Melphalan flufenamide (melflufen) is a first-in-class peptide-drug conjugate that targets aminopeptidases and rapidly and selectively releases alkylating agents into tumor cells. The phase II HORIZON ...trial evaluated the efficacy of melflufen plus dexamethasone in relapsed and refractory multiple myeloma (RRMM), a population with an important unmet medical need.
Patients with RRMM refractory to pomalidomide and/or an anti-CD38 monoclonal antibody received melflufen 40 mg intravenously on day 1 of each 28-day cycle plus once weekly oral dexamethasone at a dose of 40 mg (20 mg in patients older than 75 years). The primary end point was overall response rate (partial response or better) assessed by the investigator and confirmed by independent review. Secondary end points included duration of response, progression-free survival, overall survival, and safety. The primary analysis is complete with long-term follow-up ongoing.
Of 157 patients (median age 65 years; median five prior lines of therapy) enrolled and treated, 119 patients (76%) had triple-class-refractory disease, 55 (35%) had extramedullary disease, and 92 (59%) were refractory to previous alkylator therapy. The overall response rate was 29% in the all-treated population, with 26% in the triple-class-refractory population. In the all-treated population, median duration of response was 5.5 months, median progression-free survival was 4.2 months, and median overall survival was 11.6 months at a median follow-up of 14 months. Grade ≥ 3 treatment-emergent adverse events occurred in 96% of patients, most commonly neutropenia (79%), thrombocytopenia (76%), and anemia (43%). Pneumonia (10%) was the most common grade 3/4 nonhematologic event. Thrombocytopenia and bleeding (both grade 3/4 but fully reversible) occurred concomitantly in four patients. GI events, reported in 97 patients (62%), were predominantly grade 1/2 (93%); none were grade 4.
Melflufen plus dexamethasone showed clinically meaningful efficacy and a manageable safety profile in patients with heavily pretreated RRMM, including those with triple-class-refractory and extramedullary disease.
We hypothesized that chemoprophylaxis with the echinocandin micafungin would be an effective agent for antifungal prophylaxis during neutropenia in patients undergoing hematopoietic stem cell ...transplantation (HSCT). We therefore conducted a randomized, double-blind, multi-institutional, comparative phase III trial, involving 882 adult and pediatric patients, of 50 mg of micafungin (1 mg/kg for patients weighing <50 kg) and 400 mg of fluconazole (8 mg/kg for patients weighing <50 kg) administered once per day. Success was defined as the absence of suspected, proven, or probable invasive fungal infection (IFI) through the end of therapy and as the absence of proven or probable IFI through the end of the 4-week period after treatment. The overall efficacy of micafungin was superior to that of fluconazole as antifungal prophylaxis during the neutropenic phase after HSCT (80.0% in the micafungin arm vs. 73.5% in the fluconazole arm difference, 6.5%; 95% confidence interval, 0.9%-12%; P = .03). This randomized trial demonstrates the efficacy of an echinocandin for antifungal prophylaxis in neutropenic patients.
Hematopoietic stem cell transplantation (HSCT) is a treatment for multiple medical conditions that result in bone marrow failure and as an antineoplastic adoptive immunotherapy for hematologic ...malignancies. HSCT is associated with profound compromises in host barriers and all arms of innate and acquired immunity. The degree of immune compromise varies by type of transplant and over time. Immune reconstitution occurs within several months after autologous HSCT but takes up to a year or longer after allogeneic HSCT. In those patients who develop chronic graft-versus-host disease, immune reconstitution may take years or may never completely develop. Over time, with strengthening immune reconstitution and control of graft-versus-host disease, the risk for infection dissipates.
