Acute graft-versus-host disease (aGVHD) is a serious complication after stem cell transplantation and is associated with high non-relapse mortality. If steroid treatment as first-line therapeutic ...approach fails, treatment options are limited. In retrospective studies, ruxolitinib, a selective Janus kinase 1/2 inhibitor as well as extracorporeal photopheresis (ECP) could show high efficacy in treatment of steroid refractory acute and chronic GVHD. Here, we report single-center experience of combining JAK-inhibitor treatment with ECP in 18 patients with severe steroid refractory aGVHD of lower GI-tract. The treatment was well tolerated and no severe cytopenia (grade IV) occurred, in three patients grade III cytopenia could be observed. Response was complete or partial in 44% and 11%, respectively, resulting in an estimated 2 year overall survival of 56%. Steroids were tapered rapidly with a median time of 2 days for halving of dosage avoiding additional steroid-associated side effects. Under treatment with ruxolitinib and ECP, an increased level of regulatory T cells could be observed elucidating direct effects of this treatment on immune response.
Allogeneic hematopoietic stem-cell transplantation (HSCT) remains the only curative option for patients with advanced chronic myeloid leukemia (CML). However, outcome is dismal and of short ...follow-up. The objective of the study was to determine long-term outcome and risk factors in patients with a history of CML Blast Crisis (BC; n = 96) or accelerated phase (n = 51) transplanted between 1990 and 2018. At transplant, patients had a median age of 39 (range 7-76) years and were in ≥CP2 (n = 70), in AP (n = 40) or in BC (n = 37) with a diagnosis-HSCT interval of median 1.9 (range 0.3-24.4) years. Overall survival (OS) amounted 34% (95% CI 22-46) and progression-free survival (PFS) 26% (95% CI 16-36) at 15 years. Adverse risk factors for OS and PFS were low CD34
count in the graft, donor age (>36 years) and BC. Cumulative incidence of Non-Relapse Mortality (NRM) was 28% (95% CI 18-38) and of relapse (RI) 43% (95% CI 33-53) at 15 years. PB-HSCT and HSCT after 2008 were favorable prognostic factors for NRM, while family donor and patient age >39 years were independently associated with higher RI. HSCT resulted in long-term OS in patients with advanced CML. OS was improved in non-BC patients, with donors ≤36 years and with higher CD34
dose in the graft.
CD19-specific chimeric antigen receptor (CD19-CAR) T-cell therapies mediate durable responses in late-stage B-cell malignancies, but can be complicated by a potentially severe immune effector ...cell-associated neurotoxicity syndrome (ICANS). Despite broad efforts, the precise mechanisms of ICANS are not entirely known, and resistance to current ICANSdirected therapies (especially corticosteroids) has been observed. Recent data suggest that inflammatory cytokines and/or targeting of cerebral CD19-expressing pericytes can disrupt the blood-brain barrier and facilitate influx of immune cells, including CAR T cells. However, specific tools for CD19-CAR T-cell analysis within often minute samples of cerebrospinal fluid (CSF) are not broadly available. Here, we applied our recently developed digital polymerase chain reaction assays to monitor CD19-CAR T-cell kinetics in CSF and blood in real-world patients with neurotoxicity. Consistently, we observed a CAR T-cell enrichment within CSF in ICANS patients with further progressive accumulation despite intense corticosteroid- containing immuno-chemotherapies in a subset of patients with prolonged and therapy-resistant grade 3-4 neurotoxicity. We used next-generation T-cell receptor-b sequencing to assess the repertoire of treatment-refractory cells. Longitudinal analysis revealed a profound skewing of the T-cell receptor repertoire, which at least partly reflected selective expansion of infused T-cell clones. Interestingly, a major fraction of eventually dominating hyperexpanded T-cell clones were of non-CAR T-cell derivation. These findings hint to a role of therapy-refractory T-cell clones in severe ICANS development and prompt future systematic research to determine if CAR T cells may serve as 'door openers' and to further characterize both CAR-positive and non-CAR T cells to interrogate the transcriptional signature of these possibly pathologic T cells.
