C-MYC-positive relapsed and refractory, diffuse large B-cell lymphoma: Impact of additional "hits" and outcomes with subsequent therapy.

BACKGROUND: The impact of MYC proto-oncogene, basic helix-loop-helix (MYC) translocations (with or without additional rearrangements involving the B-cell lymphoma 2 [BCL2] or BCL6 genes) on the response to salvage therapy and survival in patients with diffuse large B-cell lymphoma (DLBCL) who experience primary treatment failure is not well defined. METHODS: This was a multicenter, retrospective study of the impact of MYC, BCL2, and BCL6 rearrangements in patients with DLBCL who failed to achieve complete remission or relapsed within 6 months after they completed upfront chemoimmunotherapy. RESULTS: The authors examined response to salvage therapy, receipt of hematopoietic cell transplantation (HCT), and survival outcomes in MYC-negative (n = 120), MYC-positive single hit (SH) (n = 20), and MYC-positive double hit/triple hit (DH/TH) (n = 35) cohorts. The overall response rate in these cohorts to first salvage therapy (51%, 50%, and 54%, respectively) and receipt of HCT (52%, 40%, and 43%, respectively) were comparable between the 3 cohorts. The 2-year overall survival rate was 29.9% in the MYC-negative cohort, 0% in the MYC-positive SH cohort, and 9.9% in the MYC-positive DH/TH cohort (P < .001), and no difference was observed between the SH and DH/TH cohorts (P = .8). The higher risk of death for patients with MYC-positive SH DLBCL (hazard ratio, 1.70; 95% confidence interval, 0.98-2.96; P = .06) and those with MYC-positive DH/TH DLBCL (hazard ratio, 2.22; 95% confidence interval, 1.41-3.50; P = .001) persisted after adjusting for covariates. For patients who underwent autologous HCT, the 2-year overall survival rate was 55.4% in the MYC-negative cohort, 0% in the MYC-positive SH cohort, and 19.4% in the MYC-positive DH/TH cohort (P < .001). All 4 MYC-positive patients who underwent allogeneic HCT relapsed in <4 months. CONCLUSIONS: Patients with MYC-positive DLBCL who experience primary treatment failure have response rates to similar to those achieved by salvage therapy compared with their MYC-negative counterparts, but their survival is dismal irrespective of additional "hits" and HCT, representing an unmet medical need. Cancer 2017;123:4411-8. © 2017 American Cancer Society.

Diffuse large B-cell lymphoma with primary treatment failure: Ultra-high risk features and benchmarking for experimental therapies.

The outcomes of patients with DLBCL and primary treatment failure (PTF) in the rituximab era are unclear. We analyzed 331 patients with PTF, defined as primary progression while on upfront chemoimmunotherapy (PP), residual disease at the end of upfront therapy (RD) or relapse < 6 months from end of therapy (early relapse; ER). Median age was 58 years and response to salvage was 41.7%. Two-year OS was 18.5% in PP, 30.6% in RD and 45.5% in ER. The presence of PP, intermediate-high/high NCCN-IPI at time of PTF or MYC translocation predicted 2-year OS of 13.6% constituting ultra-high risk (UHR) features. Among the 132 patients who underwent autologous hematopoietic cell transplantation, 2-year OS was 74.3%, 59.6% and 10.7% for patients with 0,1 and 2-3 UHR features respectively. Patients with PTF and UHR features should be prioritized for clinical trials with newer agents and innovative cellular therapy.

Extensive Intracardiac Cement Embolism in a Patient Undergoing Workup for Bone Marrow Transplant.

Cement emboli are a well-established complication of kyphoplasties and vertebroplasties and can easily be mistaken for wires. While kyphoplasties are commonly performed for vertebral fractures caused by metastases from malignancies such as multiple myeloma, the implication of cement emboli in bone marrow transplant (BMT) patients is not well documented. Our patient presented with an incidental intracardiac cement embolism found while undergoing workup for BMT. He was managed conservatively, but transplant workup was put on hold until the embolism could be removed due to the risks associated with cement emboli. The significance of cement emboli in immunocompromised patients needs to be further investigated.

