Leung, Nelson

Recent advances in the fields of hematology and oncology over the past decades are truly astounding. Higher response rates have increased the overall and progression free survival, and for certain cancers, have brought the possibility of a cure within reach. While this represents great news for many cancer patients, their longer survival is creating new challenges. Cancer patients can now live long enough to develop chronic kidney disease (CKD), receive long term dialysis, and even a kidney transplantation. There are important and significant knowledge gaps in the care of the cancer patient with CKD or end stage renal disease (ESRD). The subspecialty of Onco-Nephrology was created with the goal of optimizing the care of cancer patients with CKD or ESRD by (1) identifying crucial knowledge gaps in the proper care of these patients by (2) engaging in basic science and clinical research independently and in partnership with cancer specialists to attenuate these gaps, and (3) by educating future onco-nephrologists.

Background Immune checkpoint inhibitors (ICIs) have revolutionized cancer therapy, but to the authors' knowledge, limited data exist regarding the safety and efficacy of these agents in transplant recipients. Herein, the authors have reported their experience with 17 patients who were treated with ICIs for metastatic malignancies after undergoing solid organ transplantation. Methods Data were abstracted for solid organ transplant recipients who received ICIs for the treatment of malignancy between January 1, 2016, and September 30, 2019. The authors identified 7 kidney, 8 liver, and 2 heart transplant recipients. Outcomes of interest were adverse drug reactions, cancer progression, and patient survival. Results The most common malignancies treated with ICIs were metastatic squamous cell carcinoma (5 patients; 29%) and hepatocellular carcinoma (5 patients; 29%), which were noted exclusively among liver transplant recipients. The median duration on ICIs was 1.7 months (interquartile range, 0.4‐7.6 months). Five patients (29%) developed adverse reactions, including 4 patients (24%) with immune‐related adverse events(irAEs), 3 patients (18%) with acute allograft rejections, 1 patient (6%) with autoimmune colitis, and 1 patient (6%) with ICI‐induced cardiotoxicity (the patient was a heart transplant recipient). The cumulative incidence of cancer progression was 50% and 69%, respectively, at 6 months and 12 months. Eleven patients (65%) died over the median follow‐up period of 4.6 months (interquartile range, 1.5‐13.2 months) from the time of ICI initiation, with cancer progression being the most common cause of death. Conclusions ICIs can be used as individualized therapy in selected patients who have undergone solid organ transplantation but more studies are needed to determine how best to use these agents to improve outcomes further.

AbstractResponse assessment in light chain (AL) amyloidosis is based on serum and urine monoclonal protein studies. Newly diagnosed patients (n = 373) who achieved very good partial response or complete response (CR) to first line therapy were assessed for the survival impact of each of the monoclonal protein studies. At end of therapy (EOT), negative serum/urine immunofixation (IFE) was achieved in 61% of patients, 72% achieved normal serum free light chain ratio (sFLCR), and the median involved free light chain (iFLC) and difference between involved to uninvolved light chain (dFLC) were 17 mg/L and 5 mg/L, respectively. Overall, 46% of patients achieved a CR at EOT. At EOT, iFLC ≤20 mg/L and dFLC ≤10 mg/L were additive in survival discrimination to negative serum/urine IFE and were independent predictors of overall survival. In contrast, normalization of sFLCR did not add survival discrimination to serum/urine IFE and was not independent predictor of survival. We propose a new definition for hematological CR to include serum/urine IFE negativity plus iFLC ≤20 mg/L or dFLC ≤10 mg/L, instead of the current definition of serum/urine IFE negativity and normal sFLCR. Complete response using dFLC ≤10 mg/L had the best performance in those with significant renal dysfunction and by light chain isotype, making it the preferred partner to IFE. Validation of these results in a multicenter cohort is warranted.

AbstractTransplant‐associated thrombotic microangiopathy (TA‐TMA) has a wide range of presentations after hematopoietic stem‐cell transplantation (HSCT). We retrospectively studied the risk factors and outcomes of patients with early (≤day 100) and late (>day 100) TA‐TMA. Among the 1451 HSCT recipients, early TA‐TMA occurred in 45 (3.1%) patients at a median of 27 (3‐91) days, and late TA‐TMA in 39 (2.7%) patients at a median of 303 (122‐2595) days. Patients with early TA‐TMA were more likely to have high blood calcineurin‐inhibitor levels (P < .001) and acute graph‐vs‐host disease (GVHD, P < .001), while late TMA patients were more likely to have chronic GVHD (P < .001). The estimated median overall survival after onset of TMA for the entire cohort was 6 months. The estimated median overall survival was not reached in patients with an improvement of TMA vs 2 months in patients with no improvement (P < .001). In the early TMA group, older age (for every 10 years, HR 1.40; 95% CI 1.00‐1.94; P = .049) and bacterial infection (HR 2.42; 95% CI 0.98‐6.00; P = .056) were positively associated with mortality. Switching to MMF treatment (HR 0.40; 95% CI 0.16‐0.99; P = .047) and improvement of TMA (HR 0.08; 95% CI 0.03‐0.25; P < .001) were negatively associated with mortality in the multivariate analysis. In the late TMA group, the improvement of TMA was the only independent predictor associated with a lower risk of death (HR 0.05; 95% CI 0.02‐0.19; P < .001). Mortality rates in both early and late TMA remain unacceptably high. Future studies are needed for early diagnosis, trigger identifications, and use of targeted treatments.

