Citations

Abstract Background and Aims High dose Methotrexate (HDMTX) is an important component of several modern oncological/haematological treatment protocols due to its central nervous system penetrance. Nephrotoxicity represents a significant adverse effect and can limit therapeutic options. Therefore, strategies to prevent this are paramount. Urinary alkalinisation and large volume resuscitation to maintain adequate hydration and urine output are the typical strategies. Urinary alkalinisation prevents tubular precipitation of methotrexate and therefore, a strict urinary pH target of 7 is maintained via a continuous bicarbonate infusion. Method We describe a case report, of Iatrogenic metabolic alkalosis leading to respiratory compromise in a patient receiving HDMTX from Mayo Clinic, Rochester. Results We present the case of a 76-year-old woman with a Diffuse Large B-Cell Lymphoma with CNS involvement who presented for elective admission for her 1st cycle of HDMTX. She received 7g of Methotrexate at dosing of 8 g/m2. She received the standard urinary alkalinisation with pre- and post-hydration. Her baseline HCO3- was 28 mEq/L. Her 48 hour MTX level was elevated at 1.2 so the urinary alkalinisation protocol was continued until <0.1 mcmol/L. On day 4, she developed frequent episodes of apnoea. Her ABG demonstrated a metabolic alkalaemia pH 7.54, pCO 53, pO2 91, HCO3 45. She was transferred to the ICU for close monitoring. Her bicarbonate infusion was discontinued and she received acetazolamide. Her bicarbonate improved to 31 after 12 hours. She had a significant improvement in her respiratory status with no further episodes of apnoea. Her bicarbonate infusion was restarted due to elevated MTX levels. She was discharged home with no further complications. Conclusion Iatrogenic Metabolic alkalosis leading to respiratory compromise represents a rare but important complication of urinary alkalinsation protocols for High-dose Methotrexate therapy.

e20510 Background: pPCL is a rare and aggressive form of multiple myeloma (MM) with dismal survival outcomes compared to the remainder of MM patients. Several studies have validated the optimal cutoff for defining pPCL to be >5% circulating plasma cells (cPCs) on a peripheral blood smear due to equally poor outcomes in this less restrictive cohort. We evaluated the clinical outcomes and cytogenetic features of patients diagnosed with pPCL at our institution that were treated with novel agent induction therapies. Methods: We evaluated patients with pPCL diagnosed between 2000 – 2018 (using the 5% cut off) at Mayo Clinic, Minnesota. Data was extracted from a prospectively maintained database and from the review of electronic medical records. Patients were categorized as having high risk (HR) cytogenetics if any of the following abnormalities were present: del 17p, t(4;14), t(14;16) or t(14;20). Chi-square tests and Fisher exact tests were used to compare differences between sub-groups. Survival analysis was performed by the Kaplan-Meier method and differences assessed using the log rank test. Results: This cohort consisted of 67 patients with pPCL with a median age of 62 years (range: 34-91) of which 33 (46%) were male. The median follow up was 46 months (95% CI: 41 – 90). The median bone marrow plasma cell involvement was 84% (Range: 10 – 100) and the median cPCs percentage on the peripheral blood was 23% (range: 5 - 93). Data on primary cytogenetic abnormalities were available in 60 (85%) patients and the distribution was as follows: t(11;14) – 27 (45%), t(4;14) – 5 (8%), t(14;16) – 8 (13%), t(14;20)- 3(5%) and del 17p- 15(25%). All patients received novel agent induction therapy with 36 (54%) having received autologous stem cell transplant and 4 undergoing an allogeneic stem cell transplant. The median time to next therapy (TTNT) and overall survival (OS) for all patients was 13 months (95% CI: 9 – 17) and 24 months (95% CI: 19 – 40) respectively; 16 months and 51 months for standard risk (SR) vs. 10 months and 19 months for HR (P = 0.005 for OS), when stratified by cytogenetic risk. There were only 17 (31%) patients who were alive for ≥48 months since diagnosis (i.e. twice the median OS of this cohort); The absence of high risk cytogenetics (P = 0.049) and non-elevated LDH level (P = 0.047) at diagnosis predicted for achieving this survival goal. Conclusions: The outcomes of patients diagnosed with pPCL remain poor despite the use of novel agent induction therapy. However, some patients appear to do better than expected and this phenomenon may be influenced by the presence of HR cytogenetics.

