acute GVHD patients and one patient with chronic GVHD. MSCs effects in chronic GVHD is rarely known, although this successfully experience suggests that MSCs have been well tolerated and had a powerful immunosuppressive effects on acute GVHD. [Katarina Le Blanc et al., Lancet 2004; Olle Ringden., Transplantation 2006 ]. Here, we present our experience of using MSCs for treatment of Thirteen patients with refractory chronic GVHD. Between May 2005 and March 2007, thirteen patients (8 male, 5female) with hematological malignancies with a median age of 26(range:15 to 40) years who had received peripheral stem cells from sibling donors. All patients developed steroid resistant or extensive chronic GVHD, with progressive involvement of the skin(13), liver(10), oral mucosa(12),ocular glands(12), and thrombocytopenia (1) when the immunosuppressive agents were taped after five to twenty-four months. The MSC dose was median 1.0 ×106 cells/kg body weight of the recipient. In all, thirteen patients had at least received one dose, seven patients received more than two doses. MSC donors were in seven cases HLA-identical siblings, six unrelated mismatched donors. No side-effects were seen after MSCs infusions. All patients have responded after follow-up of the median time 15 months. One patient with moderate cGVHD had a complete responses, and discontinued all of the immunosuppressive agents without relapse more than 18.4 months after MSC infusion. Three moderate and two patients with severe chronic GVHD improved to mild degree, and six severe turned to moderate degree. Complete resolution was seen in gut(2/3), liver(5/10), skin(5/13), oral(6/12) and eye(2/12). One patient responded in skin, liver, oral mucose and eye, but developed in lung (bronchiolitis obliterans, BO) score of 2 which are considered severe chronic GVHD. Mean follow-up periods was 27m (rang: 14 to48m), Leukemia free survival(LFS)rate were 85%(11/13), and the overall survival (OS)rate were 92.3%(12/13). Our experience suggests that MSC infusion is a safe and effective adjunct therapy for refractory extensive chronic GVHD with resistance to conventional therapy. But more prospective, controlled studies with MSCs for treatment of GVHD should be performanced to evaluate this new treatment exactly.

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Sustained Graft-Versus-Lymphoma Effect among Patients (pts) with Mantle Cell Lymphoma (MCL) Given Nonmyeloablative Allogeneic Hematopoietic Cell Transplantation (HCT).

Blood ◽

10.1182/blood.v112.11.2147.2147 ◽

2008 ◽

Vol 112 (11) ◽

pp. 2147-2147 ◽

Cited By ~ 1

Author(s):

Mohamed L. Sorror ◽

Barry Storer ◽

Brenda M. Sandmaier ◽

Michael Maris ◽

Thomas Chauncey ◽

...

Keyword(s):

Acute Gvhd ◽

Hematopoietic Cell Transplantation ◽

Chronic Gvhd ◽

Progression Free Survival ◽

Median Number ◽

Therapeutic Modality ◽

High Dose ◽

Duration Of Treatment ◽

Autologous Hct

Abstract We previously reported 2-year overall survival (OS) of 65% among 33 pts with MCL given nonmyeloablative HCT (Blood2004; 104: 3535). Here, we update our results on the initial 33 pts with median follow up of 63 months and report on 20 additional pts with emphasis on: long-term disease control and resolution of chronic GVHD. Pts were conditioned with 2Gy TBI with or without fludarabine (90 mg/m2). Median age for all pts was 56 (range 33–75) years and median number of prior regimens was 4. Forty percent of pts had failed high-dose autologous HCT and an additional 11% had planned autologous HCT before allograft (4 pts had refractory disease and 2 were in PR). Comorbidity scores of ≥3 were found among 40% of pts. Forty percent of pts were not in CR/PR at HCT and 26% and 21% had marrow infiltration and lymph node size ≥5 cm, respectively. Donors were related (n=28) or unrelated (n=25). After HCT, incidences of grades II, III, and IV acute GVHD were 25%, 13%, and 9% respectively, and chronic extensive GVHD was 53%. Complete (CR) and partial remissions (PR) were seen in 71% and 3% of pts with measurable disease at HCT, respectively. Estimated 5-year rates of non-relapse mortality (NRM), progression/relapse, OS, and progression-free survival (PFS) were 27%, 22%, 58%, and 52%, respectively (Table 1). Among 19 pts in CR at HCT, 11 are alive and in CR, 7 died in CR, and one relapsed (now in CR after Rituximab and donor lymphocyte infusion). Among 13 in PR at HCT, 10 achieved CR and are alive, one died in PR, and 2 died from relapse. Among 21 pts with refractory/relapsed disease at HCT, 12 achieved CR and are alive, 2 have stable disease and are alive, and 7 relapsed (2 are alive in CR and PR after further treatment). At 5-years, 44% and 14% were alive without or with chronic GVHD requiring immunosuppression (Figure); and median duration of treatment for chronic GVHD was 33 months. Outcomes were comparable among related and unrelated recipients. Relapse rates were 47% vs. 14% among pts with vs. without LN size of ≥5 cm (p=0.02) and NRM was 41% vs.17% (p=0.05) among pts with HCT-CI scores of ≥3 vs. 0–2, respectively. Nonmyeloablative HCT is a potentially curative therapeutic modality for pts with advanced MCL, including patients who were chemotherapy-refractory, with a median PFS beyond 5 years. Sustained remissions and continuing resolution of chronic GVHD were observed with extended follow up. Pts with bulky LN might benefit from further debulking strategies before HCT. Table: Outcomes by donor type Donor Related (n = 28) Unrelated (n = 25) % % Grades III–IV non-hematological toxicities 39/18 38/26 Acute GVHD, grades II/ III/ IV 22/14/7 28/12/12 Chronic GVHD 50 55 CR 73 67 5-year NRM 26 28 5-year Progression/relapse 22 21 5-year PFS 53 51 5-year OS 59 56 5-year Pts alive with chronic GVHD requiring immunosuppression 14 7 Figure Figure