Comparison of Patient Outcomes With Two Different Formulations of Melphalan as Conditioning Chemotherapy for Autologous Hematopoietic Cell Transplantation in Multiple Myeloma.

BACKGROUND: High-dose melphalan (HDM) with autologous hematopoietic cell transplantation (AHCT) after induction chemotherapy is considered standard of care in transplant-eligible patients with newly-diagnosed multiple myeloma (MM). Alkeran melphalan has propylene glycol as a solvent (PG-mel) while Evomela utilizes a propylene glyclol-free formulation (PGF-mel). We evaluated the differences in efficacy and safety of the 2 formulations as there are no prospective head-to-head trials. METHODS: We retrospectively reviewed the medical records of all 259 consecutive MM patients who received PGF-mel as part of HDM-AHCT at The Ohio State University (OSU). The comparator group was the preceding 255 patients who received PG-mel. RESULTS: Baseline patient characteristics were similar between the 2 groups. Post-AHCT rates of relapse were comparable in the PG-mel and PGF-mel groups. Some adverse events were observed at a higher frequency in the PG-mel group compared to the PGF-mel group (grade ≥ 2 mucositis, febrile neutropenia, other infectious complications, and acute renal insufficiency). Time to neutrophil engraftment was slightly longer in the PG-mel group while time to platelet engraftment was longer in PGF-mel group. Red cell transfusion requirement was higher with the use of PG-mel but not platelet transfusion. Duration of hospitalization was slightly shorter with PGF-mel but readmission rates within 30 days of discharge were higher. CONCLUSION: Considering possible confounding factors could possibly account for observed differences in some adverse events, the comparable treatment responses, and difference in cost of the 2 formulation, The OSU reverted to PG-mel as the preferred formulation for HDM-AHCT in MM.

Outcomes After Salvage Autologous Hematopoietic Cell Transplant for Patients With Relapsed/Refractory Multiple Myeloma: A Single-Institution Experience.

BACKGROUND: The role of salvage autologous hematopoietic cell transplantation (sAHCT2) for patients with relapsed/refractory multiple myeloma (RRMM) in the era of modern therapeutics is unclear. As prospective data is limited, we conducted a retrospective analysis to determine the outcomes of sAHCT2. PATIENTS AND METHODS: We conducted a single-institution, retrospective analysis of patients who received sAHCT2 at The Ohio State University from 2000 to 2018. Patients who received a second transplant as part of a planned tandem or autologous-allogeneic transplant were excluded. RESULTS: Fifty-seven patients were treated with sAHCT2. Patients had a median of 2 lines of therapy after AHCT1 prior to their sAHCT2; 70% had prior immunomodulatory imide drugs, 82% had prior proteasome inhibitor, and 20% had prior anti-CD38 monoclonal antibodies as part of re-induction therapy. Forty-two percent of patients attained ≥VGPR prior to sAHCT2. Seventy-four were treated with melphalan 200 mg/m2 as conditioning regimen before infusion of a median of 3.8 × 106 CD34+ cells/kg. Fifty-eight percent patients had maintenance therapy and 81% patients attained CR/VGPR as the best response after sAHCT2. The median PFS and OS after sAHCT2 were 1.6 and 3.6 years, respectively. On multivariable analysis, high-risk cytogenetics, not having attained CR/VGPR, and having more than 2 lines of therapy post-AHCT1 were associated with inferior PFS. Melphalan 140 mg/m2 compared to melphalan 200 mg/m2 and no maintenance therapy compared to maintenance therapy were not associated with inferior PFS. There was no transplant-related mortality in this patient cohort. CONCLUSIONS: For MM patients deriving durable remission after their AHCT1, sAHCT2 was safe and resulted in deep and durable remissions.

Impact of interval progression before autologous stem cell transplant in patients with multiple myeloma.

