Lenalidomide, bortezomib, and dexamethasone (RVD) is standard-of-care induction for fit multiple myeloma patients, with response rate (RR)>90% in first line. Standard RVD utilizes a 21-day cycle with bortezomib IV 1.3 mg/m2 days 1, 4, 8, and 11; lenalidomide 25 mg days 1-14; and dexamethasone 160-320 mg per cycle. Bortezomib-induced neuropathy may be treatment-limiting, occurring in up to 80% of patients. Weekly administration of bortezomib, subcutaneous (SC) dosing, and extending the cycle to 28 or 35 days may optimize tolerance. Those adjustments were studied primarily in transplant-ineligible or relapsed/refractory patients. We report the results of a retrospective analysis of patients who received RVD on a 21-day cycle with weekly subcutaneous bortezomib to improve tolerability or logistics.

Introduction: Lenalidomide, bortezomib, and dexamethasone is a standard of care in the treatment of fit multiple myeloma patients due to high efficacy, with ORR exceeding 90% in the first-line setting (Richardson et al. 2010). The initial RVD regimen utilized a 21-day cycle with bortezomib administered IV 1.3 mg/m2 days 1, 4, 8, and 11; lenalidomide 25 mg administered days 1-14; and dexamethasone administered 160 to 320 mg per cycle. However, toxicity may be treatment-limiting, with bortezomib-induced neuropathy affecting up to 80% of patients. Modifications to RVD to optimize tolerance include reducing the bortezomib dose to a weekly schedule (1.6 mg/m2 IV or 1.3 mg/m2SC) and extending the cycle to 28 or 35 days (Broijl et al. 2016; O'Donnell et al. 2014). Notably, those regimens were studied in transplant-ineligible or relapsed/refractory patients. Based on regimens like CyBorD (which utilize weekly SC administration of bortezomib, are well-tolerated and are efficacious), we modified the standard 21-day RVD regimen to include 3 doses of weekly bortezomib in an attempt to preserve efficacy while minimizing toxicity. We present a retrospective analysis of both fit and transplant-ineligible patients treated at our institution using “Louisville RVD.”

Abstract Introduction Cytarabine combined with an anthracycline has long been the basis of therapy for acute myeloid leukemia (AML). Complete remission (CR) with standard therapy in patients > 60 has been reported to be 30 - 50%. Studies to improve remission rates have suggested that induction treatment using high-dose cytarabine (HDAraC) in adults age < 60 is safe and may improve survival in some patients. The use of such an aggressive induction regimen in older (>60) patients has not been extensively studied. The objective of this study was to assess tolerability and efficacy of HDAraC in patients 60 years of age or older compared to those age < 60. Methods Chart review of all patients that received induction chemotherapy with HDAraC between 2007 and 2013 at University of Louisville was done evaluating for: disease status and performance status at time of diagnosis, adverse effects during induction treatment, and treatment outcomes. HDAraC treatment in patients > 50 involved cytarabine at 1.5 g/m2 every 12 hours for 12 doses; for patients < 50, the cytarabine dose was 3g/m2 every 12 hours for 12 doses. Cytarabine was combined with 3 daily doses of idarubicin (12 mg/m2) on days 2-4 in all patients. Response was assessed with bone marrow biopsy on day 30 of induction or until neutropenia resolved. Results Seventy-seven patients received HDAraC between 2007 and 2013 (42 patients age < 60 and 35 patients age > 60. One patient < 60 and 8 patients > 60 died before day 30 without remission; 35 (83%) patients < 60 achieved CR and 21 (60%) of patients > 60 achieved CR (p=0.038). Adverse events related to induction chemotherapy were statistically significant more common in patients > 60 for respiratory failure (p=0.01), septic shock (p=0.004), bleeding complications (p=0.029), and cardiac toxicity (p=0.001), but not for kidney failure (p=0.302), gastrointestinal complications (p=0.226), neurotoxicity (p=0.105), or neutropenic fever (p=0.205). Overall toxicities, especially death within 30 days, was increased in patients > 60. Conclusions HDAraC induction in patients > 60 had a favorable CR rate (60%) compared to reported CR with conventional therapy, but with more toxicity when compared to younger patients. Additional studies involving a larger study group and subset analysis of cytogenetic and molecular markers could identify a specific elder population that may benefit from high-dose treatment. Evaluation of tools like the Comprehensive Geriatric Assessment (CGA) or a modified HCT-CI in this setting are recommended. Disclosures No relevant conflicts of interest to declare.

