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)

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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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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Patterns Of Non-Hematological Adverse Effects In Patients With Chronic Myeloid Leukemia In Chronic Phase (CML-CP) Treated With Ponatinib – Experience At a Single Institution

Blood ◽

10.1182/blood.v122.21.4019.4019 ◽

2013 ◽

Vol 122 (21) ◽

pp. 4019-4019 ◽

Cited By ~ 1

Author(s):

Preetesh Jain ◽

Hagop M. Kantarjian ◽

Carlos Guillermo Romo ◽

Alfonso Quintas-Cardama ◽

Elias Jabbour ◽

...

Keyword(s):

Risk Factors ◽

Adverse Effects ◽

Dose Reduction ◽

Research Funding ◽

Skin Toxicity ◽

Qtc Prolongation ◽

Single Institution ◽

Dry Skin ◽

Starting Dose ◽

Grade 3

Abstract Introduction Ponatinib is a multi-targeted tyrosine kinase inhibitor (TKI) efficacious in pts with refractory CML. Ponatinib inhibits other tyrosine kinases (e.g. RET, FGFR, FLT3) that may lead to off target adverse effects (AE). We report a single-institution experience of frequencies of non-hematological AE among pts on therapy with ponatinib. Methods A total of 90 pts with CML-CP[49 relapsed refractory (RR), 41 frontline] treated at our institution on clinical trials with ponatinib were analyzed. AE were recorded on each pt visit and charts were reviewed for AE and risk factors. Results For RR pts (n=49)the starting dose of ponatinib was 45 mg in 42 (86%) pts. 39 (80%) had dose interruptions, due in 17 (44%) to grade 3 thrombocytopenia and in 22 (56%) to non-hematological AE (elevated pancreatic enzymes 7 pts of whom 5 had pancreatitis; body aches and headache 7; hypertension 7; skin toxicity 5; fatigue 5). 35 pts (71%) had dose reduction to 30 or 15 mg. Hypertension (H.T.) stage 2 (≥160/100 mm Hg) occurred in 15 (31%) pts; only 2 of new onset. Blood pressure was controlled in all with antihypertensives. Other cardiovascular AE included QTc prolongation in 1 pt, atrial fibrillation in 1 pt, acute myocardial infarction in 3, venous thrombosis in 3, arterial thrombosis in 4, transient ischemic attack (TIA) in 1 and Raynaud’s in 1. No pt discontinued ponatinib due to cardiovascular AE’s. Symptomatic pancreatitis developed in 8 pts (16%). Grade 3/4 elevations in serum lipase and amylase occurred in 12 (24%) pts and 2 (4%) pts respectively. Median days to onset of pancreatitis was 24 (range 7-456). 27 pts (55%) developed cutaneous toxicity including xerosis/dry skin in 10 (37%) and grade 3 erythroderma and exfoliation of the skin in 5. Four pts died, none related to ponatinib. 13 pts went off the study: 5 went to SCT, 3 progressed, 1 pt died in CCyR of multiple co-morbidities, 1 pt had progressive melanoma, 1 pt was transferred to another hospital, and 2 for ponatinib-related AE (headache in 1 and headache, fatigue, depression, and abdominal pain in 1). For pts in frontline setting (n=41) the starting dose was 45 mg in all. 29 pts (71%) had dose interruptions due to one or more of the following: grade 3/4 pancreatic enzyme elevation in 16, myelosuppression in 4, and various non-hematological AE in 15 (skin toxicity in 4, fatigue in 2, headache in 1, chest pain in 2, elevated liver enzymes in 2, suspected seizure vs. TIA in 1, grade 3 diarrhea in 1, memory disturbances in 1, and grade 3 hypertension in 1, erectile dysfunction in 1). 24 pts (59%) had dose reduction, from 45 mg to 30 mg in 20 pts and then to 15 mg in 4 pts. H.T. stage 2 occurred in 3 (7%) pts usually among patients with pre-existing H.T. Other cardiovascular AE included grade 2 QTc prolongation in 1 pt, possible TIA vs. possible seizure in 1, and Raynaud’s in 2. Pancreatitis was seen in 12 pts (29%) with grade 1-2 and 6 pts (15%) with grade 3/4. Grade 3/4 lipase/amylase elevations occurred in 16 (39%) and 3 (7%) pts. Median days to the onset of pancreatitis were 6 (4-22). 34 pts (83%) developed skin toxicity with rash (any grade) in 25 pts (61%), xerosis/dry skin in 18 pts (44%) and grade 3 erythroderma and skin exfoliation in 2 (pts may have had ≥1 type of skin AE). 2 pts discontinued therapy, due to severe xerosis in 1 and recurrent gra 4 neutropenia in another. 1 pt developed grade 2 pericarditis possibly related to ponatinib. For all the 90 pts, risk factors for cardiovascular and pancreatic toxicities included 20 (22%) smokers, 2 heavy alcohol consumers, 27 (30%) obese (BMI ≥30 Kg/m2), 30 (33%) with hypertriglyceridemia, 17 (19%) had hypercholesterolemia and 10 pts were receiving lipid lowering therapies. Conclusions Ponatinib is generally well tolerated and AEs can usually be properly managed. AE are more common in RR pts with greater frequency of hypertension, cardiovascular complications, headache, dry mouth and dose interruptions. Most pts are able to continue therapy after dose adjustments. Disclosures: Kantarjian: ARIAD: Research Funding. Cortes:Ariad, Pfizer, Teva: Consultancy; Ariad, BMS, Novartis, Pfizer, Teva: Research Funding.