e20035 Background: HDMTX is a vital treatment of lymphoma secondary to central nervous system penetrance. MTX is nephrotoxic and may cause acute kidney injury (AKI). AKI results in delayed MTX elimination, increased hospital length of stay (LOS) and intensive care unit (ICU) stays. Our aim was to characterise the complications and associated 48-hour MTX levels in lymphoma patients undergoing HDMTX. Methods: A retrospective review of the electronic medical record was conducted to identify lymphoma patients who received HDMTX from 1/1/2002 to 12/31/18. We assessed the incidence of AKI using AKIN criteria, ICU admission, and LOS across 48 hour MTX levels per the table. Results: 2704 cycles of HDMTX were identified. The mean age was 64 years, 54% were male and 72.2% received high dose (≥8g/m2). A significant increase in AKI severity (p < 0.0001) and LOS (p < 0.01) occurred with increasing 48 hour MTX levels, (p < 0.001, Table). All 7 patients requiring dialysis had MTX levels > 10. ROC curve analysis for AKI grade ≥ 2 demonstrated a 48 hour MTX level threshold of 1.28 (AUC 0.79) with relative risk of 7.6 (95% CI 5.3-11) and odds ratio of 8.8 (95% CI 5.9-13.1). A significant increase occurred in LOS across escalating 48 hour MTX level subgroups (p < 0.01, Table). A significant rise in ICU admissions occurred with increasing MTX levels ( < 0.01% for MTX < 2 compared to 15% with MTX > 5). Conclusions: Complications of HDMTX are significantly increased with elevated 48 hour MTX levels, particularly with levels > 1 μmol/L. [Table: see text]

e20033 Background: HDMTX is an important component of lymphoma therapy due to its central nervous system penetration. Although HDMTX can be safely administered to most patients, it can cause significant toxicity with those who have prolonged exposure to high plasma concentrations of MTX due to delayed elimination. Therefore, serum MTX concentration monitoring is still a standard approach for identifying patients at high risk of developing MTX toxicity. A majority of MTX is excreted within the first 48 hours of infusion. Higher MTX plasma concentrations at 48 hrs increase the likelihood of delayed MTX elimination. This study will assess baseline characteristics associated with high 48-hour MTX levels (≥ 1µM) which has been associated with increased risk of complications. Methods: A retrospective review of the electronic medical record was conducted to identify lymphoma patients who received HDMTX from 1/1/2002 to 12/31/18. Baseline demographics including age, gender, comorbidities, body surface area, BMI, weight and baseline chronic kidney disease (CKD) were recorded. Demographics, HDMTX dosing per protocol (3.5g/m2 vs 8g/m2), HDMTX adjusted by renal function (CrCl < 100), and ratio of MTX dose to BSA (MTX/BSA) were compared to 48 hour MTX levels. Analysis was performed in JMP 15. Results: 2553 cycles were of HDMTX were identified. There was a significant association of increasing age, (p = 0.039), male patients (p < 0.001), 8g/m2 dosing (p < 0.001), higher MTX dose (p < 0.001), MTX/BSA (p < 0.001), GFR by CKD-EPI (p < 0.001) and lower number of comorbidities (p < 0.001) with 48-hour MTX levels ≥1. There was no significant association of 48-hour MTX levels ≥1 and GFR by Cockcroft-Gault (p = 0.73), baseline CKD (p = 0.78), and renal adjusted HDMTX (p = 0.52). Multivariate analysis revealed significance for MTX/BSA, gender, BSA, GFR by CKDEPI (p < 0.001), and age (P = 0.0002). Conclusions: Hematologists should be aware that age, gender, GFR by CKD-EPI, and ratio of MTX dose to BSA are associated with elevated 48-hour MTX levels ≥1.