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Outcomes after Double Umbilical Cord Blood Transplantation in Children: A Survey on Behalf of Eurocord and PDWP-EBMT

Blood ◽

10.1182/blood.v124.21.2570.2570 ◽

2014 ◽

Vol 124 (21) ◽

pp. 2570-2570

Author(s):

Federica Giannotti ◽

Annalisa Ruggeri ◽

Gerard Michel ◽

Jean-Hugues Dalle ◽

Tracey O'Brien ◽

...

Keyword(s):

Single Unit ◽

Acute Gvhd ◽

Chronic Gvhd ◽

Univariate Analysis ◽

Median Number ◽

Cell Dose ◽

Gvhd Prophylaxis ◽

Grade Ii ◽

Grade Iii

Abstract Double UCBT (dUCBT) has been used in adults to reach an acceptable cell dose. For most children a single unit with a total nucleated cell (TNC) dose >3x107/Kg can be easily identified, but that is not always the case for heavier patients (pts). Use of dUCBT might decrease relapse and increase graft-versus-host-disease (GvHD). Data on dUCBT in children are scarce in the literature. A recent randomized study in children has described similar outcomes after double compared to single UCBT. Our study provides an overview of the use of dUCBT in the pediatric population reported to Eurocord. We retrospectively analyzed the outcomes of unrelated dUCBT in 177 children transplanted between 2002 and 2012 in 61 EBMT centres. Analysis was performed separately for pts with malignant (n=139) and non-malignant (NM, n=38) diseases. Among pts with malignancies, 76 had ALL, 40 AML, 6 MDS, 2 CML, 11 NHL, 3 Hodgkin Lymphoma and 1 Multiple Myeloma. Median age at dUCBT was 15 years (1.3-17.9) and median weight was 55 kg (13-97). Disease status at dUCBT was 1st complete remission (CR) (36%), ≥2nd CR (34%) or advanced (25%), and missing in 5% of the pts. In this group, 117pts received a myeloablative conditioning (MAC) and 22 a reduced intensity regimen (RIC). Cyclophosphamide+fludarabine+TBI was administered to 41% of the pts; 55% received ATG in the conditioning. Median number of collected TNC was 5.7x107/kg (3,6-12,8). Considering the unit with the higher number of HLA incompatibilities with the recipient, 56% had 2 mismatches. GvHD prophylaxis was cyclosporine-A (CSA) based in 93% of the pts (58% received CSA + mycofenolate mofetil). Median follow-up was 31 months. Cumulative incidence (CI) of neutrophil (PMN) and platelet (PLT) engraftment was 88% at 60 days and 64% at 180 days after dUCBT, and it was achieved with a median time of 24 and 45 days, respectively. Among the 122 pts with PMN engraftment, 85/94 with available data on chimerism were full donor and, of these, 20% had dual chimerism. CI of acute GvHD grade II-IV and grade III-IV at 100 days was 51% and 26%, respectively; it was significantly higher in pts who did not receive ATG (grade II-IV: 35% vs 67%, p=0.004; grade III-IV: 12% vs 37%, p=0.0075). Chronic GvHD was observed in 24/104 pts at risk (60% extensive; 2-year (yr) CI: 18%). The 2-yr CI of relapse was 31%. In univariate analysis, RIC, advanced stage at transplantation and a collected TNC dose lower than the median, were significantly associated with higher rates of relapse.The 2-yr CI of transplant related mortality (TRM) was 27%. Overall, 73 pts died: 35 of relapse, 15 of infections, 9 of GvHD and 14 of other causes. The 2-yr disease free survival (DFS) and overall survival (OS) were 42% and 45%, respectively. Among pts with NM disorders, 24 had bone marrow failure syndrome (BMFS) (10 Fanconi Anemia, 13 Acquired Aplastic Anemia and 1 other inherited BMFS), 2 hemoglobinopathies, 7 immune deficiencies and 5 metabolic disorders. Median age at dUCBT was 11 years (0.7-17.9) and the median weight was 40 kg (13-70). In this group, 27 pts received a RIC (40% TBI based), 10 a MAC (90% busulfan based), and 1 no conditioning regimen. ATG was administered to 82% of the pts and GvHD prophylaxis was CSA-based in 77%. The median number of collected TNC was 8.4x107/kg (1,2-11,2) and 60% of the grafts had ≥2 HLA mismatches with the recipient. Median follow-up was 39 months. Overall, 28 pts achieved PMN engraftment and 16 PLT engraftment, with a median time of 23 and 61 days, respectively. In univariate analysis, pts with BMFS compared to others had a significantly lower CI of PMN engraftment (58% vs 100%, p=0.002). Among the 10 pts who did not engraft, 3 had autologous reconstitution and 3 had a subsequent allogeneic HSCT. Forteen pts developed acute GvHD grade II-IV and 10/25 pts at risk had chronic GvHD (3 extensive). Overall 21 pts died (17 with BMFS): 9 of infections, 5 of GvHD and 7 of other causes. The 2-yr OS was 42% and it was significantly lower in pts with BMFS compared to those affected by other NM disorders (28% vs 70%, p=0.03). In pts with malignancies, despite a higher incidence of acute GvHD, DFS and OS seem to be comparable to those reported in the literature for single UCBT or HSCT from other alternative stem cell sources. In the NM disorders group, despite the high cell dose, dUCBT did not seem to improve results in pts with BMFS. This survey suggests that dUCBT is feasible in children and should be considered when a single unit with an adequate cell dose is not available. Disclosures No relevant conflicts of interest to declare.