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ABL Tyrosine Kinase Inhibitors (TKIs) Are Associated with Increased Rho-Associated Kinase (ROCK) Activity That May Contribute to Vascular Toxicity in Patients with Chronic Myeloid Leukemia (CML)

Blood ◽

10.1182/blood-2018-99-111201 ◽

2018 ◽

Vol 132 (Supplement 1) ◽

pp. 1739-1739

Author(s):

Afaf Osman ◽

Brian Yu ◽

Nancy Glavin ◽

Tamar S. Polonsky ◽

James K. Liao ◽

...

Keyword(s):

Risk Factors ◽

Cardiovascular Risk ◽

Cardiovascular Risk Factors ◽

Clinical Studies ◽

Research Funding ◽

Total Duration ◽

Vascular Toxicity ◽

Downstream Target ◽

Rock Activity ◽

Over Time

Abstract Introduction The use of 2nd or 3rd generation ABL TKIs in patients with CML is associated with vascular toxicity, including peripheral arterial occlusive disease and cardiovascular and cerebrovascular events. However, Imatinib, a 1st generation TKI, has not been shown to increase risk of cardiovascular events (Douxfils J et al. JAMA Oncol 2016;2:625). Therefore, there is a need to identify risk factors and predictors of vascular toxicity for patients receiving these TKIs. In mice, inhibition of the Abl kinases results in activation of Rho and its downstream target Rho kinase (ROCK) (Zandy et al. Proc Natl Acad Sci USA 2007;104:17686). Growing evidence suggests that elevated ROCK activity plays a central role in the pathogenesis of cardiovascular disease and stroke in both animal and clinical studies. TKIs used in CML are potent inhibitors of ABL1 and ABL2 kinases. We hypothesized that CML patients receiving 2nd or 3rd generation BCR/ABL1 TKIs have higher ROCK activity than patients not receiving these TKIs, providing a putative mechanism for the vascular toxicity observed in clinical studies. Methods We measured leukocyte ROCK activity in CML patients and analyzed results based on their last TKI dose. We isolated fresh peripheral blood leukocytes from 38 patients (17 females, 21 males) with a median age of 53 years (range, 24-90 years). 4 patients had newly diagnosed untreated CML at the start of the study. One male was receiving Dasatinib for Ph+ ALL and was also included. ROCK activity was assessed in leukocytes by measuring the ratio of phospho-myosin-binding subunit (p-MBS) on myosin light-chain phosphatase, a downstream target of ROCK, to total MBS using an automated Western blotting system (Wes, ProteinSimple, San Jose, CA) (Hata T et al. Atherosclerosis 2011; 214:117). Each patient had 1-6 measurements of leukocyte ROCK activity over 1 - 18 months (n=78 measurements). Information about cardiovascular risk factors, concomitant medications, CML status, and total duration of TKI therapy was collected. For patients with multiple samples over time, ROCK activity was calculated as the mean of all samples taken while receiving the same TKI. Patients in treatment-free remission (TFR) were considered off-TKI, but those in TFR < 1 month were excluded from the analysis to reduce potential confounding effects. Results We analyzed blood samples from 4 untreated CML patients, 8 while in TFR, and 31 who were actively receiving one of the 5 TKIs (7 Imatinib, 12 Dasatinib, 9 Nilotinib, 2 Ponatinib, 1 Bosutinib). 3 patients developed acute coronary syndrome during the study and required coronary revascularization for myocardial infarction. We found no significant difference in ROCK activity when comparing all patients receiving TKIs to those not receiving TKIs. However, we found higher leukocyte ROCK activity when comparing all patients receiving 2nd and 3rd generation TKIs to those not receiving any TKI (Welch's t test, mean leukocyte ROCK activity 1.00 ± 0.06 vs 0.80 ± 0.06; p=0.03). We also found higher leukocyte ROCK activity when comparing patients receiving Dasatinib to patients receiving Imatinib (mean leukocyte ROCK activity 1.05 ± 0.09 vs 0.75 ± 0.10; p=0.04). The comparison of Imatinib to all 2nd and 3rd generation TKIs was not significant (p=0.06). Conclusions We found that patients on 2nd and 3rd generation TKIs have higher leukocyte ROCK activity compared to those not receiving TKIs, and higher leukocyte ROCK activity in patients on Dasatinib compared with patients receiving Imatinib. These results are consistent with the known lower-risk of cardiovascular side-effects observed with Imatinib in comparison to the next generation ABL TKIs. Limitations include small sample size and heterogeneity in the patient population in terms of age, cardiovascular risk factors, specific TKI used, and total duration and sequencing of TKI agents. The study continues to accrue CML subjects in order to follow individual patients over time on TKI therapy. Disclosures Larson: Ariad/Takeda: Consultancy, Research Funding; BristolMyers Squibb: Consultancy, Research Funding; Novartis: Consultancy, Research Funding; Pfizer: Consultancy, Research Funding.

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MELISSE, a Large Multicentric Observational Study to Determine Criteria and Risk Factors of Thromboembolism for Patients with Multiple Myeloma Treated with Immunomodulator Drugs

Blood ◽

10.1182/blood.v116.21.809.809 ◽

2010 ◽

Vol 116 (21) ◽

pp. 809-809

Author(s):

Xavier Leleu ◽

Laurent Daley ◽

Philippe Rodon ◽

Cyrille Hulin ◽

Ahmad AL Jijakli ◽

...

