Presenters: Karen Onel (Rheumatology) & Susan Prockop (BMT), HSS/MSKCC/NYH-WC, New York, United States
At the time of referral, he was on daily prednisone dose of 1.2 mg/kg/day and monthly pulses of methylprednisolone 500 mg and cyclophosphamide. On genetic testing, he was found to have the HLADRB1*15, and candidate gene mutation (NLK). His lung disease continued to progress with evolving tachypnea and interstitial lung disease with cystic changes that led to the decision to move forward with allo-HSCT.
His pre-transplant evaluation identified low-level CMV on bronchoalveolar lavage (BAL), for which he received induction ganciclovir prior to starting conditioning for HSCT. The patient received a haploidentical HSCT from his 7/10 mother using a conditioning regimen of Busulfan (PK 60 mg*h/L) Fludarabine, ATG, and Rituximab, with post-transplant cyclophosphamide on Days + 3 and + 4, tacrolimus, and MMF for GVHD prophylaxis.
His transplant course was complicated with persistent fevers for the first 2 weeks and at the time of engraftment on Day + 21. Several weeks after engraftment he developed increasing respiratory distress with worsening of parenchymal changes by chest CT. A repeat BAL was negative for infections except for low-level CMV. His inflammatory markers: CRP, Ferritin, and IL-6 levels were increased. He required admission to the pediatric intensive care and was placed on a high-flow nasal cannula. He received pulsed prednisone 1 mg/kg BID, resumed MMF and ultimately was discharged on overnight high-flow support.
The patient is now 8 months post-haplo-HSCT with full donor chimerism in all lineages. He remains on tacrolimus and MMF and weaning prednisone (at the time of the meeting on 0.2 mg/kg/day). His immune reconstitution is slow due to prolonged prednisone use. The patient remains on aggressive pulmonary toileting but is no longer on high-flow nasal cannula. The chest CT showed marked improvement of parenchymal changes.
Summary of discussions
The discussion, moderated by Dr. Canna, was wide-ranging, touching on many aspects of the cases presented. The main themes are summarized below.
Will the most refractory SJIA patients benefit from HSCT? First, Dr. Canna raised the question of whether there was a subset of patients with refractory systemic JIA, who have failed all available medications, who could potentially benefit from HSCT. How can we identify those patients early? The refractory SJIA patients presented at NextGen were dependent on high doses of corticosteroids despite multiple immunosuppressive medications. While this population had significant peri-HSCT complications, most have achieved SJIA remission or experienced a decreased burden of SJIA, and improved lung function. The follow-up, however, has not been long enough to define the long-term outcomes.
Dr. Driest commented that rheumatologists, being aware of possible complications of HSCT, tend to keep looking for the next medicine with the hope that they will find the right one at some point. Given the number of drugs available as well as their possible combinations, this path can be very long. For their own patient, the team had changed medications multiple times and ultimately decided that it was time for a transplant rather than trying another combination.
Dr. Onel recounted that initially, their team was not in favor of HSCT. However, as the lung disease was rapidly progressing, and lung transplantation was proposed as the next step - their thinking changed. Their concern was that poorly controlled underlying SJIA would reduce chances for successful lung transplantation. Additionally, there was a concern that the inflammatory process can reoccur in the transplanted lung leading to new lung damage. A better approach might be to arrest the child’s lung disease with the ultimate immune ablation provided by HSCT.
What is the optimal timing for transplants? / How to transplant before it’s too late, especially for lung patients? Next, Dr. Canna raised a question about the ideal timing to perform HSCT. Is it after patients have failed the approved biologic and non-biologic DMARDs or after trying other available immunosuppressive medications? The cases presented at NextGen varied in terms of SJIA duration at the time of HSCT (from 1.9 to 8.2 years) with different degree of organ damage and toxicities from treatment. For one of the patients, the transplant was such a risky procedure, that the final decision was made with the involvement of the bioethics team. Is there a way to identify these patients earlier in the course of the disease?
A parent of an SJIA-LD patient raised the question about the clinical parameters that would make a patient no longer eligible for HSCT. The consensus was that the fewer comorbidities would lead to fewer complications during HSCT. Conversely, a patient who spends years on corticosteroids and other immunosuppressants with frequent infections would be at higher risk for mortality, infections, and other side effects associated with HSCT.
Additionally, physicians agreed that although decreased pulmonary and cardiac function was a major concern, it was still possible to go through a transplant even if the patient was tracheostomy-dependent and on oxygen supplementation (with reasonable ventilator settings). In such cases, the final decision should be made by a multidisciplinary team based on very thorough evaluation.
Dr. Wall added that the transplant team must be prepared for numerous complications including ICU stays, especially if the patient had lung involvement. She added that for lung function, it is difficult to determine the exact cut-off point for HSCT eligibility when the lung is the target organ. Nevertheless, it is important to thoroughly evaluate lung function even if the imaging tests show severe lung inflammation. Dr. Grom added that SJIA-Lung patients often might be doing well and have preserved lung function despite impressive changes on high resolution chest CT.