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Extracorporeal Photopheresis (ECP) for Acute Graft-Versus Host Disease (GvHD) after Allogeneic Hematopoietic Stem Cell Transplantation (allo-HSCT)

Blood ◽

10.1182/blood.v126.23.5466.5466 ◽

2015 ◽

Vol 126 (23) ◽

pp. 5466-5466

Author(s):

Sandra Eder ◽

Marie-Thérèse Rubio ◽

Ramdane Belhocine ◽

Myriam Labopin ◽

Eolia Brissot ◽

...

Keyword(s):

Immunosuppressive Therapy ◽

Calcineurin Inhibitor ◽

Acute Gvhd ◽

Chronic Gvhd ◽

Median Number ◽

Low Grade ◽

Graft Versus Host ◽

Steroid Dependent ◽

Grade Iii ◽

Steroid Refractory

Abstract Background Graft-versus-host disease (GvHD) is a major limitation after allo-HSCT and remains a frequent cause of death. The 5-years survival is 25% and 5% for grade III and IV, respectively. Acute GvHD occurs in up to 45% of HLA-matched and up to 75% in case of unrelated donors. The standard-treatment consists of methylprednisolone (usually 2 mg/kg/day) and a calcineurin-inhibitor. No standardized second-line treatment for acute GvHD exists. Here, we report a pilot single-centre experience with extracorporeal photopheresis (ECP) for acute GvHD: the objective was to investigate the efficacy of ECP for patients with steroid-refractory/-dependent acute GvHD as well as an early intervention in patients with low-grade acute GvHD to avoid/taper steroids. Furthermore, we evaluated the reduction of immunosuppressive therapy. Patients' characteristics Between 2013 and 2014, 17 patients with acute GvHD (of whom two patients developed GvHD after donor lymphocyte infusion) were treated. Eight patients had a maximum grade of GvHD I/II (2/6 patients) and nine patients were graded as III/IV (6/3 patients). Organ involvement was as follows: skin only in 10, skin and liver in one, skin and gastrointestinal tract in two and all three organs were involved in four patients. Treatment before ECP consisted of topical steroids in one and 0.5 mg/kg methylprednisolone (due to side-effects of calcineurin-inhibitor) in the other patients with grade I. Six patients received 1 mg/kg and eight patients received 2 mg/kg methylprednisolone. One patient was treated with 2 mg/kg methylprednisolone and weekly methotrexate. Before start of ECP, one patient was steroid-free, six patients were steroid-refractory and nine patients were steroid-dependent. Thus, we treated patients with acute GvHD not only for steroid-refractory disease but also steroid-dependent disease and grade I GvHD to avoid a treatment with steroids. Results The median number of ECP sessions per patient was 12 (range, 5 - 36), seven patients received ECP twice a week. Best response to ECP was complete remission in 71%, partial response in 12% and no response in 17%, after a median number of 6 treatments (range, 2 - 9). Response was better for grade I/II: 87.5% received complete remission compared to 56% with grade III/IV, partial response was observed in 12.5% in patients with grade I/II versus 11% with grade III/IV. No responders comprised 33% with grade III/IV and 0% with grade I/II. Immunosuppressive therapy could be tapered successfully: mean reduction of steroids was 95% (range, 60 - 100) and mean reduction of calcineurin-inhibitor was 83% (range, 40 - 100). Six patients developed a rebound of GvHD during tapering (two patients) or after discontinuation (four patients) of ECP. Eleven patients (78%) developed chronic GvHD (two patients with severe grade), whereas it appeared in four patients during tapering of ECP and in seven patients after discontinuation of ECP after a median time of 116 days (range, 30 - 287). We could observe seven bacterial, 14 viral and one fungal infection in 14 patients, which are expected rates after allo-HSCT in patients with acute GvHD. After a median follow up of one year, two patients relapsed from their underlying disease and five patients died (one due to relapse and four due to infections). Conclusion In this single-centre pilot experience, we could show that ECP is an efficient and safe treatment in patients with steroid-refractory or steroid-dependent acute GvHD as well as an upfront-treatment in patients with low-grade GvHD. We were able to taper immunosuppressive therapy with a mean reduction of steroids of 95% and mean reduction of calcineurin-inhibitor of 83%. Best responses were seen in patients with I/II grade GvHD which concludes that ECP should be started as early as possible. Further studies are warranted to investigate a schedule to reduce the risk of rebound of acute GvHD (42% in our cohort) and development of chronic GvHD (78%). Disclosures Mohty: Janssen: Honoraria; Celgene: Honoraria.