Pulmonary nodules and nodular infiltrates occur frequently during treatment of hematologic malignancies and after hematopoietic cell transplantation. In patients not receiving active ...immunosuppressive therapy, the most likely culprits are primary lung cancer, chronic infectious or inactive granulomata, or even the underlying hematologic disease itself (especially in patients with lymphoma). In patients receiving active therapy or who are otherwise highly immunosuppressed, there is a wider spectrum of etiologies with infection being most likely, especially by bacteria and fungi. Characterization of the pulmonary lesion by high-resolution CT imaging is a crucial first diagnostic step. Other noninvasive tests can often be useful, but invasive testing by bronchoscopic evaluation or acquisition of tissue by one of several biopsy techniques should be performed for those at risk for malignancy or invasive infection unless contraindicated. The choice of the optimal biopsy technique should be individualized, guided by location of the lesion, suspected etiology, skill and experience of the diagnostic team, procedural risk of complications, and patient status. Although presumptive therapy targeting the most likely etiology is justified in patients suspected of serious infection while evaluation proceeds, a structured evaluation to determine the specific etiology is recommended. Interdisciplinary teamwork is highly desirable to optimize diagnosis and therapy.
We describe 2 challenging cases of cardiac transthyretin amyloidosis initially treated as cardiac amyloidosis light chain in the setting of active myeloma. Endomyocardial biopsy with mass ...spectrometry was essential to confirm the appropriate diagnosis to direct the treatment.
OBJECTIVESVoriconazole, a first-line agent for the treatment of invasive fungal infections (IFIs), is metabolized by CYP2C19. A significant proportion of patients fail to achieve therapeutic trough ...concentrations with standard weight-based voriconazole dosing, placing them at increased risk for treatment failure, which can be life threatening. We sought to test the association between the CYP2C19 genotype and subtherapeutic voriconazole concentrations in adults with IFIs.
PATIENT AND METHODSAdults receiving weight-based voriconazole dosing for the treatment of IFIs were genotyped for the CYP2C19*2, *3, and *17 polymorphisms, and CYP2C19 metabolizer phenotypes were inferred. Steady-state voriconazole trough plasma concentrations and the prevalence of subtherapeutic troughs (<2 mg/l) were compared between patients with the CYP2C19*17/*17 (ultrarapid metabolizer, UM) or *1/*17 (rapid metabolizer, RM) genotype versus those with other genotypes. Logistic regression, adjusting for clinical factors, was performed to estimate the odds of subtherapeutic concentrations.
RESULTSOf 70 patients included (mean age 52.5±18 years), 39% were RMs or UMs. Compared with patients with the other phenotypes, RMs/UMs had a lower steady-state trough concentration (4.26±2.2 vs. 2.86±2.3, P=0.0093) and a higher prevalence of subtherapeutic troughs (16 vs. 52%, P=0.0028), with an odds ratio of 5.6 (95% confidence interval1.64–19.24, P=0.0044).
CONCLUSIONOur findings indicate that adults with the CYP2C19 RM or UM phenotype are more likely to have subtherapeutic concentrations with weight-based voriconazole dosing. These results corroborate previous findings in children and support the potential clinical utility of CYP2C19 genotype-guided voriconazole dosing to avoid underexposure in RMs and UMs.
The use of allogeneic hematopoietic stem cell transplantation for the treatment of hematologic malignancies, as well as some benign hematologic disorders, has continued to grow over the last 10 ...years. The availability of this procedure to an increasing number of patients has been facilitated by the use of newer techniques, including reduced intensity conditioning (RIC) regimens, peripheral blood stem cells (PBSCs) and cord blood as donor sources, graft manipulation such as selective T-cell depletion, and other in vitro and in vivo attempts to reduce the risk and severity of graft-versus-host disease (GVHD) after transplantation without losing the potential benefits of a graft-versus-tumor effect for patients with hematologic malignancies. The underlying theme of many of these newer techniques has been to minimize the severity and duration of transplant-related immune suppression, thus reducing the risk of morbidity and mortality from infectious complications. This article reviews immune suppression and recovery that occur after allogeneic stem cell transplantation, with changes in the epidemiology, and some of the recent advances that have been made in management of infectious complications.
