Performance status, comorbidities, and cycles of methotrexate exert the greatest influence on outcomes of primary and secondary CNS lymphomas: the Lexington experience.

Primary central nervous system lymphoma (PCNSL) occurs primarily in older patients and has a worse prognosis than other extranodal lymphomas. Contemporary treatment is based on high-dose methotrexate (HD-MTX), which crosses the blood-brain barrier. Secondary CNS lymphoma (SCNSL) can occur concomitantly with systemic lymphoma or later at relapse and generally has a dismal outcome. We reviewed disease characteristics and outcomes of 103 patients (44 PCNSL and 59 SCNSL) treated at our center between 2015 and 2020. Median ages at diagnosis were 64 and 62 years, respectively. In both groups, diffuse large B cell lymphoma (DLBCL) was the major histologic type; in SCNSL, other types were also seen. SCNSL, in contrast with PCNSL, manifested with smaller tumors or cerebrospinal fluid positivity. For SCNSL the mean interval to brain involvement was 18 months (0-138). The overall survival had a trend to worse in SCNSL; median survival 11 months versus 61 months in PCNSL (p = 0.089). Progression-free survival was similar in both groups. A significant proportion of SCNSL patients with poor performance status could not obtain CNS-directed treatments. The strongest predictor of poor outcome was ECOG performance status 2 + at diagnosis for both groups. Charlson comorbidity index was predictive only for the PCNSL cohort. Tumor size was not prognostic for survival. The number of HD-MTX cycles correlated with survival, whereas the regimen itself and average cumulative dose of methotrexate did not play a role. Our study is in line with the recent literature and confirms ongoing challenges. We discuss how the outcomes of CNS lymphomas can be improved.

Treatment-Associated Acute Lymphoblastic Leukemia Following Autologous Hematopoietic Stem Cell Transplant and Lenalidomide Maintenance in Patients With Multiple Myeloma.

Secondary malignancies including leukemia are an increasing concern in patients with prior primary malignancies treated with alkylating agents or topoisomerase II inhibitors. These can also be referred to as therapy-related leukemia. Therapy-related leukemia most commonly results in myelodysplastic syndrome or acute myeloid leukemia. The alkylating agent can cause chromosomal aberrations typically manifest as deletions in chromosome 11 or loss of part of complete loss of chromosomes 5 and 7. Conversely, acute lymphoblastic leukemia (ALL) has been described following maintenance therapy with immunomodulatory (IMiD) drugs pomalidomide, thalidomide, and lenalidomide. We present a case of a 71-year-old man with a history of multiple myeloma (MM) maintained on lenalidomide after stem cell transplant who presented with treatment-associated ALL. At time of leukemic presentation, chromosomal analysis showed a near-triploid clone consistent with masked double low hyplodiploidy which is associated with a poor prognosis. The patient had a deletion of the long arm of chromosome 5 which has been described in prior case reports with ALL secondary to lenalidomide therapy. There are explicit mechanisms in the literature, which have been attributed to development of ALL after exposure to thalidomide or lenalidomide. At time of submission, there are 20 cases described in the literature linking ALL to IMiD drugs. We describe a case and review the mechanisms of lenalidomide-associated ALL.

Age Adjusted Comorbidity Risk Index Does Not Predict Outcomes in an Autologous Hematopoietic Stem Cell Transplant Population.

The hematopoietic comorbidity risk index (HCT-CI) is a pre-transplant risk assessment tool used to prognosticate morbidity and mortality of patients undergoing allogeneic hematopoietic stem cell transplantation. Recently, the HCT-CI was updated to include an age component (HCT-CI-age). Although other studies have validated this tool in allogeneic stem cell transplant recipients, it has never been studied in an autologous transplant patient population. We retrospectively reviewed 181 patients who underwent their first autologous hematopoietic stem cell transplant. We aimed (1) to assess whether an HCT-CI score of 3 or greater is associated with greater mean transplant hospital days, greater total hospital days, or greater risk of intensive care unit (ICU) utilization and (2) whether age influences any of these responses independent of HCT-CI. There were 136 patients with an HCT-CI score of 3 or higher and 45 with a score less than 3. The length of initial transplant hospitalization in days was not statistically significant (15.6 v 16.4 days, P = 0.38). Utilizing spline modeling prediction curves, transplant hospital days were estimated to increase from a mean of 15.5 days for a patient with 4 comorbidities to a mean of 22.7 days for a patient with 8 comorbidities. Age made no significant impact on any of the outcomes. The HCT-CI, with or without age, in an autologous stem cell transplantation did not predict length of hospitalization or utilization of the ICU. Patients with higher-HCT-CI scores at baseline may incrementally utilize more resources, and this should be explored in a larger cohort population.

