The impact of gender, age, race/ethnicity, and stage on quality of life in a spectrum of cutaneous lymphomas.

PURPOSE: Cutaneous lymphomas (CLs) are a group of rare, potentially disfiguring and disabling cancers that can have a significant impact on quality of life (QoL). While previous studies have shown that mycosis fungoides (MF) and Sézary syndrome (SS) impair QoL, the effect of other types of CL on QoL has not been evaluated. OBJECTIVE: To determine the impact of disease on QoL in all CL patients and to assess how QoL between the CL sub-types varies by demographic and clinical factors. METHODS: The Cutaneous Lymphoma Distress Questionnaire (CL-DQ) was used to assess QoL. All CL patients seen in a multidisciplinary CL clinic were screened for eligibility. Questionnaire responses were collected over a 22-month period between 2017 and 2019. A cross-sectional analysis of CL-DQ scores from an initial visit was performed to determine the effect of disease on QoL across CL sub-types and the potential impact of patient demographics, CL sub-type, and type of treatment. RESULTS: The study population consisted of 151 patients presenting with distinct types of cutaneous B- and T-cell lymphomas. Notable across the study population were the findings of frustration (44%), worry about progress/spread (43%), itching/pruritus (32%), and embarrassment/shame (28%). QoL was found to be most negatively affected in SS patients, females, younger patients, Black patients, and those with advanced stages of MF/SS. CONCLUSIONS: Impairment of QoL due to CL correlates with gender, age, race/ethnicity, and stage of MF/SS. While the negative impact on QoL is most pronounced in SS patients, other CL sub-types also affect QoL and impact psychosocial distress. Our findings highlight the need for QoL assessment in all CL patients and further examination of disparities noted across demographic groups.

Outcomes of Patients with Recurrent and Refractory Lymphoma Undergoing Allogeneic Hematopoietic Cell Transplantation with BEAM Conditioning and Sirolimus- and Tacrolimus-Based GVHD Prophylaxis.

The current standard of care for patients with Hodgkin lymphoma (HL) and non-Hodgkin lymphoma (NHL) is high-dose conditioning followed by autologous stem cell transplantation (ASCT). For some patients (ie, those with highest-risk disease, insufficient stem cell numbers after mobilization, or bone marrow involvement) allogeneic hematopoietic cell transplantation (alloHCT) offers the potential for cure. However, the majority of patients undergoing alloHCT receive reduced-intensity conditioning as a preparative regimen, and studies assessing outcomes of patients after alloHCT with myeloablative conditioning are limited. In this retrospective study, we reviewed outcomes of 22 patients with recurrent and refractory NHL who underwent alloHCT with myeloablative BEAM conditioning and received tacrolimus/sirolimus as graft-versus-host disease (GVHD) prophylaxis at City of Hope between 2005 and 2018. With a median follow-up of 2.6 years (range, 1.0 to 11.2 years), the probabilities of 2-year overall survival and event-free survival were 58.3% (95% confidence interval [CI], 35.0% to 75.8%) and 45.5% (95% CI, 24.4% to 64.3%), respectively. The cumulative incidence of grade II to IV acute GVHD was 45.5% (95% CI, 23.8% to 64.9%), with only 1 patient developing grade IV acute GVHD. However, chronic GVHD was seen in 55% of the patients (n = 12). Of the 22 eligible patients, 2 had undergone previous ASCT and 2 had undergone previous alloHCT. Both patients with previous ASCT developed severe regimen-related toxicity. Patients who underwent alloHCT with chemorefractory disease had lower survival rates, with 1-year OS and EFS of 44.4% and 33.0%, respectively. In conclusion, alloHCT with a BEAM preparative regimen and tacrolimus/sirolimus-based GVHD should be considered as an alternative option for patients with highest-risk lymphoma whose outcomes are expectedly poor after ASCT.

Validation of a biopsychosocial distress screening tool, "You, Your Family and COH Are a Team".

