Disclaimers. For sure everything discussed here is off label. No commercial interest or funding to disclose.

Transcription

1 BMT in SLE. Javier Bolaños Meade, MD Associate Professor of Oncology Marrow and Apheresis Collections Facility Director and Medical Director Graft versus Host Disease Programme Director Sidney Kimmel Comprehensive Cancer Centre at Johns Hopkins Division of Haematologic Malignancies

2 Disclaimers For sure everything discussed here is off label. No commercial interest or funding to disclose.

3 Clinical Case Ms. Jane Doe is a 27 YO African female diagnosed with haemoglobin S/S at birth. She had several pain crises every year requiring >3 annual hospitalisations for pain control. She was diagnosed with SLE in 2022 when presented with hair loss, skin rash and nephritis. She was treated with tacrolimis, mycophenolate mofetil, and prednisone at different times. She also received rituximab.

4 Given her clinical deterioration due to her S/S disease she underwent a non myeloablative haploidentical bone marrow transplant from her brother on September Despite some infectious complications, she recovered well.

5 Urine Protein/creatinine ratio December 2010 March 2011 July 2011 March 2012 June Her urine has no detectable protein since December Her anti DNA antibodies were positive until June 2010 (last check before her BMT, have been undetectable since her transplant. She is tapering her immunosupression (currently on prednisone 2.5 mg/day), her CBC is normal, has no new symptoms from her SLE and her alopecia is resolving.

6 Systemic Lupus Erythematosus SLE is an autoimmune disease with multiorgan effects. It does affect the skin, joints, kidneys, CNS, etc. Intermittent cyclophosphamide pulses or mycophenolate mofetil have shown to improve the outcomes of these patients. Five to 10% of patients have refractory disease.

7 What about transplant? There is limited experience on the use of BMT in SLE, mainly on patients receiving autologous transplants (some with T cell depletion). The first case of a BMT specifically to treat SLE was reported by Marmont et al. in Some small series and reports have been published since.

8 Early results using autologous BMT Report by Year Patients Response (%) Follow up (months) Marmont et al Short Musso et al Burt et al Fouillard et al Trysberg et al Ouyang et al Short Brunner et al Traynor et al Zintl et al

9 The European Group for Blood and Marrow Transplantation (EBMT)/European League Against Rheumatism (EULAR) Autoimmune Disease Working Party have registered more than 800 patients and works in close collaboration with networks in the USA where several hundred more autoimmune patients have been similarly transplanted.

10 Passweg and Tyndal reported on 55 patients with SLE reported to the EBMT/EULAR, most of them with CNS or renal involvement and with 21 failing sta In 53 patients with sufficient data for analysis, 66% achieved an initial remission, defined as a Systemic Lupus Erythematosus Disease Activity Index of 3 and steroid reduction to less than 10 mg/d. Of these, approximately one third experienced some degree of return of disease activity.

11 Figure 1 The selected outcomes of sustained remission, remission then relapse, and treatment related mortality are compared and contrasted among four different AD undergoing HSCT: SLE (n = 53), SSc (n = 57), MS (n = 85), and RA (n = 73). Jakob Passweg, Alan Tyndall Autologous Stem Cell Transplantation in Autoimmune Diseases Seminars in Hematology Volume 44, Issue

12 Data published in March 2013 from the ERBMTR on 28 patients showed at 34 months, DFS of 29% with a 5 year survival of 81%. Lupus Mar;22(3):245 53

13 It is unclear if the relapses are due to: 1) Failure to eradicate reactive lymphocytes 2) Reinfusion of reactive lymphoctes 3) Rechallenge from the auto antigen

14 Some strategies to avoid relapse then include: 1) T cell depletion 2) High dose chemotherapy without stem cell support

15 At Johns Hopkins we have treated and reported 21 patients with SLE and high dose cyclophosphamide (50 mg/kg/day x 4) as part of a randomised phase II study. At 30 months, 10 patients achieved a complete response, 4 a partial, and 7 did not respond.

16 M. Gur Lavi (1999) reported on a patient who underwent an allogeneic BMT for aplastic anaemia in the setting of SLE who at 15 years was cured from her SLE. Khorshid (2004) reported a patient with SLE and systemic sclerosis that was in remission 29 months after a non myeloablative BMT.