In transplant-eligible patients who undergo upfront autologous stem cell transplant (ASCT) for multiple myeloma (MM), standard practice is to treat with six to eight cycles of induction therapy followed by high-dose chemotherapy with ASCT. A gap between the end of induction and the day of ASCT exists to allow stem cell mobilization and collection. Despite attempts to limit the length of this interval, we noticed that some patients experience interval progression (IP) of disease between the end of induction therapy and the day of ASCT. We analyzed 408 MM patients who underwent ASCT between 2011 and 2016. The median length of the interval between end of induction and ASCT was 38 days. We observed that 26% of patients in the entire cohort and 23.6% of patients who received induction with bortezomib-lenalidomide-dexamethasone (VRD) experienced IP. These patients deepened their responses with ASCT, independently of induction regimen. In the entire cohort, IP was significantly associated with shorter PFS in the univariable analysis (Hazard Ratio, HR = 1.37, P = 0.022) but not in the multivariable analysis (HR = 1.14, P = 0.44). However, analyzing only patients who received VRD as induction, progression-free survival (PFS) remained inferior in both the univariable (HR = 2.02; P = 0.002) and the multivariable analyses (HR = 1.96; P = 0.01). T cells and natural killer (NK) cells are increasingly studied targets of immunomodulatory therapy, as immune dysfunction is known to occur in patients with MM. Peripheral blood from 35 MM patients were analyzed. At time of ASCT, patients with IP had significantly increased percentages of CD3+CD8+CD57+ CD28- (P = 0.05) and CD3+CD4+LAG3+ (P = 0.0022) T-cells, as well as less CD56bright and CD56dim NK cells bearing activated markers such as CD69, NKG2D, and CD226. These data suggest that IP can impact the length of response to ASCT; therefore, further studies on the management of these patients are needed.

Survival outcomes following autologous stem cell transplant with melphalan 140mg/m2 versus 200mg/m2 preparative regimens in patients with multiple myeloma.

The standard preparative regimen for autologous stem cell transplant (ASCT) in multiple myeloma (MM) is 200 mg/m2 of intravenous melphalan; however, a dose of 140 mg/m2 is often used when concerns exist related to patient age, performance status, organ function, and other factors. It is unclear whether a lower dose of melphalan impacts post-transplant survival outcomes. We performed a retrospective review of 930 patients with MM who underwent ASCT with 200 mg/m2 versus 140 mg/m2 melphalan. On univariable analysis, no difference in progression-free survival (PFS) was observed, however, an overall survival (OS) benefit was observed in patients receiving 200 mg/m2 melphalan (p = 0.04). Multivariable analyses showed patients receiving 140 mg/m2 faired no worse than those receiving 200 mg/m2. While a subset of younger patients with normal renal function may achieve superior OS with a standard dose of 200 mg/m2 melphalan, these findings suggest an opportunity to individualize the ASCT preparative regimen to optimize outcomes.

Impact of detectable monoclonal protein at diagnosis on outcomes in marginal zone lymphoma: a multicenter cohort study.

Given the paucity of data surrounding the prognostic relevance of monoclonal paraprotein (M-protein) in marginal zone lymphoma (MZL), we sought to evaluate the impact of detecting M-protein at diagnosis on outcomes in patients with MZL in a large retrospective cohort. The study included 547 patients receiving first-line therapy for MZL. M-protein was detectable at diagnosis in 173 (32%) patients. There was no significant difference in the time from diagnosis to initiation of any therapy (systemic and local) between the M-protein and no M-protein groups. Patients with M-protein at diagnosis had significantly inferior progression-free survival (PFS) compared with those without M-protein at diagnosis. After adjusting for factors associated with inferior PFS in univariate models, presence of M-protein remained significantly associated with inferior PFS (hazard ratio, 1.74; 95% confidence interval, 1.20-2.54; P = .004). We observed no significant difference in the PFS based on the type or quantity of M-protein at diagnosis. There were differential outcomes in PFS based on the first-line therapy in patients with M-protein at diagnosis, in that, those receiving immunochemotherapy had better outcomes compared with those receiving rituximab monotherapy. The cumulative incidence of relapse in stage 1 disease among the recipients of local therapy was higher in the presence of M-protein; however, this did not reach statistical significance. We found that M-protein at diagnosis was associated with a higher risk of histologic transformation. Because the PFS difference related to presence of M-protein was not observed in patients receiving bendamustine and rituximab, immunochemotherapy may be a preferred approach over rituximab monotherapy in this group and needs to be explored further.