Isolated extramedullary disease (EMD) is uncommon, especially in acute promyelocytic leukemia (APL) after allogeneic hematopoietic stem cell transplantation (HSCT). We review the literature and present a 32 year old woman with APL who developed multiple EMDs after allogeneic HSCT within the calvarium, and later found to have various isolated lesions including femur, humerus and thoraco lumbar vertebrae. She was treated with local radiotherapy (XRT) to EMD lesions, all-trans retinoic acid, arsenic trioxide and donor lymphocyte infusion at different time points in her clinical course, without success. Out of reported cases in clinical setting as ours, average onset of isolated EMD is 25 months and median survival 14 months. Effective treatment of isolated EMD after HSCT is not yet clear, but ATO in combination with local XRT, tamibarotene and second HSCT have shown good results in some reported cases, but accumulation of more cases is needed to elucidate optimal therapy in such setting.

The toxicity of chronic immunosuppressive agents required for organ transplant maintenance has prompted investigators to pursue approaches to induce immune tolerance. We developed an approach using a bioengineered mobilized cellular product enriched for hematopoietic stem cells (HSCs) and tolerogenic graft facilitating cells (FCs) combined with nonmyeloablative conditioning; this approach resulted in engraftment, durable chimerism, and tolerance induction in recipients with highly mismatched related and unrelated donors. Eight recipients of human leukocyte antigen (HLA)-mismatched kidney and FC/HSC transplants underwent conditioning with fludarabine, 200-centigray total body irradiation, and cyclophosphamide followed by posttransplant immunosuppression with tacrolimus and mycophenolate mofetil. Subjects ranged in age from 29 to 56 years. HLA match ranged from five of six loci with related donors to one of six loci with unrelated donors. The absolute neutrophil counts reached a nadir about 1 week after transplant, with recovery by 2 weeks. Multilineage chimerism at 1 month ranged from 6 to 100%. The conditioning was well tolerated, with outpatient management after postoperative day 2. Two subjects exhibited transient chimerism and were maintained on low-dose tacrolimus monotherapy. One subject developed viral sepsis 2 months after transplant and experienced renal artery thrombosis. Five subjects experienced durable chimerism, demonstrated immunocompetence and donor-specific tolerance by in vitro proliferative assays, and were successfully weaned off all immunosuppression 1 year after transplant. None of the recipients produced anti-donor antibody or exhibited engraftment syndrome or graft-versus-host disease. These results suggest that manipulation of a mobilized stem cell graft and nonmyeloablative conditioning represents a safe, practical, and reproducible means of inducing durable chimerism and donor-specific tolerance in solid organ transplant recipients.

