key: cord-0882351-s605qrrj
authors: Tomomasa, Dan; Isoda, Takeshi; Mitsuiki, Noriko; Yamashita, Motoi; Morishita, Aoi; Tomoda, Takahiro; Okano, Tsubasa; Endo, Akifumi; Kamiya, Takahiro; Yanagimachi, Masakatsu; Imai, Kohsuke; Kanegane, Hirokazu; Takagi, Masatoshi; Morio, Tomohiro
title: Successful ruxolitinib administration for a patient with steroid‐refractory idiopathic pneumonia syndrome following hematopoietic stem cell transplantation: A case report and literature review
date: 2021-12-22
journal: Clin Case Rep
DOI: 10.1002/ccr3.5242
sha: ad510dd856a6259eac57c379bfdc15e1fd763fa5
doc_id: 882351
cord_uid: s605qrrj

Idiopathic pneumonia syndrome (IPS) is an acute lung complication observed after the early posthematopoietic stem cell transplantation (HSCT) period. Ruxolitinib was effective for a patient with myelodysplastic syndrome who developed severe IPS after second HSCT. No severe adverse effects were observed. Ruxolitinib may be an alternative choice for HSCT‐related IPS.

Idiopathic pneumonia syndrome (IPS) is a spectrum of acute interstitial lung injuries observed after the early posthematopoietic stem cell transplantation (HSCT) period. IPS diagnosis should be confirmed to exclude lower respiratory tract infection, cardiac dysfunction, acute renal failure, and fluid overload. 1, 2 The cumulative incidence of IPS increases from 2% to 10% according to the strength of conditioning, and its onset occurs at 4-106 (median, 19) days after HSCT. 1 The prognosis is exceedingly poor, with mortality rates of 60%-80% in most studies. 1, 3 Thus, novel therapeutic strategies are required for HSCT-related IPS.

In human idiopathic pulmonary fibrosis (IPF), Janus kinase (JAK) 2 and signal transducer and activator of transcription (STAT) 3 are activated. 4 Thus, their dual inhibitor is implicated as a potential therapeutic strategy for IPF. 5 Ruxolitinib is a selective JAK1 and JAK2 inhibitor approved for the treatment of myeloproliferative neoplasms and steroid-refractory acute and chronic graft-versus-host disease (GVHD). [6] [7] [8] [9] Ruxolitinib blocks JAK1, JAK2, and STAT signaling pathways, suppresses immune responses, and has positive effects on interstitial pneumonia associated with idiopathic juvenile arthritis, bronchiolitis obliterans after HSCT, and COVID-19-related acute respiratory distress syndrome. [10] [11] [12] [13] In this study, we report administration of ruxolitinib in a patient with myelodysplastic syndrome (MDS) who developed IPS after second HSCT. year-old girl presented with recurrent fever, prolonged leukopenia, and anemia for several months. Repeated bone marrow aspirations revealed hypocellular marrow with trilineage dysplasia. Blasts (8.8% of nucleated cells) were negative for specific and nonspecific esterases. Flow cytometry analysis revealed that the blasts expressed CD13, CD15, CD33, CD38, CD58, CD117, HLA-DR, and cytoplasmic myeloperoxidase. Chromosomal G-banding detected 46, XX, −5, −7, −9, −10, −13, −14, +6 mar in 14 of 20 cells that were analyzed. Spectral karyotypingfluorescence in situ hybridization (SKY-FISH) revealed complex chromosomal aberrations with three chromosomal translocations involving chromosome 7. DNA-FISH revealed 7q31 deletion in 88% of cells. Taken together, she was diagnosed with MDS-EB-1.

She underwent AML99 protocol remission induction therapy and achieved complete remission. 14 One course of intensification therapy was conducted, followed by HSCT from her HLA-haploidentical mother with posttransplantation cyclophosphamide. Conditioning regimen was fludarabine 120 mg/m 2 total dose, busulfan every 6 h for 16 doses (target AUC, 75 mg/L*h), and melphalan 140 mg/m 2 total dose (Table 1) . GVHD prophylaxis was provided by cyclophosphamide 50 mg/kg/dose i.v. on days 3 and 4, followed by mycophenolate mofetil 15 mg/kg orally three times daily from days 5 to 35, and tacrolimus i.v. daily (Table 1) . However, hemophagocytic lymphohistiocytosis (HLH) developed after transplantation, and the donor cells were rejected. CT scan showed no evidence of active pneumonia on day 50 after first HSCT ( Figure 1A ). Second HSCT was conducted by HLA 6/8-matched cord blood transplantation (CBT) on day 65 after first HSCT (Table 1) . Conditioning regimen was fludarabine 125 mg/m 2 total dose, etoposide 450 mg/m 2 total dose, melphalan 80 mg/ m 2 total dose, and total body irradiation 4 Gy (Table 1) . GVHD prophylaxis was tacrolimus and short methotrexate ( Table 1) . Engraftment syndrome developed with desaturation and oxygen requirement on day 9. Methylprednisolone (1 mg/kg/day) was initiated on day 16. Oxygenation gradually improved, and oxygen was discontinued on day 24. Neutrophil engraftment was achieved on day 29.