OBJECTIVE: We examined the psychometric properties of a biopsychosocial screening tool "You, Your Family and City of Hope are a Team" implemented via touchpad technology (YYFcore03) at a cancer center in newly diagnosed patients and patients on active treatment, with the primary objective to evaluate concurrent validity with screening criterion measures of depression and anxiety. METHODS: YYFcore03, Patient Health Questionnaire [PHQ-9], and Generalized Anxiety Disorder [GAD-7] were administered to 608 patients in out-patient clinics. A subset of 158 patients responding a second time to YYFcore03 at a subsequent visit were included for assessing reliability. Exploratory factor analysis followed by confirmatory factor analysis were conducted to identify underlying factors. The identified factor of psychological distress (PD) was then correlated with PHQ-9 and GAD-7 for concurrent validity and to estimate sensitivity-specificity. Demographic and clinical variables associated with the PD score were identified. Test-retest reliability of PD score was examined. RESULTS: Factor analysis suggested three factors, including PD. Correlations between PD score and PHQ-9 and GAD-7 were 0.63 and 0.67, respectively. Treating PHQ-9 and GAD-7 as criterion measures, PD score had a sensitivity of 0.77 for identifying depression and 0.86 for identifying anxiety. Younger age, lower household income, and cancer (vs noncancer) diagnosis were independently associated with worse PD score. Omega total for composite reliability was 0.88; intraclass correlation was 0.78. CONCLUSIONS: The YYFcore03 administered via touchpad is a valid instrument for identifying PD in newly diagnosed patients and patients undergoing active treatment.

Total Marrow Lymphoid Irradiation/Fludarabine/ Melphalan Conditioning for Allogeneic Hematopoietic Cell Transplantation.

Reduced-intensity conditioning (RIC) regimens for hematopoietic stem cell transplantation (HCT) can reduce morbidity and mortality, but patients with advanced disease may require alternative approaches. In an initial report of RIC with fludarabine (FLU) and melphalan (MEL) with total marrow lymphoid irradiation (TMLI) in HCT for advanced hematologic malignancies in 33 patients, we found that the addition of TMLI to RIC was feasible and safe. Here we report long-term outcomes for these patients. This prospective study included 61 patients treated with TMLI to a dose of 12 Gy (1.5 Gy twice daily for 4 days), FLU (25 mg/m2/day for 5 days), and MEL (140 mg/m2/day for 1 day). Overall survival (OS), event-free survival (EFS), cumulative incidence of relapse (CIR), and nonrelapse mortality (NRM) were measured from the date of HCT. Survival outcomes were analyzed using Kaplan-Meier analysis. Patients were categorized as low/intermediate or high/very high risk using the Disease Risk Index. The median follow-up was 7.4 years. The majority of patients had acute leukemia (72%); 49% had high/very high-risk disease. The median patient age was 55 years (range, 9-70 years). Two-year OS, EFS, CIR, and NRM were 54% (95% confidence interval [CI], 41%-66%), 49% (95% CI, 36%-61%), 21% (95% CI, 13%-35%), and 30% (95% CI, 20%-43%), respectively. Five-year OS, EFS, CIR, and NRM were 42% (95% CI, 30%-54%), 41% (95% CI, 28%-53%), 26 (95% CI, 17%-40%), and 33% (95% CI, 23%-47%, respectively). Acute (any grade) and chronic (limited or extensive) graft-versus-host disease occurred in 69% and 74% of patients, respectively. The most common toxicity was mucositis. The addition of TMLI to FLU/MEL conditioning was well tolerated, with favorable outcomes. Dosage escalation of TMLI or other modifications may be needed to improve disease control.

Therapy-related acute lymphoblastic leukemia has distinct clinical and cytogenetic features compared to de novo acute lymphoblastic leukemia, but outcomes are comparable in transplanted patients.