One additional consideration is specific to patients with severe growth delays (even growth failure), who are unable to get off steroids. For such patients, there is a need for a window of time after transplantation to catch up with growth before their growth plates close. As an example, for the patient from Cincinnati who had been on corticosteroids continuously for 9 years prior to the procedure, it took 18 months to complete her steroid taper post-BMT. She started growing at 8 months after transplant.
Need for early referrals to the BMT team. The BMT specialists emphasized the importance of early referrals of refractory patients to their teams, so they can stay involved with the patient and assess donor options.
Dr. Schulert from CCHMC shared that they were now referring any SJIA patients with a refractory course, who had failed both IL-1 and IL-6 blockade as well as jak-inhibition, to the BMT team.
Plan for Retrospective Study and Need for Guidelines. Dr. Juliana Silva proposed starting a retrospective study with long-term follow-up of the cohort of transplanted SJIA-LD patients. She invited all the teams present to contribute to this effort that should include monitoring the rates of relapses and chimerism. She also emphasized the need for prospective studies of patients undergoing different standardized transplant procedures. Thus initially, the team used Flu/Melph/Campath as conditioning, but more recently they have changed the regimen to Fludarabine/Biosulphan with the hope that they would achieve better chimerism.
Dr. Abinun added that the existing European governmental HSCT guidelines were very conservative. He also emphasized the importance of publishing each case study so we could learn from these patients and improve these guidelines.
Is this group of patients too heterogeneous to draw conclusions from? Session participants had varied opinions about the heterogeneity of the refractory SJIA patients. Dr. Onel pointed out that there is a larger group of refractory SJIA patients who do not necessarily have lung disease but require multiple immunosuppressive drugs and cannot wean off steroids. She felt that refractory SJIA patients with parenchymal lung disease that have PAP features were a distinct and more homogenous group. Dr. Canna and Dr. De Benedetti thought that the SJIA patients with recurrent MAS associated with any organ involvement were on the same disease spectrum, even if the specific organs involved were not the same. In contrast, Dr. Wall felt that the presented cohort of patients was still very heterogeneous with different mechanisms driving the disease. These different perspectives make it it difficult to come up with specific guidelines.
Conditioning Regimen and Chimerism. The ideal conditioning regimen for HSCT for patients with SJIA has not been identified. Specialists from two of the centers (Newcastle & Kinderspital) observed that the reduced intensity conditioning regimen utilizing treosulfan/fludarabine might not be sufficient to ensure durable complete donor chimerism. This also came up in the long-term follow-up data presented by Dr. Silva where several of the patients relapsed and others had low chimerism. However, Dr. Silva pointed out that the relapse was not highly correlated with the drop in chimerism.
Need to control inflammation before HSCT and medications to be continued through transplant? Different teams had different opinions about the need for the continuation of the SJIA medications through the transplantation procedure. The team from Canada emphasized the need for a full control of inflammation prior to the transplant and GVHD prophylaxis. Their patient was on anakinra and emapalumab prior to the transplant and continued these medications until engraftment. The patient from CCHMC was on emapalumab before her second transplant.
The NYC team decided to keep the patient on PO prednisone (1.2 mg/kg daily), monthly pulses of IV steroids, and cyclophosphamide during the time period leading up to the transplant, but they tried to minimize immunosuppression at the time of the graft infusion. Minimizing immune suppression in the context of haploidentical-HSCT with post-transplant cyclophosphamide is critical to the success of this approach.
Dr. Driest described their struggle with getting the dose of steroid right before the transplant for their patient who had been steroid dependent during the entire course of SJIA. They kept the patient on 20 mg of steroids as this was the dose that had previously controlled her disease. At any lower dose, she was felt to be in danger of flaring. Their patient also continued anakinra through the transplantation.
Dr. Quartier described that the French team tapered the dose of steroids during the pre-transplant conditioning regimen. They stopped the immunosuppressive treatments before HSCT, with the exception of emapalumab that was continued several weeks after HSCT in the second French patient.
Risk Post-Transplant MAS. Two of the teams reported MAS post-transplant (Case
1 and Case
2). Case
1 had just 1 episode, treated with cyclosporin. Case
2 had multiple episodes that were resolved with steroids pulses and ultimately, dexamethasone pulse. One of the cases (Case
5) reported a flare during conditioning regimen, pre HSCT, and she was re-started on anakinra. The team for Case
9 reported a post-transplant episode of lung disease where it was unclear if it was MAS or another reason. That episode did resolve after treatment with steroids. Additionally, two patients (Case
6 & Case
8) who both had history of MAS were treated with emapalumab right before transplant and a few doses post-transplant.
