GVHD: new therapeutic approach. Gyd. A. Bukauskas Hematologijos, onkologijos ir transfuziologijos centras VUH Santariskiu Klinikos

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1 GVHD: new therapeutic approach Gyd. A. Bukauskas Hematologijos, onkologijos ir transfuziologijos centras VUH Santariskiu Klinikos

2 Vedolizumab Vedolizumab (Entyvio) monoclonal antibody for the treatment of ulcerative colitis and Crohn s disease. Developer Millennium Pharmaceuticals, Inc (a subsidiary of Takeda Pharmaceuticals). It binds to integrin α4β7 (LPAM 1, lymphocyte Peyer's patch adhesion molecule 1).Blocking the α4β7 integrin results in gut selective antiinflammatory activity.

3 Pathophysiology

4 Pharmacology Vedolizumab is a humanized, antiα4β7 integrin, monoclonal antibody [Takeda Pharmaceuticals America Inc., 2014]. The α4β7 integrin is a cell surface glycoprotein that is expressed on circulating B and T lymphocytes. It binds to adhesion molecules on gastrointestinal and other vascular endothelial cells to promote the influx of integrin binds specifically to the mucosal addressin cell adhesion molecule 1 and causes a decrease in gastrointestinal mucosal degradation and inflammation [Erle et al. 1994; Fedyk et al. 2012].

5 Pharmacokinetics In a dose ranging study, 36 patients with UC were administered vedolizumab as a min intravenous infusion at doses of 2, 6, or 10 mg/kg at weeks 0, 2, and 4 (induction phase) and week 12 (maintenance phase). Across all doses, the mean half life ranged from days [Parikh et al. 2012]. These pharmacokinetic parameters were confirmed in phase III trials, when 300 mg of vedolizumab was administered as a 30 min intravenous infusion at weeks 0, 2, 6, and then every 4 or 8 weeks thereafter to patients with UC and CD. The serum half life was determined to be nearly 25 days.

6 Dosing schedule

7 Dosing and administration FDA approved dosing regimen of 300 mg as a 30 min intravenous infusion on weeks 0, 2, and 6, and then every 8 weeks thereafter for both UC and CD [Takeda Pharmaceuticals America Inc., 2014]. Product labeling recommends that vedolizumab treatment be discontinued if patients do not show signs of response by week 14 [Takeda Pharmaceuticals America Inc., 2014] If patients have a non life threatening infusion reaction history then administration of acetaminophen, antihistamines, or corticosteroids should be considered before the start of the infusion [Takeda Pharmaceuticals America Inc., 2014]. However, if a serious hypersensitivity reaction occurs during vedolizumab administration, vedolizumab should be immediately discontinued and medications for treating the reaction administered to the patient (e.g. epinephrine, antihistamines, corticosteroids).

8 Drug to drug interaction Concomitant administration of vedolizumab with TNF α antagonists and natalizumab should be avoided because of increased infection risk and PML. Live vaccines should only be given to patients receiving vedolizumab if the benefit clearly outweighs the risk.

9 Safety Clinical trials evaluated safety in >3300 adults on Entyvio Including >800 patients who received Entyvio for >2 years Safety profile from UC Trials I & II and CD Trials I & III: Infusion related reactions (IRRs) Infections Progressive multifocal leukoencephalopathy (PML) Liver injury Malignancy Immunogenecity

10 Safety Infusion related reactions (IRRs) 4% of patients treated with Entyvio experienced an IRR, including anaphylaxis (1 of 1434), versus 3% of patients on placebo. Allergic reactions included dyspnea, bronchospasm, urticaria, flushing, rash, and increased blood pressure and heart rate. Most frequently observed IRRs: nausea, headache, pruritus, dizziness, fatigue, pyrexia, urticaria, and vomiting. Observed IRRs generally occurred within the first 2 hours after the infusion and resolved with no treatment or following antihistamine and/or IV hydrocortisone treatment. Infections Infection rates with Entyvio: 0.85 per patient year; placebo: 0.7 per patient year. The infections consisted primarily of nasopharyngitis, upper respiratory tract infection, sinusitis, and urinary tract infection. 2% of patients discontinued Entyvio due to infections. Serious infection rates with Entyvio: 0.07 per patient year; placebo: 0.06 per patient year. Serious infections included anal abscess, sepsis (some fatal), tuberculosis, salmonella sepsis, Listeria meningitis, giardiasis, and cytomegaloviral colitis