Abstract Abstract 832 Background: Renal transplantation is the preferred therapeutic approach for end-stage renal disease. However, the chronic use of non-specific immunosuppressive agents (IS) is costly and has significant toxicities including opportunistic infection, an increased rate of malignancy, nephrotoxicity, and other end-organ damage. The induction of donor-specific tolerance would address these limitations. Bone marrow chimerism is associated with tolerance to transplanted organs and tissues. However, the toxicity associated with conventional hematopoietic stem cell transplants (HSCT), primarily graft-versus-host disease (GVHD), and the need for aggressive ablative conditioning, has limited the therapeutic application of HSCT to tolerance induction. We have identified a novel tolerogenic bone marrow cell population of CD8+/TCR− facilitating cells (FC) that enhances engraftment of bone marrow in mismatched recipients without causing GVHD. The discovery of FC is an important finding as it opens the door to employing HSCT as a viable cell-based approach for tolerance induction. Methods: We report here the long-term follow-up for 8 HLA mismatched living donor renal transplant recipients enrolled in a tolerogenic protocol involving low-intensity conditioning (fludarabine, cyclophosphamide [50 mg/kg, day −3, +3], 200 cGy TBI) followed by HSCT and renal transplantation. Lymphocyte depleting antibody therapy was not employed. Patients received a living donor kidney transplant on day 0, followed by infusion of cryopreserved FC-enriched donor-derived CD34+ HSC (FCRx) on day +1 (0.49–4.48 × 106 FC/kg recipient body weight) and a calculated dose of T cells (Table). All subjects were discharged by post-operative day 3 and managed as outpatients. Maintenance IS consisted of tacrolimus and MMF without steroids. Weaning of immunosuppression was designed to occur over a one-year period. At 6 months, if chimerism was present and renal function and biopsy normal, the MMF was discontinued; at 9 months the tacrolimus was decreased to trough levels of 3 to 5; and at 12 months, tacrolimus was discontinued. Characteristics and degree of HLA mismatch are shown in the table. Results: The patients are now 13 to 30 months post-transplant. All patients demonstrated peripheral blood macrochimerism post-transplant, ranging from 6% to 100% at 1 month by STR molecular analysis. No patient developed acute GVHD, showed evidence of engraftment syndrome, or has developed evidence of chronic GVHD. Chimerism was lost in two of the patients at 3 and 6 months post-transplant (NW 1 and 4). These subjects received an FCRx containing the fewest numbers of FC. Renal allograft loss occurred in one patient who developed sepsis and myelosuppression following an atypical viral infection 2 months post-transplant. He was successfully rescued with banked autologous HSCT. He was subsequently re-transplanted. The seven remaining patients demonstrate donor-specific hyporesponsiveness. Five have been successfully withdrawn entirely from IS, with one patient now off all IS for 15 months (30 months post-transplant). Four of these five subjects had mismatched unrelated (UR) donors (Table). None developed anti-donor antibody by flow crossmatch. Adverse events have included single dermatome herpes zoster reactivation in 2 patients which resolved. No clinically significant CMV or polyoma viral infections have occurred. Conclusions: Low intensity conditioning in conjunction with FC-enriched HSCT can safely achieve high level, durable donor chimerism in unrelated and related HLA-mismatched kidney transplant recipients without acute or chronic GVHD. This is associated with stable renal function and successful IS withdrawal. Disclosures: Tollerud: Regenerex, LLC: Equity Ownership. King:Regenerex, LLC: Employment. Ildstad:Regenerex, LLC: Equity Ownership.

Elliott, M J.1; Ildstad, S1; Cheerva, A1; Dampier, C2; Bertolone, S1; Tollerud, D1; Herzig, G1; Herzig, R1 Author Information

Hillard M. Lazarus, Department of Medicine, University Hospitals Case Medical Center, Ireland Cancer Center, Case Western Reserve University Gordon L. Phillips, Department of Medicine, University of Rochester Medical Center, Rochester, NY Roger H. Herzig, Department of Blood and Marrow Transplant, University of Louisville, James Graham Brown Cancer Center, Louisville, KY David D. Hurd, Department of Internal Medicine, Wake Forest University School of Medicine, Winston-Salem, NC Steven N. Wolff, Department of Internal Medicine, Meharry Medical College, Nashville, TN Geoffrey P. Herzig, Department of Blood and Marrow Transplant, University of Louisville, James Graham Brown Cancer Center, Louisville, KY