Therapy-related acute lymphoblastic leukemia remains poorly defined due to a lack of large data sets recognizing the defining characteristics of this entity. We reviewed all consecutive cases of adult acute lymphoblastic leukemia treated at our institution between 2000 and 2017 and identified therapy-related cases - defined as acute lymphoblastic leukemia preceded by prior exposure to cytotoxic chemotherapy and/or radiation. Of 1022 patients with acute lymphoblastic leukemia, 93 (9.1%) were classified as therapy-related. The median latency for therapy-related acute lymphoblastic leukemia onset was 6.8 years from original diagnosis, and this was shorter for patients carrying the MLL gene rearrangement compared to those with other cytogenetics. When compared to de novo acute lymphoblastic leukemia, therapy-related patients were older (P<0.01), more often female (P<0.01), and had more MLL gene rearrangement (P<0.0001) and chromosomes 5/7 aberrations (P=0.02). Although therapy-related acute lymphoblastic leukemia was associated with inferior 2-year overall survival compared to de novo cases (46.0% vs 68.1%, P=0.001), prior exposure to cytotoxic therapy (therapy-related) did not independently impact survival in multivariate analysis (HR=1.32; 95% CI: 0.97-1.80, P=0.08). There was no survival difference (2-year = 53.4% vs 58.9%, P=0.68) between the two groups in patients who received allogenic hematopoietic cell transplantation. In conclusion, therapy-related acute lymphoblastic leukemia represents a significant proportion of adult acute lymphoblastic leukemia diagnoses, and a subset of cases carry clinical and cytogenetic abnormalities similar to therapy-related myeloid neoplasms. Although survival of therapy-related acute lymphoblastic leukemia was inferior to de novo cases, allogeneic hematopoietic cell transplantation outcomes were comparable for the two entities.

Dose capping of plerixafor in patients weighing more than 100 kg at one vial led to successful mobilization outcomes and significant cost savings.

BACKGROUND: Plerixafor is frequently used as an adjunct agent to improve mobilization of peripheral blood stem cells in many clinical settings. However, its high cost (>$8000 per single-use 24-mg vial) is a significant concern. The manufacturer-recommended dose is 0.24 mg/kg. Therefore, patients weighing more than 100 kg would require a second vial, thus doubling the drug cost per dose. We implemented a policy of capping the dose of plerixafor at 24 mg, or one vial, for patients weighing more than 100 kg. This retrospective study compares the mobilization of patients more than 100 kg who received capped doses, with historical control patients who received full, uncapped doses. STUDY DESIGN AND METHODS: Consecutive, eligible patients weighing more than 100 kg who received capped (n = 47) and full doses of plerixafor (n = 40) were identified. Plerixafor was given up-front, as a rescue agent due to suboptimal mobilization, or during remobilization. Baseline characteristics and mobilization data were collected and compared. RESULTS: Patients in the two groups showed comparable baseline characteristics. They collected similar total numbers of CD34+ cells/kg (median, 4.08 × 106 vs. 3.36 × 106 CD34+ cells/kg; p = 0.86) and achieved comparable collection success rates as defined by collecting more than 2.0 × 106 CD34+ cells/kg (98% vs. 90%, p = 0.21). However, patients who received capped doses required only half of the number of vials of plerixafor (median, 3 vials vs. 6 vials; p < 0.0001). CONCLUSION: Dose capping plerixafor at 24 mg for patients more than 100 kg is a cost-effective strategy, which achieved comparable mobilization outcomes and reduced the total number of vials of plerixafor used by half.

Correlates of resistance and relapse during blinatumomab therapy for relapsed/refractory acute lymphoblastic leukemia.