Outcomes of patients with blastoid and pleomorphic variant mantle cell lymphoma.

Mantle cell lymphoma (MCL) is a B-cell non-Hodgkin lymphoma; data indicate that blastoid and pleomorphic variants have a poor prognosis. We report characteristics and outcomes of patients with blastoid/pleomorphic variants of MCL. We retrospectively studied adults with newly diagnosed MCL treated from 2000 to 2015. Primary objectives were to describe progression-free survival (PFS) and overall survival (OS). Secondary objectives included characterization of patient characteristics and treatments. Of the 1029 patients with MCL studied, a total of 207 neoplasms were blastoid or pleomorphic variants. Median follow-up period was 82 months (range, 0.1-174 months); median PFS was 38 months (95% confidence interval [CI], 28-66) and OS was 68 months (95% CI, 45-96). Factors associated with PFS were receipt of consolidative autologous hematopoietic transplantation (auto-HCT; hazard ratio [HR], 0.52; 95% CI, 0.31-0.80; P < .05), MCL International Prognostic Index (MIPI) intermediate (HR, 2.3; 95% CI, 1.2-4.3; P < .02) and high (HR, 3.8; 95% CI, 2.0-7.4; P < .01) scores, and complete response to induction (HR, 0.29 (95% CI, 0.17-0.51). Receipt of auto-HCT was not associated with OS (HR, 0.69; 95% CI, 0.41-1.16; P = .16) but was associated with MIPI intermediate (HR, 5.7; 95% CI, 2.5-13.2; P < .01) and high (HR, 10.8; 95% CI, 4.7-24.9; P < .01) scores. We report outcomes in a large cohort of patients with blastoid/pleomorphic variant MCL. For eligible patients, receipt of auto-HCT after induction was associated with improved PFS but not OS. Higher MIPI score and auto-HCT ineligibility were associated with worse survival.

Early versus Late Discontinuation of Maintenance Therapy in Multiple Myeloma.

Maintenance therapy after autologous stem cell transplant (ASCT) in multiple myeloma (MM) is the standard treatment and recommended to be continued until disease progression. However, in the real world, patients discontinue treatment due to various reasons. We sought to determine the effect of early versus late discontinuation on survival outcomes in MM patients who underwent ASCT at The Ohio State University. We retrospectively reviewed 340 patients who underwent ASCT from 2005 to 2016 and received maintenance therapy for at least six months without progression. We compared the outcomes of patients who received maintenance for three years or less (early group) to the patients who continued maintenance beyond three years (late group). Lenalidomide (89%) and bortezomib (10%) were the most common agents used for maintenance chemotherapy. In Kaplan−Meier analysis, patients in the late group had prolonged progression-free (PFS) (p < 0.001) and overall survival (OS) (p < 0.001). The 5-year estimated OS in late group was 96% vs. 79% in the early group and 5-year PFS was 80% in late group vs. 50% in the early group. The most common reasons for discontinuation of maintenance in early group were adverse events (55.9%) and patient preference (22.5%). For the late group, it was disease progression (23.9%) and adverse events (14.3%). Fifty-five percent of patients in the late group were still on maintenance treatment at the last follow-up. Continuation of maintenance therapy was thus associated with improved outcomes, while adverse events prevented most patients from continuing treatment.

Predictive factors and outcomes for ibrutinib in relapsed/refractory marginal zone lymphoma: a multicenter cohort study.