Keyword(s):

Risk Factors ◽

Multiple Myeloma ◽

Research Funding ◽

Vascular Complications ◽

Vte Prophylaxis ◽

Line Therapy ◽

Risk Patients ◽

Data Missing ◽

Third Line ◽

Line Of Therapy

Abstract Abstract 809 Background. Immunomodulator drugs (IMiDs) are new and very promising oral agents for initial treatment and for treatment of relapse in Multiple Myeloma (MM); however, IMiDs are also associated with an increased risk of venous thromboembolism (VTE) which necessitates routine prophylaxis. Guidelines (Palumbo et al, Leukemia 2008) have proposed either aspirin or low weight molecular heparin (LWMH) for VTE prophylaxis based on a VTE risk stratification. Controversies remain regarding the best choice of VTE prophylaxis regimen in MM patients treated with IMiDs-based therapy and the criteria for the VTE risk definition. More studies are needed to better determine the criteria required for patients to receive either aspirin or LWMH as VTE prophylaxis. We designed a large multicentre observational study aimed at prospectively evaluating the incidence and risk factors of thromboembolism associated with IMiDs [either lenalidomide (Len) or thalidomide (Thal)] therapy in MM. Method. A total of 519 patients with MM treated with first to third line of therapy were included in this study. Patients were treated with IMiDs-based therapy at entry in the study, and those receiving VTE prophylaxis had to start this prior to start IMiDs (the choice was solely that of the clinician). Patients gave written informed consent according to the declaration of Helsinki. Various patient characteristics were recorded, such as age, sex, criteria of vascular complications, including adjuvant treatment such as EPO, bisphosphonates, radiotherapy, and previous history of either deep venous thrombosis (DVT) or pulmonary embolism (PE), or arterial vascular complications. The physicians were to record the risk of VTE occurrence, breakdown as low, mild and high, based on guidelines and their own appreciation of the risk. Occurrence of any thrombosis event (either venous or arterial) was to be recorded along with the descriptive characteristics of the event, how the event was managed and the outcome of the patient. The data were collected at entry in the study, and then at 4 and 12 months. Results. Out of the 519 patients, 35.66% had Thal-based and 64.34% had Len-based therapy. Overall, median age was 71, with 64.67% >65 years old and sex ratio was 249 male/268 female, similar in the 2 groups (data missing for n=2). One hundred and eighty patients were in first line therapy, 169 in second line therapy and 153 in third line therapy (data missing for n=17). Patients were treated with VTE prophylaxis as follow (data missing for n=8); 293 (57.34%) aspirin, 91 (17.81%) LWMH and 46 (9.00%) vitamin K antagonists. Surprisingly, 81 (15.85%) patients had no VTE prophylaxis. Aspirin was administered in 164 (69.79%) of low risk patients and LWMH in 33 (45.83%) of high risk patients. Investigators recorded 13 (3.65%) VTE at the 3564-months visits currently completed, with 7 DVT, 2 PE and 4 DVT+PE. Of these 13 VTE, 8 patients had aspirin, 1 had LWMH and 4 had no prophylaxis treatment. Of the 13 VTE, 1 patient was considered to have high risk of vascular complication and 12 patients either low or moderate risk, according to guidelines. The occurrence of VTE was unrelated to the regimen-based IMiD therapy and the line of therapy. Conclusion. This study further demonstrates that occurrence of VTE is low in IMiDs-based treated MM patients upon VTE prophylaxis, and that VTE prophylaxis is needed for patients treated with IMiDs-based therapy. However, despite VTE prophylaxis, we observed occurrence of VTE. These results question whether the current guidelines on VTE prophylaxis in MM patients treated with IMiDs-based therapy are accurate. Final results will be proposed with updated results at ASH 2010. Disclosures: Leleu: Celgene: Consultancy, Research Funding; Janssen Cilag: Consultancy, Research Funding; Leo Pharma: Consultancy; Amgen: Consultancy; Chugai: Research Funding; Roche: Consultancy, Research Funding; Novartis: Consultancy, Research Funding. Daley:LEO Pharma: Employment. Lamblin:LEO Pharma: Employment. Natta:LEO Pharma: Employment.

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Single Centre, Retrospective Analysis of Extracorporeal Photopheresis (ECP) Therapy in the Patients Who Are Heavily Pre-Treated for Steroid Resistant Chronic Graft-Versus-Host Disease (GVHD)

Blood ◽

10.1182/blood-2021-152640 ◽

2021 ◽

Vol 138 (Supplement 1) ◽

pp. 1806-1806

Author(s):

Swe Mar Linn ◽

Igor Novitzky-Basso ◽

Christopher J. Patriquin ◽

Ivan Pasic ◽

Wilson Lam ◽

...

Keyword(s):