Acute kidney injury and chronic kidney disease is common in multiple myeloma. Fludarabine which is part of lymphodepletion before CAR-T cell therapy is renally eliminated and its use is not ...recommended for patients with severe renal impairment defined as a glomerular filtration rate below 30ml/min/1.73m
2
. We administered fludarabine to a 58-year-old female patient with myeloma-associated severe renal impairment as part of lymphodepletion before Idecabtagen vicleucel infusion. Fludarabine was administered in reduced dose (15mg/m
2
) and cyclophosphamide with a dose of 300mg/m
2
followed by hemodialysis over six hours using a larger filter (FX-100). The therapy was well tolerated with excellent CAR-T cell expansion and complete remission which is ongoing now beyond 12 months.
We aimed to develop a concise objectifiable risk evaluation (CORE) tool for predicting non-relapse mortality (NRM) and overall survival (OS) after allogeneic hematopoietic stem cell transplantation ...(allo-HCT). A total of 1120 adult patients who had undergone allo-HCT at our center between 2013 and 2020 were divided into training, first, and second validation cohorts. Objectifiable, patient-related factors impacting NRM in univariate and multivariate analyses were: serum albumin, serum creatinine, serum C-reactive protein (CRP), heart function (LVEF), lung function (VC, FEV1), and patient age. Hazard ratios were assigned points (0-3) based on their impact on NRM and summed to the individual CORE HCT score. The CORE HCT score stratified patients into three distinct low-, intermediate-, and high-risk groups with two-year NRM rates of 9%, 22%, and 46%, respectively, and OS rates of 73%, 55%, and 35%, respectively (
< 0.001). These findings were confirmed in a first and a second recently treated validation cohort. Importantly, the CORE HCT score remained informative across various conditioning intensities, disease-specific subgroups, and donor types, but did not impact relapse incidence. A comparison of CORE HCT vs. HCT Comorbidity Index (HCT-CI) in the second validation cohort revealed better performance of the CORE HCT score with c-statistics for NRM and OS of 0.666 (SE 0.05,
= 0.001) and 0.675 (SE 0.039,
< 0.001) vs. 0.431 (SE 0.057,
= 0.223) and 0.535 (SE 0.042,
= 0.411), respectively. The CORE HCT score is a concise and objectifiable risk evaluation tool for adult patients undergoing allo-HCT for malignant disease. External multicenter validation is underway.
Relapse after allogeneic hematopoietic stem cell transplantation (AHSCT) in myelofibrosis (MF) patients remains as a significant issue despite advances in transplantation procedures and significant ...prolongation in survival. Second AHSCT is a potential treatment option but associated with high treatment-related mortality and novel less toxic conditioning regimens are needed. In 33 MF patients with relapse after AHSCT and failure to donor lymphocyte infusion (DLI) we investigated treosulfan (36–42 g/m2) in combination with fludarabine and anti-thymocyte globulin (ATG) as conditioning regimen for a second AHSCT with matched related (n = 2), unrelated (n = 23), or mismatched unrelated (n = 8) donors. All patients achieved leukocyte engraftment after a median of 11 days, and 56 ± 13% experienced acute GVHD grade II–IV at day 100. The therapy-related mortality at day 100 and at 3 years was 16% and 31%, respectively. The cumulative incidence of relapse at 5 years was 16%, resulting in a 5-year disease-free and overall survival of 45% and 47%, respectively. Treosulfan-based conditioning for second allograft in relapsed MF patients resulted in about 50% of the patients in long-term freedom from disease.
Hematopoietic cell transplantation (HCT) is a curative approach for myelofibrosis patients, but relapse is a major cause of treatment failure. We investigated the effect of donor lymphocyte infusion ...(DLI) in 37 patients with molecular (n = 17) or hematological relapse (n = 20) after HCT. Patients received median of 2 (range, 1–5) cumulative DLI (total of 91 infusions). Median starting dose was 1 × 106 cells/kg, escalated by half‐log ≥6 weeks if no response nor graft‐versus‐host disease (GvHD) occurred. Median time to first DLI was 40 weeks for molecular relapse versus 145 weeks for hematological relapse. Overall molecular complete response (mCR) at any time was 73% (n = 27) and was significantly higher for initial molecular relapse (88%) versus hematological relapse (60%; P = 0.05). The 6‐year overall survival was 77% versus 32% (P = 0.03). Acute GvHD 2–4 occurred in 22% and half of the patients achieved mCR without any GvHD. All patients who relapsed from mCR achieved after first DLI could be salvaged with subsequent DLI, showing long‐term survival. No second HCT was needed for molecular relapse versus 6 for hematological relapse. This comprehensive and largest study to date suggests molecular monitoring together with DLI as standard of care and a crucial approach to achieve excellent outcomes in relapsed myelofibrosis.