Lymphoproliferative disorders are a recognized complication of allogeneic hematopoietic cell transplantation (HCT). Most are B-cell disorders, often associated with Epstein-Barr virus infection. We report the fourth case of T-cell, large granular lymphocyte leukemia. In May 2005, a 63-year-old woman with acute myeloid leukemia in first relapse underwent reduced intensity, myeloablative, allogeneic peripheral blood HCT from her HLA-genotypically matched brother. Three months later, she received a donor-lymphocyte infusion (DLI) for recurrent leukemia. She developed acute graft-versus-host disease (GvHD) and remission of leukemia. GvHD was controlled with high-dose steroids. Multiple episodes of asymptomatic cytomegalovirus viremia were treated with pre-emptive valganciclovir. In June 2006, 10 months post-DLI, PCR-based chimerism studies revealed 100% donor peripheral blood cells. One month later, immunophenotyping of peripheral blood to evaluate neutropenia and lymphocytosis, revealed expansion of CD3+, CD8+, CD2+, CD11c+ and HLA-DR+ lymphocytes with clonally rearranged T-cell receptor genes, consistent with the diagnosis of large granular lymphocyte (LGL) leukemia. Evaluation of her donor, including bone marrow aspiration and biopsy, showed normal hematopoiesis with no evidence of LGL expansion. PCR of donor peripheral blood mononuclear cells was negative for TCRγ rearrangements. During the year since diagnosis of T-cell LGL leukemia the CBC has been stable, without specific treatment, and AML remains in remission. Discussion: lymphocytosis due to expansion of T-cell large granular lymphocytes is a rare occurrence after allogeneic HCT. Non-clonal expansion is more common, with 6 cases described in a series of 201 patients (Mohty et al. Leukemia2002; 16:2129–33). To our knowledge, this is the fourth documented case of donor-derived T-cell LGL leukemia (clonal expansion) after allogeneic HCT. The course of post-transplant LGL leukemia appears to resemble de novo disease. Of the previously reported cases, 2 patients were alive 6 and 18 months (Chang et al. Am J Clin Pathol2005; 123:196–9), and 1 died 7 months post-LGL leukemia diagnosis (Au et al. Am J Clin Pathol 2003; 120:626–30). Our patient is 12 months since diagnosis without therapy. Etiologic factors responsible for post-transplant LGL leukemia have not been identified. In all cases tested, the leukemia arose in donor cells, but was not transmitted from the donor. An association between long-term antigenic stimulation due to GvHD or viral infection has been proposed. Our patient had both GvHD and recurrent CMV viremia before developing T-cell LGL leukemia. Of interest, our patient experienced long-lasting complete remission of AML after DLI. Whether the T-cell LGL leukemia, which developed almost one year after DLI, has any impact on maintaining remission (graft-versus-leukemia effect) is unknown, but has been suggested by other authors.

Purpose: The recombinant human interleukin-1 receptor (rhu IL-1R) is a soluble truncated form of the type 1 full-length membrane-bound receptor that binds IL-1 with identical affinity to that of the membrane form. As such, it may have clinical potential by sequestering IL-1, thereby preventing it from binding to its membrane-bound receptor and eliciting a biological effect. As IL-1 has been shown to regulate leukemic cell proliferation in an autocrine fashion, a phase I trial of rhu IL-1R was conducted in patients with relapsed and refractory acute myeloid leukemia (AML). Methods: The study group comprised 11 patients who were sequentially treated on one of three dose levels, receiving a single intravenous (i.v.) bolus dose on day 1 followed by 13 days of daily subcutaneous (s.c.) injections with the option of an additional 14 days of treatment if a response of stable disease or better was achieved. Dose level 1 i.v. bolus 500 \(\)g/m2, s.c. dose 250 \(\)g/m2 per day (five patients); dose level 2 i.v. bolus 1000 \(\)g/m2, s.c. dose 500 \(\)g/m2 per day (three patients); dose level 3 i.v. bolus 2000 \(\)g/m2, s.c. dose 1000 \(\)g/m2 per day (three patients). Owing to limited drug availability, the study was designed to only examine these three dose levels. Results: rhu IL-1R was well tolerated. There was no grade 3 or 4 non-hematological toxicity related to the study drug and the maximum tolerated dose was not reached. No IL-1R-blocking antibodies developed during the course of the study. Serum levels of IL-1\(\), IL-6 and TNF were undetectable before, during and after rhu IL-1R administration. The terminal half-life after i.v. dosing was at least 7–12 h, and after s.c. dosing 2–4 days. Serum levels of rhu IL-1R up to 360- and 25-fold those of pretreatment levels were achieved after i.v. and s.c. dosing respectively. No patient had a complete, partial or minor response to treatment; four had stable disease and seven had progressive disease. Conclusions: rhu IL-1R therapy was safe but did not have any apparent antileukemic effect at the doses administered.

