Efficacy and safety of mogamulizumab by patient baseline blood tumour burden: a post hoc analysis of the MAVORIC trial.

BACKGROUND: Mogamulizumab was compared with vorinostat in the phase 3 MAVORIC trial (NCT01728805) in 372 patients with relapsed/refractory mycosis fungoides (MF) or Sézary syndrome (SS) who had failed ≥1 prior systemic therapy. Mogamulizumab significantly prolonged progression-free survival (PFS), with a superior objective response rate (ORR) vs. vorinostat. OBJECTIVES: This post hoc analysis was performed to evaluate the effect of baseline blood tumour burden on patient response to mogamulizumab. METHODS: PFS, ORR, time to next treatment (TTNT), skin response (modified Severity-Weighted Assessment Tool [mSWAT]) and safety were assessed in patients stratified by blood classification (B0 [n = 126], B1 [n = 62], or B2 [n = 184], indicating increasing blood involvement). RESULTS: Investigator-assessed PFS was longer for mogamulizumab versus vorinostat across all blood classes, significantly so for B1 and B2 patients. ORR was higher with mogamulizumab than with vorinostat in all blood classification groups and more markedly so with escalating B class (B0: 15.6% vs. 6.5%, P = 0.0549; B1: 25.8% vs. 6.5%, P = 0.2758; B2: 37.4% vs. 3.2%, P < 0.0001). TTNT was significantly longer for patients treated with mogamulizumab versus vorinostat with B1 (12.63 vs. 3.07 months; HR 0.32 [95% CI 0.16-0.67]; P = 0.0018) and B2 (13.07 vs. 3.53 months; HR 0.30 [95% CI 0.21-0.43]; P < 0.0001) blood involvement. In the mogamulizumab arm, 81 patients (43.5%) had ≥50% change in the mSWAT vs. 41 patients (22.0%) with vorinostat; mSWAT improvements with mogamulizumab occurred most often in B1 and B2 patients. Rapid, sustained reductions were seen in CD4+ CD26- cell counts and CD4:CD8 ratios in mogamulizumab patients for all B classes. Treatment-emergent adverse events were less frequent overall with mogamulizumab and similar in frequency regardless of B class. CONCLUSIONS: This post hoc analysis indicates greater clinical benefit with mogamulizumab vs. vorinostat in patients with MF and SS classified as having B1 and B2 blood involvement.

Everolimus-induced nephrotic syndrome precipitated by interaction with voriconazole in a patient with Hodgkin's lymphoma.

WHAT IS KNOWN AND OBJECTIVES: Everolimus is a small molecule that inhibits the mammalian target of rapamycin (mTOR) and is used for treatment of various solid tumours and renal transplant rejection prophylaxis. Whereas everolimus-induced proteinuria was previously observed in 3%-36% renal transplant recipients, nephrotic syndrome was not reported in cancer patients taking everolimus. However, nephrotic syndrome was reported in patients taking sirolimus. CASE SUMMARY: We report the case of a 32-year-old female with relapsed Hodgkin's lymphoma who was on everolimus for 5 years and developed nephrotic syndrome about 2 months after initiation of voriconazole. She was on 10 mg everolimus once a day and 200 mg voriconazole twice a day orally. Renal biopsy revealed thrombotic microangiopathic vasculopathy and thin basement membrane nephropathy. Discontinuation of everolimus and voriconazole rapidly improved her nephrotic syndrome. WHAT IS NEW AND CONCLUSION: We provide in-depth analysis of the underlying mechanisms of everolimus-induced nephrotic syndrome and hypothesize that voriconazole likely decreased everolimus metabolism. In the era of targeted therapy for cancer, healthcare providers should be aware of the drug-drug interaction between everolimus (as well as tyrosine kinase inhibitors) and cytochrome P450 CYP3A4 inhibitors (ie voriconazole).

Utility of ¹8fluoro-deoxyglucose positron emission tomography for prognosis and response assessments in a phase 2 study of romidepsin in patients with relapsed or refractory peripheral T-cell lymphoma.