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Propensity Score Matching Analysis Comparing Extracorporeal Photopheresis (ECP) Vs Best Available Therapy in Third Line or Later Treatment of Chronic Graft-Versus-Host Disease (cGVHD)

Blood ◽

10.1182/blood-2021-153045 ◽

2021 ◽

Vol 138 (Supplement 1) ◽

pp. 3896-3896

Author(s):

Swe Mar Linn ◽

Igor Novitzky-Basso ◽

Elizabeth Shin ◽

Christopher J. Patriquin ◽

Ivan Pasic ◽

...

Keyword(s):

Risk Factors ◽

Propensity Score ◽

Dose Reduction ◽

Research Funding ◽

Extracorporeal Photopheresis ◽

Prednisone Dose ◽

Steroid Dose ◽

Previous Therapy ◽

Third Line ◽

Over Time

Abstract *DB and DK contributed to the work equally Background Prospective randomized controlled data comparing extracorporeal photopheresis (ECP) to other treatments for chronic graft vs host disease (cGvHD) as third-line or later therapy are limited, despite its clinical benefit observed in patients (pts) who failed ≥ 2 lines of previous therapy. Our single-center experience has reported promising results, including 68.3% failure-free survival (FFS) and 85.9% overall survival (OS) at 12 months in 75 heavily pre-treated cGvHD pts treated with ECP (ASH 2021 Abstract ID 152640). The present study compared outcomes, using propensity-score matching (PSM), between ECP ("ECP group", n=74) and a historical cohort treated with best available therapy (BAT) as third-line or later treatment from 2007 to 2021 ("BAT group", n=132). Statistical endpoints such as FFS and OS, as well as steroid dose reduction were evaluated instead of overall response due to limited response assessment data available from retrospective chart review. Patients and methods The BAT group received MMF (n=71, 53.8%), prednisone (n=37, 28.0%), prednisone/cyclosporine (n=7, 5.3%), rituximab (n=7, 5.3%), and others (n=10, 7.6%). There was an imbalance in characteristics between the two groups, as expected; the ECP group had more pts with severe cGVHD (91.1% vs 20.5%; p<0.001), fewer with a previous history of acute GVHD (aGvHD: 60.8% vs 78.0%; p=0.008), and fewer on a prednisone dose ≥0.5mg/kg/day (37.8% vs. 90.5%; p<0.001). PSM analysis was applied to adjust risk factors imbalanced between groups, including cGVHD grade (mild/moderate vs severe), aGVHD history, and baseline prednisone dose (<0.5 vs. ≥ 0.5 mg/kg/day). A total of 54 pts (27 case-control pairs) were selected via PSM within 0.2 of a calliper difference, resulting in the balancing of risk factors between groups: cGVHD severity (p=0.941), aGVHD history (p=0.75) and prednisone dose ≥ 0.5 mg/kg/day (p=0.788). FFS and OS were calculated from the day of starting ECP or BAT, and were compared using Cox's hazard model. Daily prednisone dose at months 0, 3 and 6 were calculated divided by body weight (kg), and the proportions of pts on prednisone ≤ 0, 0.1, 0.2 and 0.5mg/kg/day were compared. Results In the overall cohort (n=206), with a median 29 months of follow-up, 114 treatment failures (55.3%) occurred. While the non-relapse mortality (NRM) was similar in both groups, the ECP group showed a lower rate of resistance requiring therapy switch. Failure was noted in 27 ECP pts (36.4%) due to causes including resistance/intolerance requiring a switch to other therapy (n=15; 20.3%), NRM (n=11, 14.8%), and relapse (n=1; 1.4%), while 87 failures (65.9%) were noted in BAT pts due to resistance requiring a switch to other therapy (n=63; 47.7%), NRM (n=7; 5.3%), and relapse (n=17; 12.9%). In the overall cohort, the 12-month FFS was 68.3% and 32.0% in ECP and BAT groups (p<0.0001; Fig 1A), while OS was 86.2% and 82.2% in ECP and BAT groups, respectively (p=0.333; Fig 1B). In the PSM cohort (n=54), the ECP group showed a survival benefit at 12 months: FFS was 65.8% in the ECP group vs. 30.5% in the BAT group (p=0.00226; Fig 2A), and OS was 76.6% in the ECP group vs. 67.1% in the BAT group (p=0.0977; Fig 2B). Multivariate analysis in the PSM cohort confirmed that ECP was superior to BAT for FFS (p=0.024, HR 0.317 [0.117-0.859]) when adjusted for other risk factors including cGVHD severity, aGvHD history, age, HCT-CI score and prednisone dose ≤0.5mg/kg/day. Prednisone doses were gradually reduced over time; the median doses of prednisone at months 0, 3, and 6 were 0.35, 0.22 and 0.11 mg/kg/day, respectively, in the ECP group vs. 0.96, 0.24 and 0.19mg/kg/day in the BAT group. ECP also showed better kinetics of steroid dose reduction over time; the proportions of pts who discontinued prednisone at months 0, 3 and 6 were 16.2, 17.6% and 32.4% in ECP group vs. 0.8%, 0% and 2.5% in BAT group (Fig 3). The differences in the proportion of pts (delta) who discontinued prednisone in the ECP vs. BAT groups were 15.4%, 17.6% and 29.9% at 0, 3, and 6 months, respectively. Conclusion In the current study using PSM analysis, use of ECP was associated with a superior FFS to BAT when used as third-line or later therapy in cGVHD patients who failed at least 2 lines of previous therapy. Use of ECP also allowed for better steroid tapering in comparison to BAT. Figure 1 Figure 1. Disclosures Patriquin: Alexion: Consultancy, Honoraria, Speakers Bureau; BioCryst Pharmaceuticals: Honoraria; AstraZeneca: Consultancy, Honoraria, Speakers Bureau; Apellis: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Sanofi: Honoraria. Law: Novartis: Consultancy; Actinium Pharmaceuticals: Research Funding. Lipton: Bristol Myers Squibb, Ariad, Pfizer, Novartis: Consultancy, Research Funding. Mattsson: MattssonAB medical: Current Employment, Current holder of individual stocks in a privately-held company. Kim: Novartis: Consultancy, Honoraria, Research Funding; Paladin: Consultancy, Honoraria, Research Funding; Bristol-Meier Squibb: Research Funding; Pfizer: Honoraria.

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Reduced Intensity Conditioning (RIC) Allogeneic Stem Cell Transplantation (allo-SCT) in Patients with Multiple Myeloma (MM): Long Term Follow-up in a Single Centre Series

Blood ◽

10.1182/blood.v112.11.4398.4398 ◽

2008 ◽

Vol 112 (11) ◽

pp. 4398-4398

Author(s):

Malek Benakli ◽

Redhouane Ahmednacer ◽

Amina Talbi ◽

Farih Mehdid ◽

Rachida Belhadj ◽

...

Keyword(s):