Factor Analysis ◽

Prognostic Factor ◽

Clinical Benefit ◽

Research Funding ◽

Chronic Gvhd ◽

Treatment Modalities ◽

Extracorporeal Photopheresis ◽

Single Centre ◽

Steroid Dose ◽

Line Infection

Abstract *DB and DK contributed to the work equally. Background Extracorporeal photopheresis (ECP) is a recommended second or later line of therapy for chronic GVHD (cGVHD), and is beneficial not only because of increased response but also for its lack of adverse effects, specifically systemic immune suppression, mainly from steroids. In this single centre study, we attempted to evaluate not only therapeutic efficacy of ECP, but also its steroid-sparing effect by regularly analyzing steroid dose per body weight. We also attempted to identify any predictors of response or survival after ECP, which was not well defined before. Patients and methods A total of 75 cGVHD patients (pts) who received ECP for cGVHD from 2007 to 2021 at Princess Margaret Cancer Centre were included and evaluated retrospectively. Patients and disease characteristics are as follows: median age 48.5 years (range 17-70); male 42/75 (56%); organ involvement at the time of ECP: skin (93%), oral (53%), eye (51%), gastrointestinal (25%), liver (49%), lung (57%), and musculoskeletal (n=50, 67%). Sixty-eight (91%) and 7 pts (9%) had severe and moderate grade cGVHD, respectively. Sixty-eight pts (91%) received ECP as 4 th line or beyond. They were heavily pretreated with prednisone (98%), cyclosporine (57%), tacrolimus (24%), mycophenolate mofetil (64%), azathioprine (65%), rituximab (7%), imatinib (8%), ibrunitib (3%) and ruxolitinib (1%). ECP was started twice weekly for the first 12 weeks, then twice every 2 weeks in 2012-2021, while the schedule was twice every 2 weeks from 2007-2012. If there was no response or clinical benefit noted in first 24 treatments, then ECP was discontinued. In general, we attempted to provide up to around 60 sessions based on the clinicians' discretion. The overall response rate (ORR) and clinical benefit (CB) were assessed at months 3, 6 and 12 after staring ECP. As part of standard clinical practice, NIH consensus criteria were used for grading and response assessment. CB was assessed considering clinical response as well as steroid dose reduction. Treatment failure was defined as 1) resistance to ECP requiring treatment switch, 2) non-relapse mortality (NRM), 3) relapse, 4) intolerance to ECP. Failure free survival (FFS) and overall survival (OS)were calculated from the day of ECP initiation until the endpoints of failure or death, respectively. Results ECP was started a median of 28 months (range 1-125) after development of cGVHD. ECP was performed a median of 35 times (range 6-174) with a median duration of 11 months (range 1-53). Out of 75 pts, 48 completed planned ECP successfully and 27 stopped due to no response or benefit including, of whom 14 required additional therapy, 1 stopped due to line infection, and 1 stopped due to relapse of AML. With a median 72 months of follow-up, ORR was attained in 21% (16/75), 57% (36/63) and 70% (32/46) at month 3, 6 and 12, respectively. At 6 months, ORR was observed in 47-64% across all organs assessed. No difference in ORR was noted according to the cGVHD grade; at 6 months, severe cGVHD showed similar ORR (57%) to those with moderate cGVHD (60%) (p=0.893). CB was noted in 23% (17/75), 62% (39/63), and 76% (35/46) at month 3, 6 and 12, respectively. A total of 27/75 failures (36%) and 20/75 death (27%) occurred, due to the following: ECP resistance requiring switch to other therapy (n=14, 19%), NRM (n=11, 15%), relapse of primary disease (n=1, 1%) or ECP-related complication (n=1, 1%, line infection). In the overall cohort, FFS and OS at 12 months were 68.3% and 85.9%, respectively (Figure 1). More than a half of pts stopped steroids completely within 12 months after starting ECP. The proportion of pts off steroids was 16%, 17%, 32%, and 64% at month 0, 3, 6 and 12 after starting ECP, respectively (Figure 2). Risk factor analysis did not show any predictive markers for ORR at 6 months, while prognostic factor analysis suggested the development of musculoskeletal involvement as favorable prognostic factor for FFS (p=0.003, HR 0.315 [0.147, 0.673]) even with multivariate analysis. Conclusion Our study showed that: 1) ECP is a very effective treatment for heavily pre-treated cGVHD pts who have failed other therapies; 2) More than a half of pts can stop steroids completely within 12 months after starting ECP, thus avoiding long-term toxicity risk. Further study is warranted comparing ECP with other cGVHD treatment modalities. Figure 1 Figure 1. Disclosures Patriquin: BioCryst Pharmaceuticals: Honoraria; Alexion: Consultancy, Honoraria, Speakers Bureau; 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: Paladin: Consultancy, Honoraria, Research Funding; Bristol-Meier Squibb: Research Funding; Pfizer: Honoraria; Novartis: Consultancy, Honoraria, Research Funding.

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Risk Factor Analysis for the Development of Large Granular Lymphocytosis after Allogeneic Hematopoietic Cell Transplantation: Randomized Stratification and Propensity Score Analysis

Blood ◽

10.1182/blood.v126.23.1945.1945 ◽

2015 ◽

Vol 126 (23) ◽

pp. 1945-1945

Author(s):

Marc Poch Martell ◽

Elizabeth Shin ◽

Jieun Uhm ◽

Fotios V. Michelis ◽

Auro Viswabandya ◽

...

Keyword(s):