Abstract Light chain cast nephropathy (LCCN) in multiple myeloma often leads to severe and poorly reversible acute kidney injury. Severe renal impairment influences the allocation of chemotherapy and its tolerability; it also affects patient survival. Whether renal biopsy findings add to the clinical assessment in predicting renal and patient outcomes in LCCN is uncertain. We retrospectively reviewed clinical presentation, chemotherapy regimens, hematologic response, and renal and patient outcomes in 178 patients with biopsy-proven LCCN from 10 centers in Europe and North America. A detailed pathology review, including assessment of the extent of cast formation, was performed to study correlations with initial presentation and outcomes. Patients presented with a mean estimated glomerular filtration rate (eGFR) of 13 ± 11 mL/min/1.73 m2, and 82% had stage 3 acute kidney injury. The mean number of casts was 3.2/mm2 in the cortex. Tubulointerstitial lesions were frequent: acute tubular injury (94%), tubulitis (82%), tubular rupture (62%), giant cell reaction (60%), and cortical and medullary inflammation (95% and 75%, respectively). Medullary inflammation, giant cell reaction, and the extent of cast formation correlated with eGFR value at LCCN diagnosis. During a median follow-up of 22 months, mean eGFR increased to 43 ± 30 mL/min/1.73 m2. Age, β2-microglobulin, best hematologic response, number of cortical casts per square millimeter, and degree of interstitial fibrosis/tubular atrophy (IFTA) were independently associated with a higher eGFR during follow-up. This eGFR value correlated with overall survival, independently of the hematologic response. This study shows that extent of cast formation and IFTA in LCCN predicts the quality of renal response, which, in turn, is associated with overall survival.

AbstractThe diagnosis of primary plasma cell leukemia (pPCL) has been made by quantifying circulating plasma cells (cPCs) morphologically on a peripheral blood (PB) smear. However, this technique is not sufficiently sensitive. Multiparametric flow cytometry (MFC) provides a readily available and highly sensitive method to identify and quantify cPCs that could complement PB smear assessment. However, an optimal quantitative cutoff for cPCs by MFC to identify pPCL has not been established. Thus, a total of 591 patients newly diagnosed multiple myeloma (NDMM) patients who had their PB samples evaluated morphologically by PB smear, and immunophenotypically by MFC prior to beginning therapy were evaluated. The presence of ≥200 cPCs/μL by MFC (N = 25 or 5% of the total population) was chosen to identify patients with ≥5% cPCs by PB smear with a specificity of 99% and a sensitivity of 77%. For patients with ≥200 cPCs/μL by MFC compared to the remainder of the cohort, the median Time to next therapy (TTNT) was 18 vs 30 months and the median OS was 38 vs 70 months respectively. Thus, MFC assessment of PB can be utilized in conjunction with the morphological assessment of a PB smear to aid in improving the identification of pPCL among NDMM patients.

Kidney failure is a common sequela of multiple myeloma. Tremendous progress in this disease over the past two decades has resulted in more than doubling of the median survival. Despite that, patients with irreversible kidney failure still have inferior outcomes as compared to those with intact kidney function. Kidney transplantation in these patients remains controversial. In this issue of Journal of Onco-Nephrology, two groups of clinicians caring for these patients debate the pros and cons of kidney transplantation in this population. The improvement of overall survival to 7.7 years in patients under the age of 65 years is a strong arg for kidney transplantation. In addition, the use of fluorescent in situ hybridization in risk assessment and minimal residual disease assessment for hematologic response could substantially improve patient selection for kidney transplantation. On the other hand, myeloma remains incurable and kidney failure itself is a high-risk feature. Despite advances, kidney transplantation in myeloma patients continues to present challenges with multiple myeloma relapse, rejection, and infection resulting in higher number of graft loss and death. Whether kidney transplant should be performed in patients with multiple myeloma currently remains debatable, but it may not be long before overall survival and disease control improve to the point where withholding kidney transplantation would be unethical. The questions in preparation for that day are should myeloma patients be held to the same metrics as patients without myeloma and if no, then what would be an acceptable overall and graft survival? Once the answers have been agreed upon by the experts and the governing bodies for transplantation, then proper clinical trials can be designed so that benefits can be optimized and precious resources not be wasted.

AbstractWe evaluated bone marrow minimal residual disease (MRD) negativity in 44 patients with light chain (AL) amyloidosis using next generation flow cytometry (sensitivity ≥1 × 10−5; median events analyzed: 8.7 million, range: 4.8 to 9.7 million). All patients underwent MRD testing in 2 years from start of therapy (median: 7 months). The overall MRD negative rate was 64% (n = 28). The MRD‐negative rate after one‐line of therapy was 71% (20/28). And, MRD negative rates were higher with stem‐cell transplant as first‐line therapy (86%, 18/21) vs chemotherapy alone as first‐line treatment (29%, 2/7), P = .005. The MRD negative rate amongst patients in complete response was 75% (15/20), and in very good partial response, 50% (11/22). There were two patients in partial response/rising light chains (with renal dysfunction) who were MRD negative. There were no differences in baseline characteristics of MRD negative vs MRD positive patients, except younger age amongst MRD‐negative patients. Patients with MRD negativity were more likely to have achieved cardiac response at the time of MRD assessment, 67% (8/12) vs 22% (2/7), P = .04. Renal response rates were similar in both groups. Progression free survival was assessed in the 42 patients achieving CR or VGPR. After median follow‐up of 14 months, the estimated 1‐year progression free survival in MRD negative vs MRD positive patients was 100% (26 patients, 0 events) vs 64% (16 patients, five events), P = .006, respectively. MRD assessment should be explored as a surrogate endpoint in clinical trials and MRD risk‐adapted trials may help optimize treatment in AL amyloidosis.