Complete Remission ◽

Median Time ◽

Acute Gvhd ◽

Late Onset ◽

Chronic Gvhd ◽

Conditioning Regimen ◽

Peripheral Blood Stem Cells ◽

Heavily Pretreated ◽

Blood Stem Cells

Abstract Background: RIC allo-SCT has been proposed as a strategy for retaining the graft versus myeloma effect of allo-SCT while decreasing transplant related mortality (TRM). Here, we retrospectively studied a series of 15 patients (pts) with MM treated by RIC allo-SCT. Patients and methods: Between April 2001 and December 2007, 15 pts with MM underwent RIC allo-SCT with an HLA-identical sibling donor. Initially, 8 pts had MM with Ig G, one IgA, 2 light chains, 3 non-secretory and one undetermined. Three pts were stage II and 12 stages III. At time of allo-SCT, 6 pts were in complete remission and 9 in refractory/progressive disease (2 received prior autologous transplants). Median age was 48 years (range, 38–60) and the sex-ratio (M/F) 1,5. Median time from diagnosis to RIC allo-SCT was 18 (range, 6–76) months. The conditioning regimen included Fludarabine 150mg/m2 and Melphalan 140mg/m2. GVHD prophylaxis consisted of association cyclosporine (cSA) and mycophenolate (MMF). All pts received G-CSF mobilised peripheral blood stem cells, with a median CD34+ cell count: 4,5.106/kg (range, 1.92–13). Results: Neutropenia occurred in all pts and the median duration of aplasia was 8 (range, 5–14) days. Only 3 pts (20 %) required red blood cells transfusions and 12 pts (80 %) needed platelets transfusions. Acute GVHD was observed in 6 cases (40 %) including 4 cases of grade II–IV. Eight pts (72 %) had chronic GVHD, of whom 5 with an extensive form. Three pts (20 %) had CMV reactivation at a median time 91 (range, 53–158) days after transplantation. Four pts (26 %) had late onset relapse at a median time of 826 (range, 248–1370) days. TRM was 33 % at one year after RIC allo-SCT. With a median follow-up of 50 (range 14–86) months, 5 pts (33 %) are still alive in complete remission with full donor chimerism. Ten pts (66 %) died (2 early severe infections, 3 acute GVHD, 3 after relapse, one myocardial infarction, and one public highway accident). Overall and progression-free survivals at 7 years are 37,5 % and 31,2 % respectively. Conclusion: This study suggests that RIC allo-SCT is a potential therapy for relapsed MM. However, TRM and relapse remain a matter of concern, likely due to the inclusion of refractory and heavily pretreated pts with many comorbid conditions. Future protocols, should aim for better patient selection, focussing on those pts in first chemosensitive relapse.

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Busulfan/Fludarabine/Thymoglobulin as a Reduced Intensity Conditioning Regimen for Lymphoid Malignancies.

Blood ◽

10.1182/blood.v114.22.3335.3335 ◽

2009 ◽

Vol 114 (22) ◽

pp. 3335-3335

Author(s):

Jeevan Sekhar ◽

Keith Stockerl-Goldstein ◽

Qin Zhang ◽

Amanda F Cashen ◽

Camille N. Abboud ◽

...

Keyword(s):

Median Time ◽

Acute Gvhd ◽

Chronic Gvhd ◽

Median Number ◽

Cell Transplant ◽

Single Institution ◽

Reduced Intensity Conditioning ◽

Prior Therapy ◽

Lymphoid Malignancies ◽

Reduced Intensity