The patient developed stage III gut GVHD around day 30 that was refractory to methylprednisolone and started budesonide (6 mg/day) orally once daily on day 55. However, budesonide was discontinued on day 64 due to thrombotic microangiopathy with continuous low haptoglobin below the cut off and increased transfusion requirements ( Figure 2A ). Oxygenation gradually decreased with progressing nonproductive cough and dyspnea along with elevation of serum KL-6 and surfactant protein D (SP-D) around day 50 after CBT ( Figure 2A,B) . CT scan showed remarkable progression of infiltration in the entire lung fields on days 61 and 69 ( Figure 1B ,C). Respiratory condition deteriorated, and high-flow nasal cannula (HFNC) oxygenation was required on day 73 ( Figure 2A ). Cardiac dysfunction, renal failure, and iatrogenic fluid overload were absent. Multiplex PCRs including cytomegalovirus, Pneumocystis jirovecii, SARS-CoV-2, and other viral pathogens, as documented in the Appendix S1, were negative in sputum specimens. Beta-d-glucan was not elevated in this condition. Although invasive procedures such as lung biopsy and bronchoalveolar lavage could not be applied to the patient because of the poor respiratory condition, we considered the patient to have IPS concomitant with GVHD and HLH. Six of the eight HLH 2004 diagnostic criteria were fulfilled, namely, fever, splenomegaly, pancytopenia, hypertriglyceridemia (maximum, 5180 mg/ dl), hemophagocytic lymphocytes in bone marrow, and hyperferritinemia (maximum, 17,509 ng/ml). 15 We conducted methylprednisolone pulse therapy (10 mg/kg/day, 3 days). Furthermore, based on a recent report regarding resistance to steroid and antitumor necrosis factor therapy in patients with IPS, 16 we simultaneously started ruxolitinib (20 mg/day) on day 74 ( Figure 2A ). Because ruxolitinib was not approved for refractory GVHD in Japan, administration of ruxolitinib was approved by the Evaluation Committee for Unapproved or Off-label Drugs at Tokyo Medical and Dental University (No: 2019-038), and written informed consent was obtained from a parent of the patient. Respiratory status remarkably improved, with successful cessation of HFNC oxygenation on day 85 and no further requirement for oxygenation on day 89 ( Figure 2A ). CT scan revealed no infiltration shadows on day 96 ( Figure 1D ). Stool condition also gradually improved after ruxolitinib administration and became normal on day 91 ( Figure 2A ). Although SP-D rapidly decreased during the first month, KL-6 slowly reduced over 2 months ( Figure 2B ). Serum ferritin, soluble interleukin-2 receptor (sIL-2R), and C-reactive protein (CRP) sharply improved ( Figure 2B ). Neutropenia (grade 3), anemia (grade 3), and thrombocytopenia (grade 3) were manageable by reduction in ruxolitinib to 5 mg/day on day 131 ( Figure 2C ). However, KL-6 started to elevate, and ruxolitinib was increased to 10 mg/day on day 145 ( Figure 2B ). Complete chimerism was confirmed by shorttandem repeat analysis on days 64, 98, and 365. The MDS clone was not detected by chromosome 7q deletion FISH on days 98 and 365. Ruxolitinib and tacrolimus were successfully stopped on days 378 and 519, respectively. The patient has remained without any respiratory symptoms with stable KL-6, after cessation of ruxolitinib and tacrolimus ( Figure 2B ).