BACKGROUND: For patients with peripheral T-cell lymphoma (PTCL), the value of (18)fluoro-deoxyglucose positron emission tomography (FDG-PET) scans for assessing prognosis and response to treatment remains unclear. The utility of FDG-PET, in addition to conventional radiology, was examined as a planned exploratory end point in the pivotal phase 2 trial of romidepsin for the treatment of relapsed/refractory PTCL. PATIENTS AND METHODS: Patients received romidepsin at a dose of 14 mg/m(2) on days 1, 8, and 15 of 28-day cycles. The primary end point was the rate of confirmed/unconfirmed complete response (CR/CRu) as assessed by International Workshop Criteria (IWC) using conventional radiology. For the exploratory PET end point, patients with at least baseline FDG-PET scans were assessed by IWC + PET criteria. RESULTS: Of 130 patients, 110 had baseline FDG-PET scans, and 105 were PET positive at baseline. The use of IWC + PET criteria increased the objective response rate to 30% compared with 26% by conventional radiology. Durations of response were well differentiated by both conventional radiology response criteria [CR/CRu versus partial response (PR), P = 0.0001] and PET status (negative versus positive, P < 0.0001). Patients who achieved CR/CRu had prolonged progression-free survival (PFS, median 25.9 months) compared with other response groups (P = 0.0007). Patients who achieved PR or stable disease (SD) had similar PFS (median 7.2 and 6.3 months, respectively, P = 0.6427). When grouping PR and SD patients by PET status, patients with PET-negative versus PET-positive disease had a median PFS of 18.2 versus 7.1 months (P = 0.0923). CONCLUSIONS: Routine use of FDG-PET does not obviate conventional staging, but may aid in determining prognosis and refine response assessments for patients with PTCL, particularly for those who do not achieve CR/CRu by conventional staging. The optimal way to incorporate FDG-PET scans for patients with PTCL remains to be determined. TRIAL REGISTRATION: NCT00426764.

Outcomes of auto-SCT for lymphoma in subjects aged 70 years and over.

The safety and efficacy of auto-SCT for lymphoma in older patients is not well established, particularly in those ≥70 years old. We performed a retrospective analysis comparing 17 auto-SCT recipients ≥70 years old with 39 recipients aged 65-69 years. Hematopoietic cell transplantation comorbidity index (HCT-CI) scores were similar in both groups. Nonrelapse mortality (NRM) was increased in patients aged 70 years and older (hazard ratio (HR) 6.04, P=0.0029), and OS was decreased (HR 1.98, P=0.082). 1-year NRM was 35% in patients aged ≥70 years vs 8% in those aged 65-69 years (P=0.017). The incidence of in-hospital falls was higher in those aged ≥70 years (29 vs 8%, P=0.047). In a secondary exploratory analysis, we found that the occurrence of in-hospital falls was strongly associated with inferior OS (HR 3.36, P=0.0023) and NRM (HR 4.60, P=0.009) among all patients of aged 65 years and older. We conclude that auto-SCT is feasible in older patients but that mortality rates appear increased in those over age of 70 years. In-hospital falls were correlated with higher mortality, and prevention of falls may improve outcomes. Susceptibility to falls may indicate underlying frailty and should be explored prospectively as a means of selecting older patients for auto-SCT.

Pivotal phase III trial of two dose levels of denileukin diftitox for the treatment of cutaneous T-cell lymphoma.

PURPOSE: The objective of this phase III study was to determine the efficacy, safety, and pharmacokinetics of denileukin diftitox (DAB389IL-2, Ontak [Ligand Pharmaceuticals Inc, San Diego, CA]) in patients with stage Ib to IVa cutaneous T-cell lymphoma (CTCL) who have previously received other therapeutic interventions. PATIENTS AND METHODS: Patients with biopsy-proven CTCL that expressed CD25 on > or = 20% of lymphocytes were assigned to one of two dose levels (9 or 18 microg/kg/d) of denileukin diftitox administered 5 consecutive days every 3 weeks for up to 8 cycles. Patients were monitored for toxicity and clinical efficacy, the latter assessed by changes in disease burden and quality of life measurements. Antibody levels of antidenileukin diftitox and anti-interleukin-2 and serum concentrations of denileukin diftitox were also measured. RESULTS: Overall, 30% of the 71 patients with CTCL treated with denileukin diftitox had an objective response (20% partial response; 10% complete response). The response rate and duration of response based on the time of the first dose of study drug for all responders (median of 6.9 months with a range of 2.7 to more than 46.1 months) were not statistically different between the two doses. Adverse events consisted of flu-like symptoms (fever/chills, nausea/vomiting, and myalgias/arthralgias), acute infusion-related events (hypotension, dyspnea, chest pain, and back pain), and a vascular leak syndrome (hypotension, hypoalbuminemia, edema). In addition, 61% of the patients experienced transient elevations of hepatic transaminase levels with 17% grade 3 or 4. Hypoalbuminemia occurred in 79%, including 15% with grade 3 or 4 changes. Tolerability at 9 and 18 microg/kg/d was similar, and there was no evidence of cumulative toxicity. CONCLUSION: Denileukin diftitox has been shown to be a useful and important agent in the treatment of patients whose CTCL is persistent or recurrent despite other therapeutic interventions.

Immunogenetic analysis of bone marrow aspirates in patients with non-Hodgkin lymphomas.