Risk Factors ◽

T Cell ◽

Propensity Score ◽

Propensity Score Matching ◽

Research Funding ◽

Hematopoietic Cell Transplantation ◽

Chronic Gvhd ◽

Allogeneic Hct ◽

Chronic Antigenic Stimulation ◽

Donor Type

Abstract Introduction Large granular lymphocytes (LGL) are a morphologically recognizable subpopulation of lymphocytes comprising an immunophenotypically heterogeneous population of activated CD3+ T cells and CD3- natural killer (NK) cells that mediate non-MHC-restricted cytotoxicity. Increased number of circulating LGL can be found as a response to viral infections, autoimmune disease or malignant neoplasms, as a result of chronic antigenic stimulation. Of interest, LGL lymphocytosis has been reported to occur following hematopoietic cell transplantation (HCT), with a variable incidence of up to 20%. This population display improved transplant outcomes with a lower incidence of non-relapse mortality and relapse (Kim, BMT, 2013; Nann-Rütti, BBMT, 2012). The aim of the present study is to determine the risk factors associated with the development of LGL lymphocytosis after allogeneic HCT. Methods A total of 826 patients who underwent an allogeneic HCT at Princess Margaret Cancer Centre, Toronto, Canada from 2000 to 2012 were retrospectively analyzed. LGL lymphocytosis was defined as the presence of at least two of the followings: 1) Sustained peripheral blood lymphocyte count ≥3.0 x 109/L observed in at least three consecutive determinations over a period of 2-3 months; 2) Predominance (≥30%) of LGL lymphocytes in the peripheral blood, as assessed by morphologic or immunophenotypic criteria; 3) T-cell receptor monoclonality assessed by PCR. The patient population was divided into discovery and replication sets using 2 different methods: stratified randomization and propensity score matching, using relevant baseline variables such as donor type, CMV serostatus, conditioning, T-cell depletion. Results No significant imbalances were found between the discovery and replication sets in terms of relevant baseline characteristics and clinical outcomes, for both the randomly divided patients and the propensity score matched groups. The overall incidence of LGL lymphocytosis was 14.5% at 3 years. The incidence of LGL lymphocytosis was similar across all subgroups of patients, both for the randomly divided groups and the propensity score matching (P-value not significant). A multivariable analysis of the risk factors for the development of LGL lymphocytosis was performed, including the following variables: grades 3-4 acute graft-versus-host-disease (GVHD), chronic GVHD, CMV viremia, CMV serostatus of the recipient, donor type, transplant year and T-cell depletion (TCD) for GVHD prophylaxis. In the stratified randomization analysis, the following risk factors were identified: 1) Discovery set: chronic GVHD (Hazard Ratio: 8.3, 95% CI: 3.1-22.6, P<0.001), CMV viremia (HR: 2.7, 95% CI: 1.5-4.7, P<0.001) and use of an unrelated donor (HR: 2.1, 95% CI: 1.2-3.7, P=0.01). 2) Replication set: chronic GVHD (HR: 38.9, 95% CI: 5.3-284.9, P<0.001) and CMV viremia (HR 3.8, 95% CI: 2.2-6.6, P<0.001). For the propensity score matching analysis the risk factors for the development of LGL lymphocytosis were the following: 1) Discovery set: chronic GVHD (HR: 22.9, 95% CI: 3.2-169.3, P=0.002) and CMV viremia (HR: 2.2, 95% CI: 1.1-4.2, P=0.02). 2) Replication set: chronic GVHD (HR: 28.9, 95% CI: 3.9-212.5, P<0.001), CMV viremia (HR: 3.6, 95% CI: 1.9-6.7, P<0.001). Conclusions Chronic GVHD and CMV viremia are strongly associated with the development of LGL lymphocytosis following allogeneic HCT. This may reflect a chronic antigenic stimulation in the setting of GVHD and CMV infection, leading to the expansion of LGL. However, the underlying mechanisms of LGL activation and expansion in the allogeneic HCT setting still remain unclear. Thus, further investigations are needed to elucidate these mechanisms in particular in the setting of GVHD. Disclosures Lipton: Pfizer: Consultancy, Research Funding; Ariad: Consultancy, Research Funding; Teva: Consultancy, Research Funding; Bristol-Myers Squibb: Consultancy, Research Funding; Novartis Pharmaceuticals: Consultancy, Research Funding. Kim:Bristol-Myers Squibb: Consultancy, Research Funding; Novartis Pharmaceuticals: Consultancy, Research Funding.

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A Single Institution Retrospective Review of Characteristics and Outcomes of Patients Requiring Chronic Dose Reduction of TKIs Given As Front-Line Therapy for Chronic Phase CML

Blood ◽

10.1182/blood.v126.23.5171.5171 ◽

2015 ◽

Vol 126 (23) ◽

pp. 5171-5171

Author(s):

Jamie L. Koprivnikar ◽

James K. McCloskey ◽

Yucai Wang ◽

Genique Stanislaus ◽

Stuart L. Goldberg ◽

...

Keyword(s):