8549 Background: Proteinuria evaluation is essential for diagnosing and monitoring of renal involvement in light chain (AL) amyloidosis. A 24 hour protein collection (24h UP) is the gold standard for proteinuria assessment however it is cumbersome and can be inaccurate. A spot urine albumin to creatinine ratio (uACR) has been proposed as a convenient method to estimate 24hUP. We aimed to validate the correlation between uACR and 24hUP in a large cohort of patients. Methods: We retrospectively studied systemic AL amyloidosis patients evaluated between 2010 and 2019 at Mayo Clinic, with a uACR and 24hUP collected less than 7 days apart. Linear regression analysis was used to construct a prediction model for 24hUP with uACR as the primary predictor. Possible confounders (age, gender, body mass index, morning versus afternoon spot urine collection, estimated glomerular filtration rate) for the primary relationship between uACR and 24h UP were evaluated in the model. We used receiver operating characteristic (ROC) analysis to identify the best uACR cutoff to predict significant proteinuria (defined as a 24hUP > 500mg). Results: We included 665 patients, with a median age of 66 years (IQR 59-72). The spot urine was collected in the morning (before 1200 hours) in 382 (57%) patients, and in the afternoon in 283 (43%) patients. The median 24hUP was 321 (IQR 129-2512.5) mg, median uACR was 107 (IQR 13.5-1845) mg/g, and median serum creatinine was 1.2 (IQR 1-1.8) mg/dL. The uACR correlated well with 24h UP (Pearson’s r= 0.83, 95% CI 0.80-0.85). Linear regression showed that E (24h UPi) = 362 + 1.05(uACRi), and this model was statistically and clinically significant (p < 0.001 and R2 of 0.68, respectively). Age, gender, body mass index, eGFR, and time of day of spot urine collection did not confound the primary relationship between uACR and 24hUP, and no collinearity was observed. A uACR cutoff of > 280 mg/g was the best predictor of a 24hUP > 500 mg (area under the ROC curve 0.98, sensitivity 92%, specificity 97%). For simplicity, we assessed the predictive value of uACR > 300 mg/g for 24h UP > 500 mg. Among patients with 24huACR > 300 mg/g 264 (96%) had a 24hUP > 500 mg, and 31 (7%) of patients with uACR < 300 mg/g had a 24h UP > 500 mg (p < 0.001). Conclusions: In systemic AL amyloid patients, we showed that uACR on a random urine sample correlated well with 24h UP, and can be used to estimate proteinuria with a linear regression model. Based on these findings, and the convenience of uACR testing for patients, we propose that uACR should be used to monitor renal response to AL amyloidosis therapy.

8516 Background: The role of induction therapy prior to autologous stem cell transplant (ASCT) in immunoglobulin light chain (AL) amyloidosis remains controversial. Data on the prognostic impact of response to induction in a transplanted cohort are lacking. The aim of this study was to assess the impact of response to induction therapy on survival in patients undergoing ASCT for AL amyloidosis. Methods: We conducted a retrospective study of all newly diagnosed AL amyloidosis patients who received induction prior to ASCT between January 2007 and August 2017 at Mayo Clinic, Rochester, Minnesota. Patients receiving only corticosteroids prior to transplant were excluded as were those with an involved light chain of less than 5 mg/dL (not measurable for response). Results: 134 patients met inclusion criteria. The median age at diagnosis was 60 (range 36-74) and 85 (63%) were men. The most commonly used induction regimen was proteasome inhibitor-based (73.1%, n=98). The overall response rate to induction was 83% (complete response 17%, very good partial response 30% and partial response 36%). With a median follow up of 56.5 months, the median PFS and OS was 48.5 months and not reached, respectively. Response depth to induction therapy was associated with improved PFS and OS and was independent of the bone marrow plasma cell percentage. The median PFS was not reached for patients achieving ≥VGPR prior to ASCT and 33.8 months for patient achieving PR or less (P=0.001). The median OS was longer in patients with deeper responses (not reached for patients achieving ≥VGPR vs. 128 months for patients achieving PR or less (P=0.02). On multivariable analysis, independent predictors of OS were melphalan conditioning dose (RR= 0.38; P=0.018) and depth of response prior to transplant (RR 2.52; P=0.039). Conclusions: Hematologic response prior to transplant predicts post-transplant outcomes in patients with AL amyloidosis. [Table: see text]