Abstract Abstract 3335 Poster Board III-223 Introduction Over the last decade there has been an increase in the use of reduced intensity conditioning (RIC) regimens to mitigate transplant related toxicity while maintaining graft viability and maximizing the graft versus disease effect. There is an abundance of data on busulfan (Bu) based RIC for myeloid malignancies; however, there is a paucity of data on Bu based RIC regimen for allografting in lymphoid malignancies. We conducted a retrospective analysis of a large cohort of patients treated at a single institution who were transplanted using a uniform RIC regimen of Bu/Fludarabine (Flu)/Thymoglobulin (Thymo) for a variety of lymphoid neoplasms. Methods We identified 40 patients (pts) who were transplanted for lymphoid malignancies between 2004 and 2008 using the RIC regimen of Bu 0.8 mg/kg q6 hrs x 8 doses on d-4 and d-3, Flu 30 mg/m2 IV daily on days -7 to -3, and Thymo 2 mg/kg x 4 doses on d-4 to d-1. Graft versus host disease (GVHD) prophylaxis consisted of tacrolimus (0.03 mg/kg starting d-2)/methotrexate (5mg/m2 on d+1, 3, 6, 11)/mycophenolate (15mg/kg bid starting d-2) in 34 pts (85%), tacrolimus/methotrexate in 5 patients (12.5%), cyclosporine/mycophenolate/methotrexate in 1 pt (2.5%). Chimerism analysis was done on days +30, 90, 180, and 365. Demographics Median age was 54 (range 35-65) years; males 26 (65%) and females 14 (35%); CLL/SLL 22 (55%), non-Hodgkins lymphoma 15 (37.5%) and transformed lymphomas 3 (7.5%). Median number of lines of therapy prior to transplant was 4 (range 0-12). 12 pts (30%) were refractory to initial therapy (less than a PR). 15 pts (37.5%) had received prior radiation therapy (XRT). 12 pts (30%) had undergone a prior autologous stem cell transplant (ASCT). 22 pts (55%) had chemo-sensitive disease at the time of transplant, and 18 (45%) had disease refractory to their pre-transplant regimen. The donor was related (RD) in 10 pts (25%) and unrelated (URD) in 30 pts (75%). The graft source was peripheral blood for 36 pts (90%) and bone marrow in 4 pts (10%). Median number of CD34+ cells infused was 7.9×10 6 (range, 1.1-17.9) /kg recipient body wt. Results Median time to absolute neutrophil count recovery was 12 (0-21) days. Median time to platelet recovery was 18 days (9-57 days). Median time to 100% donor chimerism was 39 (24-321) days. After a median follow-up of 25.8 (0.87-48.9) months, Kaplan-Meier estimates of median overall survival (OS) and progression-free survival (PFS) were 11.3 months and 9.9 months, respectively. The 2-yr OS and PFS were both 44%. We performed an analysis of the effects of histology, number of lines of prior therapy, prior XRT, prior ASCT, disease status at time of transplant, and graft source (URD vs RD) on OS and PFS (Table 1). Non-relapse mortality (NRM) at 100 days, 1 year, and 2 years was 8% (95% CI, 3-22%), 33% (95% CI, 20-52%), and 41% (95% CI, 26-60%), respectively. Acute GVHD was seen in 19 pts (48%) with Grade III/ IV acute GVHD in 9 pts (23%). Chronic GVHD was seen in 17 pts (43%), limited in 5 pts (13%), extensive in 12 pts (30%). Acute GVHD was more common among pts receiving URD vs RD transplants (35% vs. 13%, p=0.016), but incidence of chronic GVHD did not differ between these two cohorts. Conclusion This analysis represents the largest single institution experience using the RIC regimen of Bu/Flu/Thymo in lymphoid malignancies. Our results demonstrate that this Bu based RIC regimen can successfully be used to allograft heavily pre-treated patients with lymphoid malignancies, with prompt and durable engraftment and relatively low early NRM. In this patient population, OS and PFS were not significantly associated with lymphoma histology, prior therapy, or chemosensitivity. Disclosures DiPersio: Genzyme Corp.: Honoraria. Vij:Otsuka Pharmaceuticals: Research Funding.