Introduction
The Janus-Activated Kinase (JAK) 1/2 -inhibitor ruxolitinib is approved for the treatment of symptomatic myelofibrosis (MF) regardless of the JAK2 mutational status. Ruxolitinib can ...reduce constitutional symptoms and spleen size resulting in an improvement of the performance status and also in a potential prolonged survival. Here we investigated the efficacy and toxicity of ruxolitinib in MF patients who relapsed after allogeneic stem cell transplantation.
Patients and methods
Between the years 2012 and 2016, 10 myelofibrosis patients of our department who relapsed after allogeneic stem cell transplantation received ruxolitinib. Stem cell donor was matched related (MRD) in two patients, matched unrelated (MUD) in six and mismatch unrelated MMUD in two patients. The median age of the patients was 61 years (r: 41-72). The median time from allogeneic transplantation until the start of ruxolitinib treatment was 23.8 months (r: 2.7-85.7). The median treatment duration was 143.5 days (r: 12-369). The median dose of ruxolitinib was 10 mg bid (r: 5-20mg) according to toxicity. Two patients had already received ruxolitinib prior to allogeneic transplantation. All patients had mixed chimerism at start of ruxolitinib. Two patients had already received donor lymphocyte infusions (DLI) prior to ruxolitinib. Two patients started with DLI beginning at day +30 and at day +147 within ruxolitinib treatment. Seven patients were positive for the JAK2V617 mutation and one patient for CALR mutation. Constitutional symptoms were observed in seven patients and splenomegaly in six patients before treatment start. One patient had aGvHD (skin) and three had cGvHD (oral mucosa, skin, liver) at the time of treatment start. In seven patients bone marrow histology was available before and during ruxolitinib treatment.
Results
We observed an improvement of constitutional symptoms in six patients (86%). The palpable spleen size was reduced in five patients (83%) with splenomegaly (≥50% n=4, <50% n=1). In five of six patients who were dependent on blood and/or thrombocyte transfusions a reduction of the transfusion frequency was seen. Due to thrombocytopenia (CTC grade 3 and 4) dose reduction was necessary in two patients. One patient newly developed leukocytopenia within ruxolitinib treatment (CTC grade 3); before ruxolitinib one patient had grade 1 leukocytopenia and worsened to grade 3. Prior to ruxolitinib the median chimerism was 57% (r: 0-99.7) whereas during ruxolitinib treatment the median chimerism dropped to a median of 0% (r: 0-93.8). The median JAK2-alllele-level before ruxolitinib was 0.87 (r: 0.03-91.3) versus 8.35 (r: 1.83-29.9) during ruxolitinib treatment. The one patient harboring the CALR mutation had an increase of the allelic burden from 0.56 to 1.68. In five of the patients with an available bone marrow biopsy an aggravation of bone marrow fibrosis could be seen whereas no progression could be seen in two patients. The peripheral blast count increased in three patients, in one patient peripheral blasts newly developed. Progressive disease could be seen in all patients (100%) despite of reduction of spleen size, improvement of constitutional symptoms or a prolonged transfusion interval. Three patients transformed to AML. All patients with GvHD had an improvement and or even complete resolution of their GvHD. One patient developed aGvHD of the skin during ruxolitinib treatment but in this patient immunosuppressive therapy had already been stopped at day +30 due to mixed chimerism. No severe infectious complications were seen. None of the patients had to stop ruxolitinib due to side effects.
Conclusion
The Janus-Activated Kinase (JAK) 1/2 -inhibitor ruxolitinib can lead to a reduction of spleen size, an improvement of MF-associated constitutional symptoms and a reduction of the blood transfusion-interval in patients with relapse after allogeneic transplantation. However, ruxolitinib does not lead to an increase of donor chimerism. It seems to have little impact on the JAK2V617F-allele level. A further aggravation of bone marrow fibrosis was seen in most of the patients. Despite of clinical improvement all patients experienced further progression of myelofibrosis and three patients even transformed to AML. Furthermore in those patients with GvHD an improvement or even complete resolution of the GvHD was seen.
Kroeger:Novartis: Honoraria, Research Funding.
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