Phase 2 study of venetoclax plus carfilzomib and dexamethasone in patients with relapsed/refractory multiple myeloma.

Proteins in the antiapoptotic B-cell lymphoma 2 (BCL-2) family play a role in the pathophysiology of multiple myeloma (MM). Venetoclax is a highly selective, potent, oral BCL-2 inhibitor that induces apoptosis of MM cells, and its efficacy may be potentiated through combination with agents that increase BCL-2 dependency or have complementary mechanisms of action. The safety, tolerability, pharmacokinetics, and antitumor activity of venetoclax in combination with carfilzomib and dexamethasone (VenKd) in adults with relapsed/refractory MM (RRMM) were investigated in this phase 2 dose-escalation study. Oral venetoclax (400 or 800 mg) was administered daily in combination with intravenous carfilzomib (27, 56, or 70 mg/m2) and oral dexamethasone (20 or 40 mg) in 4 dose-finding cohorts. The expansion cohort received venetoclax 800 mg, carfilzomib 70 mg/m2, and dexamethasone 40 mg. Forty-nine patients received treatment. Median prior lines of therapy was 1 (range, 1-3), and median time in the study was 27 months. The most common treatment-emergent adverse events were diarrhea (65%), fatigue (47%), nausea (47%), and lymphopenia (35%). Serious adverse events occurred in 26 (53%) patients. Of 3 treatment-emergent deaths, 1 was considered treatment related. The overall response rate was 80% in all patients, 92% in patients with t(11;14) (n = 13), and 75% in patients without (n = 36). The rate of complete response or better was 41%. Median progression-free survival was 22.8 months. Treatment with VenKd was well tolerated and showed promising response rates in this RRMM patient population, with greater responses observed in patients with t(11;14). This trial is registered at www.clinicaltrials.gov as #NCT02899052.

Ten-year survival outcomes for patients with early stage classical Hodgkin lymphoma: An analysis from Kentucky Cancer Registry.

OBJECTIVE/BACKGROUND: Early stage classical Hodgkin lymphoma (cHL) has an excellent outcome. Recent studies focus on decreasing toxicity related to the addition of radiation along with chemotherapy. Real-life reporting of the addition of radiation to chemotherapy is lacking. This study investigates the outcomes obtained from a statewide cancer registry for early stage cHL patients treated with chemotherapy alone (CT) versus patients treated with the combined modality of chemotherapy and radiation (CMT). METHODS: A retrospective study of cHL patients diagnosed and treated was identified using a statewide cancer registry from 2005 to 2014. Patients with early stage disease (I, II) were then grouped on the basis of the presence of B symptoms into favorable and unfavorable groups. Baseline characteristics (age, gender, extranodal involvement, and histology) as well as overall survival were compared for both groups depending on whether they received CT or CMT as first line therapy for their cHL. RESULTS: A total of 961 patients were identified; of those, 127 were excluded as they received only radiation or another form of treatment. Of the remaining patients, 293 were categorized as early stage favorable cHL (Group 1) and 130 adults were in the unfavorable cHL (Group 2). There were 335 patients with advanced stage cHL (Group 3) and 76 patients in an unknown stage. The 10-year overall survival for Group 1 was 81.3% versus 76.3% for Group 2 and 52.7% for Group 3. For Group 1, 10-year overall survival was 86.7% with CMT versus 75.1% for those receiving CT only (p = .004). For Group 2, there was no difference in 10-year overall survival between the CMT group (80.0%) and CT (72.5%) (p = .73). CONCLUSION: While radiation therapy might increase long-term toxicity in cHL, in our large data cohort, radiotherapy consolidation as part of the initial therapy for early stage disease provides superior survival at 10 years, especially in favorable risk cHL.