11 Safety Progressive multifocal leukoencephalopathy (PML) No cases of PML reported in clinical studies; risk of PML cannot be ruled out. John Cunningham (JC) virus infection resulting in PML and death has occurred in patients treated with a different integrin antagonist. No claims of comparative safety to other integrin antagonists can be made based on this data Liver injury Entyvio should be discontinued in patients with jaundice or other evidence of significant liver injury. Three patients reported serious adverse reactions of hepatitis with Entyvio. One additional case of serious hepatitis was seen in the open label trial. These adverse reactions occurred following 2 to 5 Entyvio doses; however, it is unclear if the reactions indicated drug induced or autoimmune etiology There have been reports of elevations of transaminases and/or bilirubin in patients receiving Entyvio All patients recovered following discontinuation of therapy with or without treatment with corticosteroids

12 Safety Adverse reactions Adverse reactions were reported in 52% of patients treated with Entyvio (n=1434) and 45% of patients treated with placebo (n=297) Over 52 weeks, 7% of patients treated with Entyvio experienced serious adverse reactions compared to 4% of patients treated with placebo

13 Safety Malignancy Malignancies (excluding dysplasia and basal cell carcinoma) were reported in 0.4% (6 of 1434) of patients treated with Entyvio and in 0.3% (1 of 297) of patients treated with placebo. Malignancies reported in patients treated with Entyvio included colon cancer (n=2), transitional cell carcinoma (n=1), breast cancer (n=1), carcinoid tumor of appendix (n=1), and squamous cell carcinoma (n=1) Malignancies (excluding dysplasia and basal cell carcinoma) observed during the ongoing open label long term extension trial included B cell lymphoma, breast cancer, colon cancer, malignant hepatic neoplasm, malignant lung neoplasm, malignant melanoma, lung cancer of primary neuroendocrine carcinoma, renal cancer, and squamous cell carcinoma The number of malignancies in the clinical trials was small; however, long term exposure was limited Immunogenicity The rate of detectable anti vedolizumab antibodies at any time during the 52 weeks of continuous treatment with Entyvio was 4% The frequency of antibodies detected in patients who received Entyvio was 13% at 24 weeks after the last dose of study drug 56 of 1434 patients (4%) who received continuous treatment with Entyvio were anti vedolizumab antibody positive at any time during treatment 9 of 56 patients were persistently positive (at 2 or more study visits) for anti vedolizumab antibody, and 33 of 56 developed neutralizing antibodies to vedolizumab. Among 8 of these 9 subjects, 6 had undetectable vedolizumab concentrations and 2 had reduced vedolizumab concentrations. None of the 9 subjects with persistently positive anti vedolizumab antibody achieved clinical remission at Weeks 6 or 52 in the controlled trials.

14 FDA and EMEA approval 20 May 2014, vedolizumab (Entyvio) FDA approval Tx moderate to severe ulcerative colitis and moderate to severe Crohn's disease. May 27, 2014, Entyvio was EMEA approval Tx ulcerative colitis and Crohn's disease in the 28 European Union states as well as Norway, Iceland and Lichtenstein. April 28, 2015 Health Canada approval.

15 Clinicaltrials.gov vedolizumab 18 studies

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19 Cost consideration The average wholesale cost of a 300 mg vial of vedolizumab in the US is $ [The Redbook (On Line), 2014]. Based on the recommended dosing of 300 mg on weeks 0, 2, 6, and then every 8 weeks thereafter, the cost of vedolizumab for the initial year of treatment is approximately $52,000 and for subsequent years approximately $34,700. To date, cost effectiveness analyses comparing vedolizumab with other therapies approved for UC and CD have not been performed.