Ibrutinib is effective in the treatment of relapsed/refractory (R/R) marginal zone lymphoma (MZL) with an overall response rate (ORR) of 48%. However, factors associated with response (or lack thereof) to ibrutinib in R/R MZL in clinical practice are largely unknown. To answer this question, we performed a multicenter (25 US centers) cohort study and divided the study population into three groups: "ibrutinib responders"-patients who achieved complete or partial response (CR/PR) to ibrutinib; "stable disease (SD)"; and "primary progressors (PP)"-patients with progression of disease as their best response to ibrutinib. One hundred and nineteen patients met the eligibility criteria with 58%/17% ORR/CR, 29% with SD, and 13% with PP. The median PFS and OS were 29 and 71.4 months, respectively, with no difference in PFS or OS based on the ibrutinib line of therapy or type of therapy before ibrutinib. Patients with complex cytogenetics had an inferior PFS (HR = 3.08, 95% CI 1.23-7.67, p = 0.02), while those with both complex cytogenetics (HR = 3.00, 95% CI 1.03-8.68, p = 0.04) and PP (HR = 13.94, 95% CI 5.17-37.62, p < 0.001) had inferior OS. Only primary refractory disease to first-line therapy predicted a higher probability of PP to ibrutinib (RR = 3.77, 95% CI 1.15-12.33, p = 0.03). In this largest study to date evaluating outcomes of R/R MZL treated with ibrutinib, we show that patients with primary refractory disease and those with PP on ibrutinib are very high-risk subsets and need to be prioritized for experimental therapies.

Antineutrophil Cytoplasmic Autoantibody-Associated Vasculitis with Kidney Involvement in a Patient with AL Amyloidosis.

Antineutrophil cytoplasmic autoantibody (ANCA) vasculitis has occasionally been associated with other systemic glomerulonephritis, such as anti-glomerular basement membrane disease. Here, we report the first clinical case of ANCA-associated crescentic glomerulonephritis with AL amyloidosis. An 81-years-old gentleman presented to the hospital with acute kidney injury (serum creatinine 4.7 mg/dL) on a background of chronic kidney disease and volume overload. Autoimmune serology was remarkable for p-ANCA and myeloperoxidase positivity. A renal biopsy confirmed pauci-immune glomerulonephritis and lambda light-chain amyloid deposition (confirmed on liquid chromatography and tandem mass spectrometry). The patient was initially managed with rituximab and subsequently transitioned to bortezomib-based chemotherapy but died due to decompensated heart failure. This case report promotes greater awareness of the unusual presentation of amyloidosis and guides future research and treatment.

Pulmonary Haemosiderosis Secondary to Hereditary Haemochromatosis; a Case Report.

Introduction: Hereditary haemochromatosis (HH) is an autosomal recessive disease of increased intestinal absorption of iron, leading to accumulation in tissues which may progress to organ damage, most commonly in the liver. Iron deposition in the liver can lead to cirrhosis and hepatocellular carcinoma. Other common manifestations of haemochromatosis include diabetes, bronzing of the skin, arthropathy and cardiomyopathy. Here, we describe a case of pulmonary haemosiderosis secondary to HH. Case Description: A 49-year-old male with no medical history or family history of iron overload presented with fatigue, shortness of breath and chest pain after a recent finding of elevated ferritin. The patient was found to have biallelic C282Y mutations of the human homeostatic iron regulator protein (HFE) protein and after further workup with laboratory tests and imaging was diagnosed with HH with secondary pulmonary haemosiderosis. The patient is receiving twice weekly phlebotomies and has had an overall improvement in his symptoms. Practical Implications: The presentation of haemochromatosis can vary widely depending on the severity of iron overload and the presence of conditions that predispose organ dysfunction. Pulmonary haemosiderosis is a very rare manifestation of HH. This report illustrates the various manifestations of this disease and provides insight into this rare presentation to improve the diagnosis of this disease.

Myelodysplastic Syndrome with Transfusion Dependence Treated with Venetoclax.