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Background: Melphalan flufenamide (melflufen) is a first-in-class peptide-drug conjugate (PDC) that leverages aminopeptidases and rapidly releases alkylating agents inside tumor ...cells. Melflufen has a mechanism of action distinct from other alkylating agents (Slipicevic et al. AACR 2020. Abs. 1843). In the O-12-M1 (NCT01897714) and HORIZON (OP-106; NCT02963493) studies, melflufen plus dex showed meaningful efficacy and a clinically manageable safety profile in pts with RRMM (Richardson et al. Lancet Haematol. 2020;7:5; Richardson et al. J Clin Oncol. 2020;Dec 9 Epub). This pooled analysis examines pts from these studies exposed to prior alkylators. Methods: Both the O-12-M1 and HORIZON studies included pts with RRMM who received ≥ 2 prior lines of therapy (LoTs) and had a primary endpoint of overall response rate (ORR). Secondary endpoints included progression-free survival (PFS) and safety. Data from the 2 studies were pooled and analyzed according to previous exposure and refractoriness to alkylators before study entry. Refractoriness to prior alkylator therapy was defined as disease that failed to achieve a minimal response or progressed while on therapy, or within 60 d of last therapy. Results: Of 202 pts (HORIZON: n = 157, cutoff January 14, 2020; O-12-M1: n = 45, cutoff October 29, 2019), 178 (88%) had been exposed to alkylators in ≥ 1 prior LoT (see Table for subgroups). Pts exposed and refractory to alkylators in ≥ 2 LoTs had the highest number of pts refractory to an alkylator in the last LoT (61%), and 82% were refractory to an alkylator within 12 mo of study entry. Meaningful response rates were seen in all subgroups, except for pts who were exposed and refractory to alkylators in ≥ 2 prior LoTs (see Table). PFS trended toward being shorter with higher exposure and refractoriness to prior alkylators. Results should be interpreted with caution due to limited pt numbers. Grade 3/4 adverse events (AEs) were similar between pts exposed to prior alkylators (O-12-M1: 85%; HORIZON: 89%) and the overall population (O-12-M1: 84%; HORIZON: 89%). The most common AEs were hematologic, but were mostly reversible and clinically manageable. Nonhematologic AEs were infrequent and primarily grade 1/2. Conclusions: Melflufen in combination with dex showed meaningful efficacy and a clinically manageable safety profile in pts with RRMM exposed/refractory to prior alkylators. Clinical trial information: NCT02963493 and NCT01897714. Table: see text
Immune effector cell-associated neurotoxicity syndrome (ICANS) secondary to chimeric antigen receptor T-cell therapy is common in adult patients with relapsed/refractory (R/R) B-cell acute ...lymphoblastic leukemia (ALL), but imaging findings during neurologic toxicity and their meaning have yet to be systematically described in this patient population. Brexucabtagene autoleucel (brexu-cel) is a CD19-directed autologous T-cell immunotherapy for the treatment of adult patients with R/R B-cell ALL that can enter the central nervous system. We present a case of an adult patient with R/R B-cell ALL and prior leptomeningeal disease who developed neurologic toxicity and new findings on magnetic resonance imaging of the brain while receiving brexu-cel. We interpret the patient's neuroimaging studies within clinical context to differentiate ICANS from active treatment of residual leukemia.
Background
Peripheral blood stem cell (PBSC) mobilization is routinely undertaken prior to autologous stem cell transplantation (ASCT) in patients with multiple myeloma (MM). A number of studies have ...identified risk factors for poor PBSC mobilization, however, little data exists to correlate mobilization with disease‐specific outcomes in this patient population. Prospective work in MM has demonstrated similar outcomes in a homogenous patient population.
Methods
In this single institution analysis, we retrospectively studied the impact of poor PBSC mobilization on progression free survival (PFS) and OS in MM patients undergoing PBSC mobilization. Poor mobilizers are defined as patients that collected < 4 × 106 CD34+ cells/kg over maximum of 5 apheresis days, or those that required ≥2 mobilization cycles to achieve this target.
Results
We confirm that poor PBSC mobilization is significantly associated with a shortened PFS (P = .0012) and OS (P = .0005) compared with good mobilizers. Our univariate analysis also shows that independent risk factors for poor mobilization include male gender, higher ideal body weight, and a greater median number of lines of chemotherapy prior to PBSC mobilization. However, by multivariate analysis, only number of prior lines of chemotherapy remains significantly predictive of poor mobilization (Odds ratio 1.857, P = .0095). The use of high‐dose G‐CSF (> 10 mcg/kg/day) and/or plerixafor can significantly improve mobilization and ASCT chances in this population.
Discussion
These data indicate that poor mobilization can be predictable and is associated with more aggressive disease biology and worse outcomes, warranting intensive post‐ASCT management.
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