20 Conclusions Vedolizumab is an α4β7 integrin antagonist approved for use in patients with moderate to severe UC or CD who are considered non responders, have relapsing disease, or are unable to tolerate TNF α antagonists or who or have an inadequate response with, are intolerant to, or demonstrate dependence on corticosteroids. When administered according to approved dosing in patient with moderate to severe CD and UC, vedolizumab induces clinical response rates up to 31.4% and 47.1% at week 6 and clinical remission rates at week 52 up to 39% and 41.8%. Unlike other FDA approved integrin antagonists, vedolizumab is gastrointestinal selective and has not shown evidence of causing PML; however, postmarketing studies are ongoing to ensure patient safety for this serious AE. Other serious AEs reported in trials with vedolizumab include serious infections, malignancies, and anaphylaxis. Further assessment of vedolizumab earlier in the course of these diseases and in combination with other therapies is warranted.

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22 Patients and methods Patients were recruited at the University Medical Centers of Freiburg, Marburg, Basel, Munich, Essen, Bonn, Frankfurt, Cologne, Paris, Berlin, Hamburg, Düsseldorf, Dresden, Würzburg, Stanford, Gothenburg, Nijmegen, Utrecht and Patras between January 2012 and April This cohort was selected by including all patients that were reported to receive ruxolitinib for agvhd or cgvhd by the different centers and no reported patient was excluded. Histological GVHD grading was performed on the basis of a published staging system and clinical grading was according to criteria for agvhd or cgvhd.

23 Inclusion criteria Sr GVHD at least 1 week for agvhd or 3 weeks for cgvhd based on previous definitions for SR agvhd21 or SR cgvhd. Steroids 1mg/kg/d.

24 Rx Ruxolitinb: add on immunosuppression 5 10mg bid Acute GVHD A CR to ruxolitinib was defined as the absence of any symptoms related to GVHD. A PR was defined as the improvement of at least one stage in the severity of agvhd in one organ without deterioration in any other organ. A response had to last for at least 3 weeks. Treatment failure was defined: absence of improvement of agvhd, deterioration of agvhd in any organ by at least one stage, development of agvhd manifestations in a previously unaffected organ, use of any additional agents to control the disease. Patients were scored for their best response at any time after starting treatment with ruxolitinib, with follow up censored at the onset of any subsequent systemic immunosuppressive therapy.

25 Rx Ruxolitinb: add on immunosuppression 5 10mg bid Chronic GVHD: Organ sites considered for GVHD scoring included skin, mouth, eyes, intestinal tract, liver, lungs, joints and fascia and the genital tract. Each organ or site was scored according to a 4 point scale (0 3), 0 representing no involvement 3 reflecting severe impairment. A CR to ruxolitinib was defined as the absence of any symptoms related to cgvhd. PR of cgvhd was defined as the discontinuation or long lasting (4 weeks) reduction of all systemic immunosuppressive therapy by at least 50%. Failure was defined: the use of any additional agents to control GVHD once treatment with ruxolitinib had started, including the resumption of agents used earlier or an increase in the dose of any immunosuppressive treatment. Discontinuation of treatment with ruxolitinib because of toxicity was not considered a treatment failure. The duration of response was calculated from the time of onset of response after initiation of treatment with ruxolitinib until: the end of the follow up, GVHD relapse, the development of new or the deterioration of pre existing GVHD symptoms, the reinstitution of any additional agents to control the disease.

26 Cytokine measurements The levels of IL 6, soluble IL 2R and CD3+HLA DR+ T cells were analyzed from peripheral blood on the day before or within 5 days after starting ruxolitinib in 10 random patients at Freiburg University Medical Center.

27 Statistics Overall survival (OS) was calculated as the time from start of treatment with ruxolitinib to death from any cause. The duration of response was assessed for responders only by calculating the time from first observation of response to the first observation of GVHD relapse or progression.

28 Pts characteristics: agvhd and cgvhd

29 Results: agvhd 54 agvhd pts, with 34/54 (63%) patients having multiple organ involvement. All pts had grades 3 or 4 agvhd and 39/54 (72.2%) patients were beyond second line treatment for agvhd. Median Nr. of previous agvhd therapies was 3 (range: 1 7). ORR was 81.5% (44/54) including 25 CRs (46.3%). The median time to response was 1.5 (1 11) weeks after initiation of ruxolitinib treatment.