Myelodysplastic syndromes are characterized by ineffective hematopoiesis in one or more lineages of the bone marrow. They are a group of heterogeneous clonal stem cell malignancies with a high risk to progress to acute myeloid leukemia. Currently, there are no curative FDA-approved medications for myelodysplastic syndromes. Hematopoietic cell transplantation is potentially the only curative option; however, treatment is often unavailable due to age and comorbidities. Hypomethylating agents, azacitidine and decitabine, and the immunomodulatory agent, lenalidomide, are the only FDA approved medications for the treatment of MDS, all of which are noncurative. Venetoclax, an inhibitor of the antiapoptotic protein BCL-2 used to treat chronic lymphocytic leukemia, is currently being evaluated in clinical trials as a monotherapy in high-risk myelodysplastic syndromes/acute myeloid leukemia. We present a patient with transfusion-dependent myelodysplastic syndromes refractory to the current standard of care treatment not a candidate for hematopoietic cell transplantation who responded well to monotherapy treatment with venetoclax and has since remained transfusion-independent.

A Rare Manifestation of a Rare Disease: Mantle Cell Lymphoma Presenting With Aseptic Meningitis.

Mantle cell lymphoma (MCL) is a rare form of non-Hodgkin lymphoma characterized by clonal proliferation of follicular mantle zone B lymphocytes. It is caused by abnormal chromosomal translocation t(11;14) resulting in aberrant expression of cyclin D1. This leads to activation of anti-apoptotic pathways and abnormal proliferation of MCL cells. Patients can present with an indolent course or a fulminant disease with short overall survival. The disease frequently involves extranodal organs, but rarely manifests with neurological symptoms. We report a rare case of aberrant CD5-negative MCL presenting with aseptic meningitis.

Efficacy of salvage chemotherapy in diffuse large B cell lymphoma with primary treatment failure according to putative cell of origin.

We evaluated outcome of 235 primary treatment failure (PTF) diffuse large B-cell lymphoma (DLBCL) patients based on salvage chemotherapy regimen and putative cell-of-origin (COO). Patients were divided into two groups; group A (n = 38) received high-dose cytarabine containing regimen, either DHAP or ESHAP. Patients in group B (n = 197) received ifosfamide, carboplatin, and etoposide (ICE) +/- rituximab. No difference in overall response rates (CR + PR) was observed based on salvage chemotherapy regimen and COO. After adjustment for the presence of ultra high-risk features, overall survival of germinal center B-cell like (GCB) DLBCL patients in group A was not significantly different from survival in group B (HR 0.86, 95% CI 0.46-1.60, p = .64). Similarly, within non-GCB DLBCL cohort, survival in group A was comparable to group B (HR 0.53, 95% CI 0.20-1.44, p = .21). We did not find an outcome difference between two commonly used salvage chemotherapy regimens in patients with PTF DLBCL based on COO.

Outcomes of patients with multiple myeloma refractory to CD38-targeted monoclonal antibody therapy.

The introduction of CD38-targeting monoclonal antibodies (CD38 MoABs), daratumumab and isatuximab, has significantly impacted the management of patients with multiple myeloma (MM). Outcomes of patients with MM refractory to CD38 MoABs have not been described. We analyzed outcomes of 275 MM patients at 14 academic centers with disease refractory to CD38 MoABs. Median interval between MM diagnosis and refractoriness to CD38 MoAB (T0) was 50.1 months. The median overall survival (OS) from T0 for the entire cohort was 8.6 [95% C.I. 7.5-9.9] months, ranging from 11.2 months for patients not simultaneously refractory to an immunomodulatory (IMiD) agent and a proteasome inhibitor (PI) to 5.6 months for "penta-refractory" patients (refractory to CD38 MoAB, 2 PIs and 2 IMiDs). At least one subsequent treatment regimen was employed after T0 in 249 (90%) patients. Overall response rate to first regimen after T0 was 31% with median progression-free survival (PFS) and OS of 3.4 and 9.3 months, respectively. PFS was best achieved with combinations of carfilzomib and alkylator (median 5.7 months), and daratumumab and IMiD (median 4.5 months). Patients with MM refractory to CD38 MoAB have poor prognosis and this study provides benchmark for new therapies to be tested in this population.