We searched for relevant literature using the key phrase "idiopathic pneumonia syndrome hematopoietic transplantation" in PubMed. Among 127 articles identified, we selected 11 articles after excluding case reports, duplicates, meta-analyses, reviews, text in languages other than English, biological studies, other lung complications, and autologous stem cell transplantation. The incidences of IPS were 6.7%-11.8% in children and 8.3%-12% in adults with myeloablative conditioning, which tended to be higher than the corresponding rates in patients with nonmyeloablative conditioning. Despite treatments involving steroids, positive pressure ventilation, mechanical ventilation, and anti-inflammatory biologics, the mortality rates of IPS were 55%-87.5% in children and 70%-85% in adults. Prospective studies using etanercept showed high response rates in children but found resistance in adults ( Table 2 ).

The findings for the present case suggest that ruxolitinib is effective with permissible adverse effects for HSCT-related IPS. Rapid resolution of respiratory symptoms, gut GVHD, secondary HLH, radiographic findings, and inflammatory markers was observed. Transfusion independence, methylprednisolone discontinuation, hospital discharge, and management in the outpatient setting were also achieved after ruxolitinib administration. Patients with IPS following HSCT tended to develop acute GVHD (grades II-IV) compared with non-IPS patients. 17 The IPS group contained more patients with prior HSCT. 17 Thus, IPS etiology may involve combined effects of cellular injury, including toxic effects of conditioning, immune-mediated injury, and occult infections. 1,2 Consistent with these past reports, our patient developed IPS plausibly associated with repeated conditioning for second HSCT, steroid-refractory GVHD, and secondary HLH. Ruxolitinib effectively alleviated not only progressive IPS but also all of the other complications. Ruxolitinib is a potent and selective inhibitor of JAK1 and JAK2, has strong selectivity against JAK3, and modestly inhibits Tyk2. 13 Ruxolitinib maximally inhibited cytokineinduced phosphorylated STAT3 (pSTAT3) at 1-2 h after administration. A return to normal pSTAT3 was observed 24 h after cessation of ruxolitinib. 18 In an animal model, a dual inhibitor of JAK2 and STAT3 alleviated bleomycininduced lung fibrosis along with reduction in collagen deposition. 4 In the clinical setting, ruxolitinib potentially inhibited JAK/STAT pathway-derived cytokines, including IL-6, IFN-gamma, and several others associated with refractory GVHD, primary or secondary HLH, IPF, and COVID-19-related acute respiratory distress syndrome. 4, 12, [19] [20] [21] [22] [23] Remarkable reductions in ferritin and sIL-2R were observed in our patient, resembling the reported response pattern for secondary HLH. 21,23 KL-6 and SP-D were useful markers for tracking the patient's disease status.

Plasma IL-6 is significantly elevated in patients with IPS, and pulmonary-derived IL-6 often exacerbates IPS, leading to resistance to steroids and antitumor necrosis factor therapy. 16 We speculate that the elevated CRP in our patient may have been due to IL-6 dysregulation. 24 Although no definite conclusion can be drawn without measuring the cytokine profiles, including the IL-6 concentration, the reduction in CRP along with other inflammatory markers in our patient plausibly reflected IL-6/ JAK/STAT pathway inhibition after ruxolitinib administration ( Figure 2B ).

In conclusion, ruxolitinib was effective for IPS without any severe adverse effects except for manageable pancytopenia in our patient. Ruxolitinib may be an alternative choice for not only HSCT-related IPS under steroid-refractory GVHD but also other secondary cytokine-mediated interstitial lung diseases. However, this study involves only one case without measurement of precise cytokine profiles. Further prospective studies are warranted to determine whether ruxolitinib salvage therapy is effective for IPS after HSCT.

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This work was supported in part by the Grants-in-Aid for Young Scientists (18K15661 and 21H02878). The authors thank Ms. Naomi Terada at the Department of Pediatrics and Developmental Biology, Tokyo Medical and Dental

University (TMDU), for performing the multiplex PCR on the patient's sputum samples, and staff at the Department of Laboratory Medicine, TMDU, for performing the SARS-CoV-2 PCR. The authors also thank Alison Sherwin, PhD, from Edanz (https://jp.edanz.com/ac) for editing a draft of this manuscript.

The authors declare that they have no conflict of interest regarding this article.

All authors contributed to conception and design of the study. DT, TI, NM, MY, AM, TT, TO, TK, and MY contributed to data acquisition. DT, TI, NM, MY, and TT contributed to systematic review. All authors contributed to analysis and/or interpretation of data. DT, TI, HK, and MT drafted the manuscript. All authors critically revised the manuscript for important intellectual content. All authors reviewed the manuscript before publication.

Written informed consent was obtained from the patient to publish this report in accordance with the journal's patient consent policy.

The data that support the findings of this study are available from the corresponding author upon reasonable request.