30 Results: agvhd Skin and intestinal GVHD responds to ruxolitinib. (a) A representative patient with cutaneous acute GVHD is shown prior and 1 week after ruxolitinib. (b) A representative patient with cutaneous chronic GVHD is shown prior and 3 weeks after ruxolitinib. (c) Serial biopsies of the intestinal tract of a patient with GVHD are displayed. Biopsies were taken 1 day before start of ruxolitinib and 4 weeks after ruxolitinib had been started.

31 Results: The absolute number of activated T cells (CD3+HLA DR+) were measured in 8/25 patients and levels of IL 6 and the soluble IL 2 (R) receptor were determined in 12/25 patients treated at the Transplant Center Freiburg. Significant decline in all three pro inflammatory parameters during ruxolitinib treatment compared with the day before the drug was started and all of these patients responded to ruxolitinib treatment.

32 Results: agvhd The 6 month survival estimate was 79% ( %, 95% CI) in patients treated with ruxolitinib for SR agvhd. The median follow up time was 26.5 (3 106) weeks for SR agvhd patients. The GVHD relapse rate was analyzed for patients who had achieved CR or PR. Relapses in agvhd occurred in 6.8% (3/44) of ruxolitinibresponsive patients (2 PR, 1 CR).

33 Results: cgvhd 41 pts cgvhd involving the skin, the liver, intestinal tract, the lungs and musculoskeletal tissues. In 29/41 (70.7%) of patients more than one organ system was involved. All pts had moderate (n = 6/41, 14.6%) to severe (n = 35, 85.4%) cgvhd. Most pts were beyond second line treatment for cgvhd, with a median number of 3 prior treatments (range: 1 10) before ruxolitinib was administered The ORR was 85.4% (35/41), with 78% (32/41) PR and 7.3% (3/41) CR. 14.6% (6/41) of the patients showed no response. Responses to ruxolitinib were not restricted to specific organ systems affected by SR cgvhd. The median time to response was 3 (1 25) weeks after initiation of ruxolitinib treatment.

34 Results: cgvhd The 6 month survival estimate was 97.4% ( %, 95% CI) for patients treated with ruxolitinib for SR cgvhd. GVHD relapsed in 5.7% (2/35) of ruxolitinib responsive (CR or PR) patients with cgvhd. The median follow up was 22.4 (3 135) weeks for cgvhd patients. One of the patients with cgvhd who developed metastatic squamous cell carcinoma of the lung and died of this disease.

35 Results: AE s

36 Disscussion Pts had a median of three immunosuppressive treatments before ruxolitinib for both acute and chronic GVHD. Despite this heavily pre treated population, the ORR was 81.5% (44/54) in agvhd including 25 CRs (46.3%). In cgvhd, the ORR was 85.4% (35/41) with the majority of patients achieving a PR (78%). The time to response was variable, with a maximum of 25 weeks in a patient with cgvhd and a minimum of 1 week, indicating the heterogeneous biology of SR cgvhd in individual patients. Responses were durable as shown by the long GVHD relapse free survival rates in both agvhd and cgvhd patients.

37 Discussion Our data suggest that response rates of both SR agvhd and SR cgvhd to ruxolitinib were favorable compared with other second line GVHD therapies reported. The mtor inhibitors (sirolimus or everolimus). Response rates to mtor inhibitors of 24 72% were reported in a phase 2 trial (21 patients) and in two retrospective analyses (22 and 34 patients). MMF. The reported ORR to MMF range between 15 and 31%. The reported ORR of agvhd to ECP range between 47 and 65%. ATG yielded response rates ranging from 8 to 56% in SR agvhd. A particular side effect of ATG was Epstein Barr virus associated posttransplant lymphoproliferative disorder, which we did not observe in patients treated with ruxolitinib.

38 Disscussion Alemtuzumab: ORR 50 65% Methotrexate: 58% (41 in patients) Given the limitation of a direct comparison from different studies, these ORR appear lower when compared with the ORR of 81% seen in our retrospective cohort of SR agvhd patients exposed to ruxolitinib. Intestinal SR agvhd might affect the bioavailability of ruxolinitib. The fact that 36/42 of the patients with intestinal SR agvhd responded suggest that ruxolitinib is resorbed at least partially. Serum levels of ruxolitinib were not evaluated.