Abducens Nerve Palsy as Initial Presentation of Multiple Myeloma and Intracranial Plasmacytoma.

Central Nervous System (CNS) involvement in multiple myeloma and/or multifocal solitary plasmacytoma is rare. Although they are unique entities, multiple myeloma (MM) and plasmacytoma represent a spectrum of plasma cell neoplastic diseases that can sometimes occur concurrently. Plasmacytomas very often present as late-stage sequelae of MM. In this case report, we report a 53-year-old female presenting with right abducens cranial nerve (CN) VI palsy as an initial presentation secondary to lesion of the right clivus.

Phase I Study of the Investigational Aurora A Kinase Inhibitor Alisertib plus Rituximab or Rituximab/Vincristine in Relapsed/Refractory Aggressive B-cell Lymphoma.

PURPOSE: The aurora A kinase inhibitor alisertib demonstrated single-agent clinical activity and preclinical synergy with vincristine/rituximab in B-cell non-Hodgkin lymphoma (B-NHL). This phase I study aimed to determine the safety and recommended phase II dose (RP2D) of alisertib in combination with rituximab ± vincristine in patients with relapsed/refractory aggressive B-NHL. PATIENTS AND METHODS: Patients with relapsed/refractory, diffuse, large, or other aggressive B-NHL received oral alisertib 50 mg b.i.d. days 1 to 7, plus i.v. rituximab 375 mg/m2 on day 1, for up to eight 21-day cycles (MR). Patients in subsequent cohorts (3 + 3 design) received increasing doses of alisertib (30 mg starting dose; 10 mg increments) b.i.d. days 1 to 7 plus rituximab and vincristine [1.4 mg/m2 (maximum 2 mg) days 1, 8] for 8 cycles (MRV). Patients benefiting could continue single-agent alisertib beyond 8 cycles. Cell-of-origin and MYC/BCL2 IHC was performed on available archival tissue. RESULTS: Forty-five patients participated. The alisertib RP2D for MR was 50 mg b.i.d. For MRV (n = 32), the RP2D was determined as 40 mg b.i.d. [1 dose-limiting toxicity (DLT) at 40 mg; 2 DLTs at 50 mg]. Drug-related adverse events were reported in 89% of patients, the most common was neutropenia (47%). Seven patients had complete responses (CR), 7 had partial responses (PRs); 9 of 20 (45%) patients at the MRV RP2D responded (4 CRs, 5 PRs), all with non-germinal center B-cell (GCB) diffuse large B-cell lymphoma (DLBCL). CONCLUSIONS: The combination of alisertib 50 mg b.i.d. plus rituximab or alisertib 40 mg b.i.d. plus rituximab and vincristine was well tolerated and demonstrated activity in non-GCB DLBCL.

Age adjusted hematopoietic stem cell transplant comorbidity index predicts survival in a T-cell depleted cohort.

OBJECTIVES: Allogeneic hematopoietic stem cell transplant (HCT) continues to evolve with the treatment in higher risk patient population. This practice mandates stringent update and validation of risk stratification prior to undergoing such a complex and potentially fatal procedure. We examined the adoption of the new comorbidity index (HCT-CI/Age) proposed by the Seattle group after the addition of age variable and compared it to the pre-transplant assessment of mortality (PAM) that already incorporates age as part of its evaluation criteria. METHODS: A retrospective analysis of adult patients who underwent HCT at our institution from January 2010 through August 2014 was performed. Kaplan-Meier's curve, log-rank tests, Cox model and Pearson correlation was used in the analysis. RESULTS: Of the 114 patients that underwent allogeneic transplant in our institution, 75.4% were ≥40 years old. More than 58% had a DLCO ≤80%. Although scores were positively correlated (correlation coefficient 0.43, p < 0.001), HCT-CI/Age more accurately predicted 2-year overall survival (OS) and non-relapse mortality (NRM) in patients with lower (0-4) and higher (5-7) scores (52% and 36% versus 24% and 76%, p = 0.004, 0.003 respectively). PAM score did not reach statistical significance for difference in OS nor NRM between the low (<24) and high-risk (≥24) groups (p = 0.19 for both). CONCLUSIONS: Despite our small sample population, HCT-CI/Age was more discriminative to identify patients with poor outcome that might benefit from intensified management strategies or other therapeutic approaches rather than allogeneic HCT.