Risk Factors ◽

Dose Reduction ◽

Research Funding ◽

Chronic Phase ◽

Control Group ◽

First Line ◽

Full Dose ◽

Line Therapy ◽

Dose Reductions

Abstract Background: The development of tyrosine kinase inhibitors (TKIs) has dramatically changed the landscape of chronic myelogenous leukemia (CML) treatment. Dosing of TKIs is standardized and is based on the phase of disease at presentation, but is not altered based on body surface area (BSA), sex, or other patient characteristics. These medications are generally well tolerated, however, hematologic and non-hematologic toxicities are not infrequent. While the package insert of all three TKIs (imatinib, dasatinib, nilotinib) commonly used in first line therapy provides specific dose-reduction instructions for hematologic toxicity, only nilotinib has a standard recommended dose for nonhematologic toxicity. Long-term data on the effects of dose-reduction of TKI therapy based on toxicity is lacking. Furthermore, there is little data on risk factors for TKI intolerance. Thus, we sought to identify characteristics of patients requiring dose reductions as a part of first-line TKI treatment for chronic phase CML as well to determine the long-term outcome of these patients in a retrospective fashion. Methods: Using billing records, we identified all patients seen at our institution for treatment of chronic phase CML between November 1, 2010 and July 16, 2015. We then reviewed the records of all such patients to identify individuals requiring chronic dose reductions of first-line treatments for chronic phase CML. We identified a control group of patients by capturing all patients tolerating full dose first-line TKI therapy during a pre-specified period. This control group was used to determine risk factors for TKI intolerance. Results: A total of 18 patients were identified who required long-term dose reduction of first-line TKI therapy with a median follow up time of 34.72 months (range 12.47-124.07). The mean time on full dose therapy prior to dose reduction was 7.08 months (range 0-37.27). The median time spent on reduced dose therapy was 26.37 months (range 4.90-118.93). Eighty-nine percent of patients remained in a major molecular response 4 (MR4) despite dose reduction. Median progression free survival (PFS), as defined by loss of MMR, of dose-reduced patients had not yet been reached. One, two, and three year PFS rates were 100%, 93.8%, and 85.2% respectively. When compared to the control group of patients tolerating front line therapy at full-dose, patients requiring dose reduction were more likely to be female: 78% vs 48% (P=0.045) and have a lower BSA: 1.77 versus 1.99 mg/m2 (P=0.010). Discussion: This small, retrospective analysis identifies several potential important risk factors for TKI dose reduction including female sex and lower BSA. Based on the available control group, it cannot be determined if either of these are independent variables. The majority of patients remained in MR4 despite dose reductions. Both of the 2 patients (12.5%) who did not were able to regain MR4 status after switching to an alternate TKI, suggesting that long-term treatment with reduced dose TKIs is reasonable so long as patients are closely monitored. Our data suggest the possible utility of dose adjustments based on BSA for patients who are intolerant of TKI therapy. Table 1. TKI administered degree of dose reduction. Patient Number TKI Dose 1 Dasatinib 20 mg QOD 2 Dasatinib 10 mg daily 3 Dasatinib 40 mg daily* 4 Imatinib 300 mg daily 5 Imatinib 200 mg alternating with 300 mg daily 6 Dasatinib 40 mg daily 7 Imatinib 300 mg daily* 8 Dasatinib 50 mg daily 9 Dasatinib 40 mg daily 10 Dasatinib 70 mg daily 11 Nilotinib 450 mg daily 12 Dasatinib 40 mg daily 13 Nilotinib 450 mg daily 14 Dasatinib 50 mg daily 15 Dasatinib 40 mg daily 16 Imatinib 300 mg daily 17 Dasatinib 35 mg daily 18 Dasatinib 70 mg daily *Indicates loss of MR4 while on therapy Table 2. Risk factors for TKI dose reduction. Full dose group Dose reduction group P value Number 29 18 Gender Male Female 1514 414 0.045 (chi-square) BSA 1.99±0.28 1.77±0.25 0.010 (t test) BMI 30.27±6.34 27.20±4.28 0.084 (t test) Figure 1. PFS as defined by loss of MMR for patients on chronically dose-reduced TKIs. Figure 1. PFS as defined by loss of MMR for patients on chronically dose-reduced TKIs. Disclosures Koprivnikar: Alexion: Consultancy. McCloskey:Novartis: Consultancy; Pfizer: Consultancy. Goldberg:Pfizer: Research Funding; COTA: Employment, Equity Ownership, Other: Leadership, Stock; Ariad: Research Funding, Speakers Bureau; BMS: Research Funding, Speakers Bureau; Novartis: Research Funding, Speakers Bureau. Faderl:Celgene Corp.: Other: Advisory Board.

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

Blood ◽

10.1182/blood-2020-136164 ◽

2020 ◽

Vol 136 (Supplement 1) ◽

pp. 45-47

Author(s):

Jennifer White ◽

Nada Hamad ◽

Swe Mar Linn ◽

Igor Nicolas Novitzky-Basso ◽

Omar Abduljalil ◽

...

Keyword(s):

Retrospective Study ◽

Dose Reduction ◽

Clinical Benefit ◽

Acute Gvhd ◽

Chronic Gvhd ◽

Median Number ◽

Steroid Resistant ◽

Prednisone Dose ◽

Steroid Dose ◽

Heavily Pretreated

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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Development of a Dynamic Model for Personalized Risk Assessment in Large B-Cell Lymphoma

Blood ◽

10.1182/blood.v130.suppl_1.826.826 ◽

2017 ◽

Vol 130 (Suppl_1) ◽

pp. 826-826

Author(s):

David M. Kurtz ◽

Florian Scherer ◽

Michael Jin ◽

Joanne Soo ◽

Alexander Craig ◽

...

Keyword(s):