39 Disscussion The 6 month survival estimate was 79% ( %, 95% CI) in our patients treated with ruxolitinib for SR agvhd. The weighted average 6 month survival estimate across 25 studies on SR agvhd was 49%. Within these retrospective or phase 2 trials, the largest study analyzed the impact of horse ATG as a second line treatment and included 79 patients. The 6 month survival estimate for this study was 44%. ECP was given to 23 pts with SR agvhd with a reported 6 month survival rate of 57%. In contrast to our survey, this study also analyzed grade II agvhd patients (n=10), while our survey included only grades III or IV agvhd patients. Patients with SR agvhd treated with daclizumab and infliximab died at a median of 35 days from initiation of daclizumab/infliximab. The 6 month survival estimate ranged from 44 to 61% 40 pts in SR GVHD patients treated with alemtuzumab.

40 Discussion ORR of SR cgvhd to ruxolitinib was 85.4%. Most studies including sirolimus, MMF, ECP, IL 2 or CYA reported ORR of 45 72%. However as for SR agvhd, a randomized phase II or III trial will be necessary to draw definitive conclusions. Furthermore the confidence intervals of responses from previous trials are wide, making a direct comparison difficult.

41 Discussion Mechanism of how JAK1/2 inhibition could interfere with the allogeneic immune response while established immunosuppressive medications have failed remains unclear. Likely that interfering with the immune response at multiple levels via JAK1/2 inhibition might be more potent than targeting individual pathways such as the calcineurin/nfat or mtor pathways. Cytokine signals in target cells are integrated via cytokine receptor mediated JAK1 and JAK2 phosphorylation as for example gamma chain cytokines that promote the pathogenesis of GVHD. Furthermore, besides their role in T cells, JAK1 and 2 were shown to be required for the activation of neutrophilsand DCs, which both contribute to GVHD.

42 Discussion Safety profile of ruxolitinib is rather favorable. AE: cytopenias in both patient cohorts. This side effect is reversible upon discontinuation of the drug. Cytopenias had preceded ruxolitinib treatment in 51.9% (28/54) and 14.6% (6/41) of the patients with SR agvhd or SR cgvhd, respectively. The frequency of cytopenias was not unexpectedly high but requires regular monitoring of blood counts in patients receiving ruxolitinib as a salvage treatment for SR GVHD.

43 Discussion CMV reactivation acute (33.3%) and chronic (14.6%) SR GVHD patients, indicates that CMV copy numbers need to be closely monitored in patients receiving ruxolitinib as a salvage treatment for GVHD, and that antiviral therapy needs to be started rapidly when needed. A comparable frequency of CMV reactivation was reported in patients treated with other immunosuppressive drugs including steroids, infliximab, alemtuzumab, MMF or CYA. GVHD severity was correlated with CMV reactivation in multiple reported studies. Therefore, better control of GVHD by ruxolitinib could in the longterm also improve CMV control as reported for MSC treatment.

44 Discussion Important: in pts receiving novel immunosuppressive treatments is a potential loss of the GVL effect, leading to increased relapse risk. Relapse of the underlying malignancy in ruxolitinib exposed patients was low, as only 9.3% (5/54) and 2.4% (1/41) of the patients with acute or chronic GVHD. This frequency is comparable to other studies and suggests that ruxolitinib treatment is not linked to a higher relapse risk when compared with other currently applied immunosuppressive drugs.

45 Disccusion Overall, this retrospective survey of a large patient number treated with ruxolitinib due to SR agvhd and SR cgvhd in various European and US transplant centers highlights the therapeutic potential of JAK inhibitors in the treatment of SR GVHD. JAK inhibitor treatment was safe and well tolerated in this heavily pre treated patient cohort. The high ORR above 80% in both SR agvhd and SR cgvhd supports the potential clinical value of this compound as salvage therapy for SR GVHD. Importantly, the 6 month overall survival for ruxolitinib treated SR agvhd patients was higher than those previously reported for any other treatment modality in this particular scenario. Our results set the stage for future testing of ruxolitinib in acute and chronic SR GVHD against best available therapy in prospective clinical trials.