AbstractMetaphase cytogenetic abnormalities, plasma cell proliferation index (PCPro), and gain 1q by fluorescence in situ hybridization (FISH) are associated with inferior survival in newly diagnosed multiple myeloma (MM) treated with novel agents; however, their role in risk stratification is unclear in the era of the revised International Staging System (R-ISS). The objective of this study was to determine if these predictors improve risk stratification in newly diagnosed MM when accounting for R-ISS and age. We studied a retrospective cohort of 483 patients with newly diagnosed MM treated with proteasome inhibitors and/or immunomodulators. On multivariable analysis, R-ISS, age, metaphase cytogenetic abnormalities (both in aggregate and for specific abnormalities), PCPro, and FISH gain 1q were associated with inferior progression-free (PFS) and overall survival (OS). We devised a risk scoring system based on hazard ratios from multivariable analyses and assigned patients to low-, intermediate-, and high-risk groups based on their cumulative scores. The addition of metaphase cytogenetic abnormalities, PCPro, and FISH gain 1q to a risk scoring system accounting for R-ISS and age did not improve risk discrimination of Kaplan-Meier estimates for PFS or OS. Moreover, they did not improve prognostic performance when evaluated by Uno’s censoring-adjusted C-statistic. Lastly, we performed a paired analysis of metaphase cytogenetic and interphase FISH abnormalities, which revealed the former to be insensitive for the detection of prognostic chromosomal abnormalities. Ultimately, metaphase cytogenetics lack sensitivity for important chromosomal aberrations and, along with PCPro and FISH gain 1q, do not improve risk stratification in MM when accounting for R-ISS and age.

Abstract Background Studies comparing all treatment options for frequently-relapsing/steroid-dependent (FR/SD) minimal change disease (MCD) in adults are lacking. Methods Medical records of 76 adults with FR/SD MCD who were treated with corticosteroids as the first-line therapy were reviewed. Treatment options were compared for the time to relapse, change of therapy and progression (relapse on full-dose treatment). Results Second-line treatments included rituximab (RTX; n = 13), mycophenolate mofetil (MMF; n = 12), calcineurin inhibitors (CNI; n = 26) and cyclophosphamide (CTX; n = 16). During the second-line treatments, 48 (71.6%) patients relapsed at median 17 (range 2–100) months. The majority of relapses occurred during dose tapering or off drug. Twenty of 65 (30.8%) changed therapy after the first relapse. The median time to relapse after the second line was 66 versus 28 months in RTX versus non-RTX groups (P = 0.170). The median time to change of treatment was 66 and 44 months, respectively (P = 0.060). Last-line treatment options included RTX (n = 8), MMF (n = 4), CNI (n = 3) and CTX (n = 2). Seven (41.2%) patients had a relapse during the last-line treatment at median 39 (range 5–112) months. The median time to relapse was 48 versus 34 months in the RTX versus non-RTX groups (P = 0.727). One patient in the RTX group died presumably of heart failure. No major adverse event was observed. During the median follow-up of 81 (range 9–355) months, no patients developed end-stage renal disease. Conclusions Relapse is frequent in MCD in adults. Patients treated with RTX may be less likely to require a change of therapy and more likely to come off immunosuppressive drugs.

Abstract Light chain deposition disease (LCDD) is a systemic disorder characterized by deposition of nonamyloid monotypic light chains throughout the body. Renal dysfunction is a ubiquitous manifestation of the disease. Reports suggest that high-dose chemotherapy and autologous stem cell transplantation may be beneficial in the treatment of LCDD. However, the impact of autologous stem cell transplantation on renal function is unclear. This study retrospectively reviewed the effect of autologous stem cell transplantation on renal function in six patients with LCDD. Two patients had concurrent multiple myeloma, and one patient was on hemodialysis prior to transplantation. Patients received chemotherapy with dexamethasone alone or dexamethasone plus thalidomide prior to transplantation. Conditioning was performed with high-dose intravenous melphalan. All patients survived transplantation, but one sustained multi-organ failure shortly afterwards and died. Another patient required temporary hemodialysis following transplantation. All surviving patients achieved a hematologic response, although one ultimately relapsed and required further chemotherapy. Renal parameters also improved. On average, proteinuria levels decreased by 83% in four patients and increased by 1% in one patient. Creatine clearance calculated by the Modification of Diet in Renal Disease (MDRD) Study prediction equation improved by an average of 40%. This review suggests that autologous stem cell transplantation may be an effective therapy for renal dysfunction associated with LCDD. Clinical Characteristics of LCDD Patients at Presentation Characteristic Number or range Median *Modification of Diet in Renal Disease Study prediction equation Sex 4 male, 2 female Age (years) 35-61 44 Beta-2 microglobulin, μ/ml 3.58-11 4.12 Albumin, g/dl 1.8-4.2 3.85 Creatinine, mg/dl 1.8-5.4 2.45 MDRD*, ml/min 12-50 26.5 Serum M protein, g/dl 0 0 Serum free light chains, mg/dl (n = 5) 2.18-312 19.6 24-hour urine protein, mg 131-10,251 679