Risk Factors ◽

Board Of Directors ◽

Research Funding ◽

Risk Model ◽

Disease Risk ◽

B Cell Lymphoma ◽

Molecular Response ◽

Advisory Committees ◽

Net Reclassification Improvement ◽

Over Time

Abstract Background: Outcomes for patients with diffuse large B-cell lymphoma (DLBCL) remain heterogeneous. Several clinical and molecular risk factors have been described, both at time of diagnosis (i.e., International Prognostic Index and cell of origin) and during therapy (i.e., interim PET scans). However, these risk factors fail to consistently identify individuals destined for treatment failure. We recently described circulating tumor DNA (ctDNA) as a novel biomarker in DLBCL, demonstrating pretreatment ctDNA levels are prognostic of outcomes (Scherer F, Sci Transl Med 2016). A major advantage of ctDNA assessment is the ability to collect serial assessments over time. However, the best approach for integrating multiple ctDNA measurements with established prognostic factors remains unknown. Using the dynamics of ctDNA, we developed a method to quantify personalized disease risk as it changes during therapy. Methods: We profiled 468 samples from 125 subjects collected during their first three cycles of immunochemotherapy using cancer personalized profiling by deep sequencing (CAPP-Seq). Early ctDNA dynamics were correlated with outcomes in a training cohort to define a response threshold that was tested in a validation cohort. Finally, we integrated ctDNA and clinical factors to dynamically assess disease risk over time in a continuous model. Results: Prior to therapy, ctDNA was detectable in 98% of subjects. Pretreatment levels of ctDNA were prognostic of event-free survival in patients receiving either frontline anthracycline-based (n=92) or salvage regimens (n=33) (EFS: HR 2.7, 95% CI 1.5-4.7, P=0.0005), confirming prior results. In the training cohort, ctDNA levels changed rapidly, with a 2-log or 100-fold decrease after one cycle (early molecular response, EMR) stratifying outcomes (Fig 1A). In the validation cohort, patients achieving EMR had superior outcomes at 24-months to those who did not (Fig 1B) (EFS: HR 24, 95% CI 6.6-89, P<0.0001). These results remained significant in subgroups of patients receiving either frontline or salvage therapy. Circulating tumor DNA levels continued to decline during cycle 2, such that a distinct threshold after two cycles could also be trained. After two cycles, a 2.5-log decrease (major molecular response, MMR) also stratified patients for EFS (HR: 8.6, 95% CI 2.2-33, P=0.002). Next, we integrated serial ctDNA measurements with established risk-factors to develop a model to predict an individual's disease risk. This model - the Continuous Individualized Risk Index (CIRI) - provides a personalized estimate of disease risk over time. As more information becomes available during a patient's course of disease, CIRI updates the disease risk, integrating the new information (Fig 1C). In patients receiving frontline therapy, CIRI outperformed the IPI for identification of 24-month EFS and OS (Fig 1D-E) (EFS24: AUC 0.64 vs 0.79; net reclassification improvement 0.47, P=0.02; OS: AUC 0.56 vs 0.84; net reclassification improvement 0.74, P=0.004). Conclusions: Baseline and interim ctDNA measurements have prognostic significance in aggressive lymphomas. Integration of serial ctDNA measurements through a continuous, dynamic risk model can identify personalized outcome probabilities, yielding superior risk estimates. Dynamic risk assessment is potentially widely applicable and could guide future personalized therapeutic approaches. Figure 1: A) A spider-plot depicts the dynamics of ctDNA during the first two cycles of therapy in 14 subjects. B) A Kaplan-Meier estimate depicts EFS for patients achieving or not achieving EMR. C) A schema for CIRI is shown. When a patient is diagnosed with DLBCL, the IPI is calculated, giving an initial estimate of risk. Additional pretreatment risk factors (i.e., cell of origin and pretreatment ctDNA) can be added, thereby updating the estimate of risk. As a patient undergoes therapy, further predictors of risk are obtained, such as ctDNA at cycle 2 and cycle 3, and interim imaging. These predictors can be used to update the patient's estimated risk. Below is a CIRI risk model for two exemplar patients with the same initial pretreatment risk factors. Patient P214 (red) died of disease at day 210, while patient P224 (blue) is in a continued complete response. D) AUC for prediction of EFS and OS by IPI, EMR, interim PET scans, and CIRI. E) A Kaplan-Meier estimate demonstrates risk stratification of EFS by CIRI. Disclosures Advani: Sutro: Consultancy; Cell Medica: Research Funding; Janssen: Research Funding; Bristol-Myers Squibb: Consultancy, Research Funding; Celgene: Research Funding; Nanostring: Consultancy; Bayer Healthcare Pharmaceuticals: Research Funding; Juno Therapeutics: Consultancy; FortySeven: Research Funding; Gilead: Consultancy; Spectrum: Consultancy; Pharmacyclics: Research Funding; Agensys: Research Funding; Regeneron: Research Funding; Millennium: Research Funding; Infinity: Research Funding; Merck: Research Funding; Kura: Research Funding; Pharmacyclics: Consultancy; Seattle Genetics: Research Funding; Genentech: Research Funding. Newman: Roche: Consultancy. Westin: Celgene: Membership on an entity's Board of Directors or advisory committees; Apotex: Membership on an entity's Board of Directors or advisory committees; Kite Pharma: Membership on an entity's Board of Directors or advisory committees; Novartis Pharmaceuticals Corporation: Membership on an entity's Board of Directors or advisory committees. Gaidano: Janssen: Consultancy, Honoraria; Roche: Consultancy, Honoraria; Amgen: Consultancy, Honoraria; Gilead: Consultancy, Honoraria; AbbVie: Consultancy, Honoraria. Diehn: Varian Medical Systems: Research Funding; Roche: Consultancy; Novartis: Consultancy; Quanticel Pharmaceuticals: Consultancy. Alizadeh: Genentech: Consultancy; Celgene: Consultancy; CiberMed: Consultancy; Roche: Consultancy; Gilead: Consultancy.

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Propensity Score Matching Analysis Comparing Ruxolitinib Vs Historical Controls in 2 nd Line or Beyond Treatment for Chronic Gvhd after Therapy Failure

Blood ◽

10.1182/blood-2021-151683 ◽

2021 ◽

Vol 138 (Supplement 1) ◽

pp. 1805-1805

Author(s):

Igor Novitzky-Basso ◽

Swe Mar Linn ◽

Jennifer White ◽

Mohamed Elemary ◽

Anargyros Xenocostas ◽

...