17 In summary High dose chemotherapy, with or without stem cell support, can induce responses on patients suffering from SLE. Allogeneic BMT deserve to be studied. The theoretical benefit of this is the lack of reinfusion of reactive lymphocytes and the establishment of a new immune system that will eradicate these alloreactive lymphocytes and may not react to the same antigens triggering SLE.

18 Allogeneic BMT Replaces the blood forming and immune systems of a patient with those of a healthy donor Chemotherapy +/ radia on therapy intravenous infusion of bone marrow Can be used to cure: Blood cancers (100,000/year) Sickle cell disease (80,000 to 100,000 in the USA) Systemic lupus erythematosus (250,000) HIV/AIDS (1.1 million) About 7,000 transplants performed in U.S. in 2011

19 Tolerance: the Burnet/Medawar paradigm The immune system discriminates self from non self The self/non self discrimination is learned during foetal and neonatal development All new antigens, including tumour antigens, that appear during adulthood are non self The immune system has a role in the surveillance and elimination of cancer

20 What are we doing at Johns Hopkins? Cyclophosphamide induced tolerance Proliferating ALLOREACTIVE cells are killed* anti CMV anti CMV anti HSV anti HSV Non proliferating non alloreactive cells are spared*

21 The donor issue Aversa F and Martelli MF Springer Semin Immunol 26: 155, 2004

22 So what are we proposing at Johns Hopkins? We want to perform nonmyeloablative bone marrow transplants with post BMT cyclophosphamide.

23 We have shown already that post BMT prophylaxis can be an effective way to prevent severe acute and chronic GvHD. We have used it in both, myeloablative and nonmyeloablative conditionings.

24 Single agent cyclophosphamide for GvHD prophylaxis

25 Acute GvHD Grade II IV Grade III IV Unrelated 53% Related 39% Rejection/death/ Relapse competing model

26 Chronic GvHD NRM

27 But these results we just saw are using myeloablative conditioning. What about with nonmyeloablative conditioning?

28 Engraftment Graft failure: 27/204 evaluable = 13%

29 GvHD

30 Mortality...

31 OS and EFS

32 OS by diagnosis

33 Of course these results are on patients with malignant diseases. Have we used these schema with patients without cancer? If so, is it effective?

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36 So yes, we have done it. But does it work? Clearly transplanting people with cancer and without cancer is not the same. Why should we assume that this can be done to patients with SLE?

37 Bolaños-Meade J et al. Blood 2012;120: by American Society of Hematology

38 Importantly, with this approach almost everybody has a donor.

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41 So we have shown that nonmyeloablative BMT with posttransplantion cyclophosphamide can be done with low toxicity, very low rates of GvHD, low mortality on patients without cancer. Remember the data published in March 2013 from the ERBMTR on 28 patients receiving autotransplants showed at 34 months, DFS of 29% with a 5 year survival of 81%.

42 Patients with SLE can be compared to a degree to patients with sickle cell disease. Both have some degree of renal impairment and some have CNS disease. But SLE patients have the great advantage that they have received immunosuppression during the course of their illness, making graft failure/rejection less likely than in sickle cell disease patients.

43 Besides, SLE patients do not have history of transfusion dependence, so de risk of alloimmunisation is less than in SCD patients, again decreasing the risk of graft rejection/failure.

44 Given the low toxicities and almost universal availability of donors, we believe that our schema should translate into an effective therapy for patients with SLE that is refractory to conventional therapies.

45 In summary High dose chemotherapy, with or without stem cell support, can induce responses on patients suffering from SLE. Allogeneic BMT deserve to be studied. The theoretical benefit of this is the lack of reinfusion of reactive lymphocytes and the establishment of a new immune system that will eradicate these alloreactive lymphocytes and may not react to the same antigens triggering SLE.

46 In summary With our low toxicity schema, we believe that we can offer a curative option to almost any patient with SLE who has disease refractory to standard therapy. Study will be open by this summer!

47 Thanks Special thank you to: Robert Brodsky, MD (Haematology) Michele Petri, MD (Rheumatology) Leo Luznik, MD (BMT) Ephraim Fuchs, MD (BMT) Richard J. Jones, MD (BMT)