Improvement in Lung Disease post-transplant. The Toronto/Ottawa team had seen significant improvement in the chest CT a year after the transplant. The patient, however, remained on ruxolitinib post-transplant, and there was a question as to whether the improvement in the lung disease was due to HSCT or to the ruxolitinib. Indeed, ruxolitinib has been effective for lung disease in primary immunodeficiencies like CT04. This also raised a second question whether ruxolitinib should be used for lung disease in SJIA before transplant in general. Dr. Wall mentioned that their patient had failed a different JAK-inhibitor prior to the transplant. Currently, the team is happy with the lung response and does not want to discontinue ruxolitinib. The fascinating part for them was that they had started sirolimus for an atypical rash for GVHD, and the rash exploded. They stopped sirolimus and went to ruxolitinib and the rash melted away. Overall, the team felt humbled with the results of this challenging transplant. They emphasized the importance of controlling the inflammation pre-transplant and continuing the medications as part of GVHD prophylaxis. Dr. Roth added that he had been surprised by how reversible the advanced lung disease was in their patient. Even if some of this improvement could be attributed to the ruxolitinib, his team felt that most of the benefit was coming from resetting the immune system via HSCT. He also mentioned that they are increasing the use of ruxolitinib in patients for MAS.
HLA Type. Dr. Canna also raised the question about the role of HLA-DRB1*15 which has recently been identified as a risk factor for the lung disease in SJIA patients [
2]. He was wondering whether the HLA type should be taken into consideration while looking for a donor. Dr. Prockop replied that typical donor HLA matching done for HSCT is more important for transplant outcome than considering the SJIA-LD HLA type as a way to screen donors.
Long term morbidity. Dr. Nigrovic raised the issue of long-term morbidity after transplant, particularly secondary malignancies. The BMT specialists pointed out that they did not see any such issues in their cases so far, though it is too soon to tell with this current cohort. Dr. Marsh thought that there was a risk of secondary malignancies, while Dr. Wall pointed out that so far, there were no reports of second malignancies for pediatric patients with inflammatory disorders undergoing HSCT.
Autologous Transplant. Dr. Canna next raised the question of whether autologous transplantation should be considered for these patients. Dr. Silva pointed out that autologous transplants were performed in SJIA in the past, but there were several relapses, and/or patients did not go into remission. Dr. Wall added that a reset of the immune system might be sufficient for adult patients, but not for pediatric patients (where genetic defects are more likely to be part of the pathology compared with adults), and therefore they need an allo-HSCT.
Dr. Abinun added that with autologous transplantation cases, MAS was a major issue in these patients, and that reducing inflammation (pre-transplant) was the way to solve this problem. He mentioned that the Dutch group was closely studying the immune reconstitution following autologous transplantation and hopefully this research would provide more answers in the future.
Control of inflammation before HSCT, Chimerism and SJIA remission. The importance of a good control of inflammatory activity prior to HSCT was again brought up by several BMT specialists. Dr. Abinun commented that most issues he sees in these patients during transplantation are inflammation-related, and the same issues can also have an impact on the post-HSCT course including chimerism. He also finds is disheartening that even full donor chimerism in SJIA patients after HSCT, does not mean that the disease is cured. Perhaps, this suggests a role for non-hematopoietic cells in the development of SJIA. He discussed these issues in more detail in his recent publication [
9].
Insurance issues. All teams reported that they did not have insurance issues in HSCT getting approved. Dr. Marsh mentioned that for other similar patients who have an inborn error of immunity and no genetic diagnosis, they usually send a letter to the insurance company as part of the transplant package. It might take a follow-up conversation with someone at the insurance company but typically it’s not a barrier.
Conditioning for refractory SJIA associated with liver disease. One of the parents asked about HSCT in patients with SJIA and liver involvement. Several BMT experts agreed that for patients with liver disease, there is a need to adjust the conditioning agents used.
Summary and future directions
In summary, the entire group of the participants agreed that there is a subset of patients with refractory systemic JIA, who have failed all available medications and are likely to benefit from HSCT. The increasing experience with HSCT in SJIA, suggests that despite the complicated post-HSCT course, short-term, the transplanted patients either achieved SJIA remission (or reduced burden of disease) with improved lung function. Longer follow-up, however, is needed to better define the long-term outcomes.
The optimal timing for the procedure still needs to be determined, but the emerging consensus is that it should occur earlier before significant organ damage is accumulated. The group unanimously agreed that BMT teams should be consulted early, and both Rheumatology and BMT specialists should work together to determine when HSCT is appropriate. Increased pre-HSCT organ damage, lungs in particular, decreases the chances for a successful outcome of the procedure. However, since lungs are the target organ in SJIA-LD, patients with moderate or even severe lung damage still may be eligible for the procedure.
Although reduced intensity conditioning regimens have improved the outcome of HSCT in general, there is a remote concern that such regimens may increase the risk of SJIA relapse after the transplantation. Long term registries should help address this question.
The entire group agreed that a good control of inflammatory SJIA activity prior to HSCT markedly increases chances to achieve a good outcome, and therefore, it is reasonable to continue SJIA/MAS medications until transplantation. The need to continue these medications (emapalumab and Jak-inhibitors in particular) after the procedure still needs to be determined.