Keyword(s):

Risk Factors ◽

Propensity Score ◽

Propensity Score Matching ◽

Board Of Directors ◽

Research Funding ◽

Therapy Failure ◽

Advisory Committees ◽

Line Therapy ◽

Heavily Pretreated ◽

Severe Grade

Abstract Background The REACH3 study has reported greater overall response and failure-free survival (FFS) with Ruxolitinib (RUX) as 2 nd line therapy for steroid-refractory chronic graft versus host disease (cGVHD) in comparison to best available therapy (BAT; NEJM 2021). In addition, our Canadian retrospective study as a real-world experience has reported a promising activity of 64.6% FFS and 83.3% overall survival (OS) at 12 months in 115 patients (pts) treated with RUX from 2016 to 2021 for heavily pretreated cGVHD (ASH 2021). Also, 47.6% pts could reduce corticosteroid dose below 0.1mg/kg/day within 6 months. The present study compared treatment outcomes using a propensity-score matching (PSM) analysis between RUX pts ("RUX group", n=115) and a historical cohort of cGVHD pts treated with BAT as 2 nd line therapy or beyond from 2005 to 2013 ("BAT group", n=311). Statistical endpoints such as FFS, OS and steroid dose reduction were evaluated instead of overall response due to limited response assessment available from retrospective chart reviews. Patients and methods BAT included mycophenolate (43%), prednisone (29%), prednisone/cyclosporine (12%), extracorporeal photopheresis (6%), rituximab (3%), and others (7%). The pts and disease characteristics between the RUX vs BAT groups were not well balanced, as expected: RUX group showed a higher number of pts with severe grade GVHD (59.1% in RUX vs. 20.3% in BAT; p<0.0001), and more heavily pretreated with 4 th line or beyond (84.3% in RUX vs. 17.0% in BAT; p<0.0001). FFS and OS were calculated from the day of starting RUX or BAT therapy, while daily prednisone doses at months 0, 3 and 6 were calculated divided by body weight (kg). PSM analysis was applied to adjust risk factors that were unbalanced between the 2 groups, including GVHD severity at therapy start (mild/moderate vs severe grade), HCT-CI score (0-2 vs 3 or beyond), and treatment line (2nd vs 3rd vs 4th line or beyond). A total of 100 patients (i.e. 50 case-control pairs) were finally extracted through PSM process within 0.2 of calliper difference. PSM analysis balanced out the risk factors between the 2 groups: GVHD severity (p=1.0), HCT-CI score (p=1.0) and treatment line (p=1.0). The FFS and OS rate at 12 months were compared using Cox's proportional hazard model. Results In the overall population (n=426), with a median 19 months follow-up duration, 244 failures (57.3%) were noted. While both groups showed similar failure rates due to non-relapse mortality (NRM), the RUX group showed significantly lower failure rate from cGvHD resistance requiring therapy switch. Failure was noted in 40 pts (33.4%) in RUX due to resistance requiring a switch of therapy (n=23; 20.0%), NRM (n=14, 12.2%) and relapse (n=3; 2.6%), while failure occurred in 204 pts (65.6%) in BAT due to resistance requiring a switch of therapy (n=142; 45.7%), NRM (n=36; 11.6%) and relapse (n=26; 12.7%). The 12 months' FFS rate were 64.7% and 40.1% in RUX vs. BAT group (p<0.0001; Fig 1A), while the 12 months' OS rate were 83.4% and 83.7% in RUX vs. BAT group (p=0.913; Fig 1B). In the propensity score matched (PSM) cohort (n=100), the RUX group showed a survival benefit over the BAT group: the 12 months' FFS rate was 74.0% and 29.7% in RUX vs. BAT group (p<0.0001; Fig 2A), while the 12 months' OS rate were 90.5% and 80.2% in RUX vs. BAT group (p=0.109; Fig 2B). Multivariate analysis in the PSM cohort confirmed that RUX is superior to BAT for FFS (p<0.001, HR 0.267 [0.139-0.516]) together with HCT-CI score 0-2 vs ≥3 (p=0.037, HR 0.490 [0.251-0.959]) with a trend to better survival in RUX over BAT (p=0.110, HR 0.402 [0.131-1.228]). The prednisone dose was gradually reduced over time: the median doses of prednisone at months 0, 3, and 6 were 0.34, 0.16 and 0.02 mg/kg/day in the RUX group, and 0.95, 0.24 and 0.15 mg/kg/day at months 0, 3 and 6 in the BAT group. RUX facilitates the discontinuation of prednisone. The proportions of patients who discontinued prednisone at months 0, 3 and 6 were 8.7%, 15.9% and 24.1% in RUX, and 0.7%, 0% and 2.0% in BAT group. The differences in proportions of pts that discontinued prednisone between the RUX vs BAT groups at months 0, 3, and 6 were 8.0%, 15.9% and 22.1% (Fig 3). Conclusion: The current PSM analysis study suggests that RUX showed a superior FFS to BAT as 2nd line therapy or beyond in cGVHD patients after therapy failure. RUX showed better steroid tapering compared to BAT. Figure 1 Figure 1. Disclosures White: Novartis: Honoraria. Elemary: Pfizer, Janssen: Membership on an entity's Board of Directors or advisory committees; Jazz, BMS, Abbvie, Novartis, Pfiz: Membership on an entity's Board of Directors or advisory committees. Hamad: Novartis: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau. Law: Novartis: Consultancy; Actinium Pharmaceuticals: Research Funding. Kim: Bristol-Meier Squibb: Research Funding; Paladin: Honoraria, Research Funding; Novartis: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Pfizer: Honoraria, Research Funding.

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