Heart transplantation in cardiac amyloidosis.

"Cardiac amyloidosis" is the term commonly used to reflect the deposition of abnormal protein amyloid in the heart. This process can result from several different forms, most commonly from light-chain (AL) amyloidosis and transthyretin (ATTR) amyloidosis, which in turn can represent wild-type (ATTRwt) or genetic form. Regardless of the origin, cardiac involvement is usually associated with poor prognosis, especially in AL amyloidosis. Although several treatment options, including chemotherapy, exist for different forms of the disease, cardiac transplantation is increasingly considered. However, high mortality on the transplantation list, typical for patients with amyloidosis, and suboptimal post-transplant outcomes are major issues. We are reviewing the literature and summarizing pros and cons of listing patients with amyloidosis for cardiac or combine organ transplant, appropriate work-up, and intermediate and long-term outcomes. Both AL and ATTR amyloidosis are included in this review.

Evaluating the optimal serum ferritin level to identify hemophagocytic lymphohistiocytosis in the critical care setting.

Ferritin is known to be involved in numerous physiological roles, such as iron storage, as well as various pathological conditions and in generalized inflammatory states. Hyperferritinemia is also encountered in the setting of hemophagocytic lymphohistiocytosis (HLH). Current diagnostic criteria exist to define HLH based on several clinical and biochemical markers, including the serum ferritin level. In this study, we retrospectively evaluated the value of ferritin >500 ng/mL in diagnosing HLH in 344 consecutive patients admitted to the medical intensive care unit at our hospital. Nine cases of HLH were identified. Comparison of the HLH with the non-HLH group showed that their maximum median serum ferritin level was 25,652 (range 1977-100,727 ng/mL) versus 1180 (503-85,168 ng/mL) (P < 0.001), platelets were 30 (5-92 × 10(3)/µL) versus 113 (0-507 × 10(3)/µL) (P < 0.001), absolute neutrophil counts were 2.56 (0.02-23.7 × 10(3)/µL) versus 7.7 (0.01-82.7 × 10(3)/µL) (P = 0.002), and triglycerides were 255 (156-394 mg/dL) versus 127 (17-624 mg/dL) (P = 0.002), respectively. Using a receiver operating characteristic curve, the optimal maximum serum ferritin level for the diagnosis of HLH was 3951 ng/mL, exceeding the current diagnostic cutoff set forth in the HLH-2004 guidelines. These data suggest that a higher cutoff value of ferritin level may have improved utility in the diagnosis of secondary HLH in the critical care setting.

Fatal rhizopus pneumonia in allogeneic stem cell transplant patients despite posaconazole prophylaxis: two cases and review of the literature.

Posaconazole is a triazole with broad spectrum of activity against multiple fungi including members of the fungal order Mucorales. This activity has been shown both in clinical and in vitro studies, which are critically reviewed here. It has become very popular in prophylaxis in acute myelogenous leukemia (AML) induction and in the graft-versus-host disease (GVHD) settings after 2 recent prospective trials that showed advantage of posaconazole prophylaxis compared to fluconazole or itraconazole. In this report, 2 patients are presented, in whom, despite posaconazole prophylaxis, invasive and ultimately fatal Rhizopus pulmonary infections developed. These cases are similar to a previously reported case of Rhizopus infection in a stem cell transplant recipient who also received posaconazole, indicating a potential newly recognized pattern of breakthrough infections in patients receiving posaconazole prophylaxis.