BACKGROUND:Acute renal failure, with or without massive proteinuria, is a rare idiosyncratic toxicity of interferon (IFN)-alpha therapy. The authors sought to review their experience with this toxicity as well as the world literature on the subject.METHODS:The authors describe two patients with chronic myeloid leukemia treated with IFN-alpha following high dose chemotherapy who developed renal failure and proteinuria after 3 and 4 weeks of IFN-alpha therapy, respectively. Fifteen previously reported cases of renal failure and proteinuria associated with IFN-alpha therapy are also reviewed.RESULTS:Renal biopsies performed on the authors' two patients revealed focal segmental glomerulosclerosis. However, the other reported patients with IFN-alpha-associated renal failure and massive proteinuria had an assortment of pathologic findings.CONCLUSIONS:The specific renal pathology associated with proteinuria may be a consequence of the condition and not its cause; differences in renal pathology may be caused by other predisposing factors. Patients treated with IFN-alpha following high dose chemotherapy, with or without autologous transplantation, should be followed for the development of proteinuria and renal failure.

Autopsies were performed on four patients who had been treated with high-dose BCNU therapy for visceral, cutaneous, or lymphoid malignancies. Three had developed an encephalopathy or encephalomyelopathy within five weeks before death. In all four patients distinctive lesions were found within the central nervous system that were either (1) discrete foci of swollen axis cylinders and myelin vacuolization or (2) larger, symmetric areas of edema with white and gray matter necrosis. Fibrinoid necrosis and fibrin microthrombi were much more prominent in the latter. The small discrete foci of axonal and myelin alterations are similar, if not identical, to lesions previously associated with cranial radiation or combined cranial radiotherapy and chemotherapy. The larger lesions share features with "methotrexate encephalopathy" and delayed radionecrosis. The presence of these lesions in these patients, who had not received cranial radiation, suggests that high-dose BCNU therapy alone is associated with, and may produce, certain distinctive structural changes in the central nervous system. The presence of fibrinoid necrosis and fibrin microthrombi suggests that this possible pathologic effect of BCNU could be mediated by the drug's effect on the cerebrospinal vasculature.

Adults with acute leukemia and malignant lymphoma in relapse after conventional therapy are treated with cyclophosphamide and total body irradiation (TBI) followed by autologous bone marrow transplants. For cobalt TBI, patients seated in a stand angled 45° above the floor are treated in a single fraction with sequential right and left lateral 87 cm ×87 cm fields at 220 cm source-axis distance (SAD) using a 5000 Ci cobalt unit. Typical lateral diameters, mid-plane dose rates, mid-plane doses, and maximum doses are: Hips, 34 cm, 8 rad/min, 900 rad, and 1050 rad; and shoulders, 38 cm, 7.7 rad/min, 800 rad, 1080 rad. The estimated lung dose is 1000 to 1100 rad. A compensator limits the dose to the head to 1000 rad. Estimated organ doses are: small intestine, liver and kidneys-1100 rad, and heart-1200 rad. Phantom dosimetry and dosimetry on patients treated reveals that these doses are delivered within 5 % accuracy. Patient tolerance of treatment, and some biological considerations of low dose rate therapy are reviewed. Certain dosimetry features of an alternate treatment at 370 cm SAD, using 25 MV photons are also presented.

SUMMARY Acute lethal graft-versus-host (GVH) disease regularly follows transplantation of allogeneic bone marrow in rhesus monkeys prepared with lethal irradiation. GVH disease does not occur when frozen autologous marrow is used to protect irradiated animals. Using cyclophosphamide we have been able to interrupt the early course of acute GVH disease in allografted monkeys and have “rescued” recipients by providing hematopoietic reconstitution with stored frozen autologous marrow. This treatment prevented progression of acute lethal GVH reactions which are seen in untreated recipients and has allowed recovery of normal hematopoietic function with prolonged survival. These experiments have demonstrated the feasibility in primates of rescue from acute GVH disease using a cytotoxic drug to destroy the graft and stored autologous marrow to provide hematological reconstitution of the recipient. This procedure may prove useful in the management of severe GVH reactions and in the manipulation of GVH disease in attempts of immunotherapy of malignancy.