The immunogenetic analysis (IGA) on the staging bone marrow aspirates in 15 patients with non-Hodgkin lymphoma (NHL) is reported. We found the sensitivity of IGA and morphologic examination in detecting bone marrow involvement by malignant lymphoma to be 91% and 82%, respectively. In 11 cases there was agreement between the morphologic findings and IGA. In 8 of these 11 cases, IGA confirmed the morphologic involvement of the bone marrow by demonstrating clonal rearrangement of either the immunoglobulin heavy- and/or light-chain or the T-cell receptor beta chain (TCR) genes. In 3 of these 11 cases, morphology showed no involvement and IGA showed germline configurations for both the immunoglobulin heavy- and light-chain or the TCR genes. In 2 additional cases the techniques proved to be complementary, as involvement was detected by only 1 of the 2 procedures. In 1 of these 2 cases, IGA showed gene rearrangement while morphologic examination was negative for involvement by NHL, while in the other case, morphologic examination showed involvement by NHL, but IGA did not show gene rearrangement. IGA was also useful in determining the clonality of solitary lymphoid nodules in the 2 remaining cases when morphologic interpretation was equivocal. In the 12 cases with bone marrow involvement, the immunophenotype and immunogenotype agreed in 11 cases. In the one case in which there was a discordance between the immunophenotype and immunogenotype, the immunophenotype was incorrectly interpreted as B-cell lineage, while the immunogenotype demonstrated a T-cell lineage. IGA also demonstrated a clonal population in 1 case of T-chronic lymphocytic leukemia where other techniques could not demonstrate the clonality of the pathologic process. IGA analysis may detect bone marrow involvement in NHL which may not be detected by morphologic examination because of patchy distribution.

Acute hepatic injury after the withdrawal of immunosuppressive chemotherapy in patients with hepatitis B.

Five patients with lymphoproliferative malignancies and chronic hepatitis B suffered severe acute hepatic injury after the withdrawal of multiagent chemotherapy that included high-dose corticosteroid. Four patients died of hepatic failure, three of whom received corticosteroid as treatment for the hepatic injury. We believe that the cause of this entity is massive immune-associated cytolysis of hepatitis B virus infected hepatocytes occurring after a period of immunosuppression and increased viral replication. The literature regarding this complication of chemotherapy and its pathophysiology is reviewed.

Acute myeloid leukemia, FAB M-1 microgranular variant: a multiparameter study.

Acute leukemia was diagnosed in 62 adults and children over a recent 13-month period. Using light microscopy, cytochemical profiles, surface markers, and cytogenetics, 25 cases were classified as acute myeloid leukemia (AML) and 32 as acute lymphoblastic leukemia (ALL). The remaining 5 cases of de novo acute leukemia were unclassifiable. The routine cytochemical battery used on these 62 cases included: myeloperoxidase, sudan black B, nonspecific esterase, and periodic acid-Schiff (PAS). Flow markers utilized were: T3, T4, T5, T8, T10, T11, B1, B4, kappa, lambda, Ia, CALLA, Mo1, Mo2, My4, My7, My8, and My9. TdT was performed by immunoperoxidase and ELISA methods. The five unclassified cases were cytochemically negative and expressed no B- or T-cell-specific antigens, or TdT positivity. The morphologic differential diagnosis was between FAB L-2 and M-1. Karyotypic abnormalities involving chromosomes 3 and 7 were suggestive of myeloid origin in 2 of 4 patients studied. Flow cytometry demonstrated My7 on greater than 50% of blasts from two cases. Myeloperoxidase ultracytochemistry showed reaction product in small primary granules of blasts from all 5 cases. Positive cells contained only 1-2 granules/cell profile. The number of positive cells per case was in the range 10-20%. We conclude from this study that ultracytochemistry is very useful in providing definitive diagnosis and accurate subclassification of some AML FAB M-1 cases, particularly when light microscopic cytochemistry, cytogenetics, and flow cytometric markers are noncontributory. We propose to designate these acute "unclassified" leukemias as AML FAB M-1 "microgranular" type.

Third-World Hodgkin's disease at Los Angeles County-University of Southern California Medical Center.

The reported experience with Hodgkin's disease (HD) in the United States has come primarily from large referral centers that attract a predominantly white population of high socioeconomic status (SES). The majority of these patients had the nodular sclerosis (NS) histologic subtype and asymptomatic stage I/II disease. We have reviewed the records of 178 patients with HD seen within the past 17 years at Los Angeles County-University of Southern California Medical Center (LAC/USC), which is a nonreferral, government-operated facility. Our patient population was found to be heterogeneous, with 38% white, 22% black, and 36% Hispanic. Systemic "B" symptoms were noted in 62% of patients at diagnosis, and 63% had advanced disease (stage III or IV). NS pathologic subtype was present in only 52% of the group. Comparison between the races revealed: (1) Hispanics had a higher incidence of lymphocyte depleted subtype and less NS than whites (P less than .06); (2) whites had equal distribution between stages I/II and III/IV; (3) blacks and Hispanics presented more frequently with stage III/IV (P = .10); and (4) extranodal involvement occurred most often in bone in whites, and was equally distributed between liver, lung, and bone in blacks and Hispanics. We conclude that the lower SES, mixed racial population seen at our institution more closely resembles the reports of HD in Third-World countries and is characterized by advanced symptomatic disease. Further, the clinical pathologic characteristics of HD in the United States may vary significantly, depending upon the precise ethnic and socioeconomic status of the patients being served.