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Treatment of Relapsed and Refractory Acute Myeloid Leukemia with a Salvage FLAG-IDA Chemotherapy Regimen Followed by a HLA Matched Related Allogeneic PBSC Infusion without Additional Conditioning.

Blood ◽

10.1182/blood.v110.11.5050.5050 ◽

2007 ◽

Vol 110 (11) ◽

pp. 5050-5050 ◽

Cited By ~ 1

Author(s):

Mammen Chandy ◽

Vikram Mathews ◽

T. Rajasekar ◽

Auro Viswabandya ◽

Kavitha M. Lakshmi ◽

...

Keyword(s):

Stem Cell ◽

Median Time ◽

Low Dose ◽

Acute Gvhd ◽

Chemotherapy Regimen ◽

Chronic Gvhd ◽

Median Number ◽

Salvage Chemotherapy ◽

Cell Dose ◽

Refractory Aml

Abstract The clinical outcome of relapsed and refractory AML is dismal. Attempts in this setting to induce a remission, prior to an allogeneic SCT, are frequently frustrated by either failure to respond to chemotherapy or deterioration in the clinical status post chemotherapy. Since December 2005, patients with relapsed and refractory AML were offered salvage chemotherapy with a FLAG-IDA regimen (consisted of G-CSF 10mcg/kg/day starting day −1, Fludarabine 30 mg/m2 x 5 days, Cytosine 2gm/m2 x 5 days and Idarubicin 10mg/m2 x 3 days). On day 10 of chemotherapy a G-CSF mobilized PBSC harvest from a complete HLA matched related donor was infused, targeting a cell dose of 5 x 108 MNC/kg. GVHD prophylaxis consisted of low dose cyclosporine (1.5 mg/kg/day) ± short course low dose methotrexate. Eleven patients were treated with this regimen. The median age was 40 years (range: 2 – 51). There were 7 (64%) males. There were 6 relapsed cases (5 relapse-1 and one relapse-2) and 5 primary refractory cases. Of the relapsed cases, two had relapsed following a prior allogeneic SCT. Among the patients with relapsed AML, the median number of chemotherapy cycles prior to transplant was 3 (range: 2 – 5) and the median time to transplant from relapse was 5 months (range: 5 – 10). Among the 5 refractory patients, the median number of chemotherapy regimens received prior to transplant was 2 (range: 1 – 3) and the median time from diagnosis to transplant was 3 months (range: 1 – 6 months). The median number of bone marrow blasts pre-transplant was 38% (range: 5 – 70). Five cases had an ECOG performance score of 0–1 while 4 had an ECOG score of 2 and 2 had an ECOG score of 3. Salvage FLAG-IDA chemotherapy regimen was well tolerated in all cases. The median cell dose infused on day 10 was 6.59 x 108 MNC/kg (range: 3.5 – 12.73). All but one patient engrafted with a median time to ANC > 500/mm3 of 13 days (range: 9 – 21) post stem cell infusion and Platelet count > 20,000/mm3 of 12 days (range: 9 – 17). One patient failed to engraft and died on day 9 secondary to a fungal pneumonia. Nine patients achieved a complete donor chimerism on day +30 post stem cell infusion. Six (55%) developed grade 2–4 acute GVHD while 2 (18%) developed grade 3–4 acute GVHD. Six of eight who could be evaluated developed chronic GVHD, all had extensive chronic GVHD. Four patients relapsed following transplant at a median of 118 days post transplant (range: 26 – 140). At the time of this analysis 5 (45%) patients are alive and in remission at a mean follow up of 278 days (range: 119 – 551). Of the remaining 6 patients, 4 relapsed and died, 1 died prior to engraftment from a fungal pneumonia and one patient died in remission from an acute cardiac event. FLAG-IDA salvage chemotherapy followed by an allogeneic PBSC graft infusion on day 10 is a reasonable option to consider for patients in this clinical situation.

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Tandem Auto-Allo in Acute Myeloid Leukemia (AML) Patients in First Complete Remission (CR).

Blood ◽

10.1182/blood.v114.22.3355.3355 ◽

2009 ◽

Vol 114 (22) ◽

pp. 3355-3355

Author(s):

Luca Castagna ◽

Sabine Furst ◽

Thomas Prébet ◽

Jean El Cheikh ◽

Aude Charbonnier ◽

...

Keyword(s):

Stem Cell ◽

Cause Of Death ◽

Relapse Rate ◽

Acute Gvhd ◽

Prognostic Score ◽

Chronic Gvhd ◽

Median Number ◽

Prognostic Scores ◽

High Dose

Abstract Abstract 3355 Poster Board III-243 Background. High and intermediate risk AML can benefit by allogeneic stem cell transplantation in first CR. The use of reduced intensity conditioning regimens (ALLO-RIC) decreases the toxicity even if the relapse rate is more pronounced. To contrast the high relapse rate we hypothyzed that if a better quality of remission could be achieved, the relapse incidence could be lowered. Patients and methods. From 2001 to 2008, 31 AML patients in first CR received a tandem auto-allo program. The median number of white blood cell was 3 × 10e9/l (range 0.9-235), 13% of patients have extramedullary localisations. In 13% AML was secondary to previous CT treatment. Cytogenetic was abnormal in 36% of pts. After one or two induction chemotherapies (CT), all but two patients received a consolidation course with high-dose cytarabine (HD-ARAC) CT, followed by autologous stem cell harvest. Then, HD melphalan (HD-PAM 140 mg/m2) followed by autologous stem cells reinfusion was administered, followed by ALLO-RIC. RIC consisted of fludarabine plus (2 Gy) TBI (3 pts) or fludarabine, oral or intravenous busulfan (8 mg/kg) in two days, and anti thymocyte globulin (2.5 or 5 mg/kg). Graft versus host disease (GVHD) prophylaxis was cyclosporine (CyA) plus mycofenolate mofetil (3 pts) or CyA alone (28 pts). Donors were all but one HLA identical sibling. The median number of allogeneic CD34+ and CD3+ cells was 6.1 × 10e6/Kg (range 1.9-11) and 315 (range 166-609). Prognostic scores (HCT-CI, PAM, EBMT) were retrospectively calculated for each patient. All pts have a performance status ≥ 90%. Results. The median follow-up was from diagnosis and ALLO-RIC 40 and 34 months, respectively. The median time between last CT and HD-PAM was 51 days (range 30-77) and HD-PAM and ALLO-RIC was 69 days (55-176). Treatment related mortality after HD-PAM was null. Prognostic scores were: HCT-CI score 0-2= 53% (16 pts), ≥3= 47% (14 pts), 1 pt not evaluable; PAM score 9-16= 30% (10 pts), 17-23= 67% (19 pts), 24-30= 3% (1 pt); EBMT score 1= 9% (3 pts), 2= 78% (24 pts), 3= 13% (4 pts). At last follow-up, 42% of pts (n= 13) died: 5 due to disease relapse and 8 because of toxicity. Grade II-IV acute GVHD and chronic GVHD incidence were respectively 26% and 65% (extensive 84%). GVHD was the cause of death in seven pts. Six pts (19%) reactived CMV, without disease, and 1 pt not survived to an interstitial pneumonitis. The 5-year overall survival (OS), relapse free survival (RFS), and 1-year TRM were 60%, 60%, and 15%, respectively. In multivariate analysis, prognostic scores did not influence TRM and OS. Conclusions. This report showed that i) tandem auto-allo is feasible in AML pts; ii) acute GVHD incidence is not increased iii) prognostic score did not impact on TRM and survival; iv) the TRM is quite low with GVHD as main cause of death. A retrospective comparison with a cohort of pts not receiving HD-PAM is on going. Disclosures: No relevant conflicts of interest to declare.

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