We retrospectively analyzed 65 patients with refractory/relapsed (r/r) ALL who were treated with blinatumomab for predictors of leukemia response as well as clinical patterns of relapse and resistance with particular focus on downregulation of CD19 expression and extramedullary disease (EM-ALL). The complete remission (CR) rate was 51%, and 15 (45%) responders underwent allogeneic hematopoietic cell transplantation (HCT) in CR. High leukemia burden (bone marrow blasts >50%) (P = .02), history of prior EM-ALL (P = .005), and active EM-ALL at the time of initiating blinatumomab (P = .05) predicted lower CR rate. Among refractory cases, 13 (41%) had evidence of EM-ALL progression, and CD19 expression was negative or dim in 18% and 23%, respectively. Among responders, 20 (61%) subsequently relapsed among whom EM-ALL relapse occurred in 8 (40%) patients, and CD19 expression was negative or dim in 35 and 6% of evaluable cases, respectively. Pretreatment moderate/strong CD19 expression (P = .01) and history of prior EM-ALL during ALL course (P = .04) were risk factors for developing EM-ALL at progression/relapse. However, no pretreatment factors predicted progression/relapse with CD19-negative ALL. Overall-survival (OS) and even-free survival were improved for patients underwent allogeneic HCT compared to responders who did not. Furthermore, OS was superior for patients responded to blinatumomab compared to those who did not. Extramedullary and CD19-negative disease are common during blinatumomab failure in r/r ALL. In addition to high leukemia burden, concurrent or prior history EM-ALL were associated with lower response to blinatumomab. Higher CD19 expression as well as prior history of EM-ALL were associated with EM-ALL at the time of blinatumomab failure.

Implications and Management of Central Nervous System Involvement before Allogeneic Hematopoietic Cell Transplantation in Acute Lymphoblastic Leukemia.

Acute lymphoblastic leukemia (ALL) with a history of central nervous system (CNS) involvement, either at diagnosis or relapse, poses challenges when the decision is made to proceed with allogeneic hematopoietic cell transplantation (alloHCT), as there is no evidence-based consensus on the best peri-transplantation approach to reduce subsequent CNS relapse risk. Here, we retrospectively analyzed outcomes of 87 patients with ALL and a history of CNS involvement who later underwent alloHCT. Patients with pretransplantation CNS involvement had higher risk of CNS relapse after transplantation (2-year CNS relapse: 9.6% versus 1.4%, P < .0001), inferior event-free survival (EFS) (hazard ratio [HR], 1.52; P = .003), and worse overall survival (OS) (HR, 1.55; P = .003) compared with patients without pretransplantation CNS involvement (n = 543). There was no difference in post-transplantation CNS relapse, EFS, or OS among patients presenting with CNS involvement at diagnosis, those with isolated CNS relapse, and those with combined bone marrow and CNS relapse before HCT. Interestingly, neither pretransplantation cranial irradiation, use of total body irradiation-based conditioning, nor post-transplantation prophylactic intrathecal chemotherapy were associated with a reduction of CNS relapse risk after transplantation. Thus, among the patients in the cohort studied, there was no clear benefit of CNS-directed therapy in the peri-transplantation period among patients who had prior CNS involvement and underwent subsequent alloHCT.

Influence of Absorption, Distribution, Metabolism, and Excretion Genomic Variants on Tacrolimus/Sirolimus Blood Levels and Graft-versus-Host Disease after Allogeneic Hematopoietic Cell Transplantation.

Allelic variants of genes implicated in drug absorption, distribution, metabolism, and excretion (ADME) determine the pharmacokinetic variability of many medications and are increasingly recognized as important factors determining the success or failure of medical treatments. Both tacrolimus and sirolimus have narrow therapeutic ranges maintained by therapeutic drug monitoring (TDM). Using an ADME panel that covers >99% of the PharmaADME working group core list (188 single nucleotide polymorphism [SNP] and 12 copy number variant [CNV] assays in 36 pharmacogenetically relevant genes), we studied 177 patients who underwent allogeneic hematopoietic cell transplantation (HCT) using tacrolimus/sirolimus-based graft-versus-host disease (GVHD) prophylaxis. We tested for possible associations between ADME variants and tacrolimus/sirolimus drug levels, concentration/dose (C/D) ratio, and clinical endpoints, including acute GVHD. A total of 62 SNP and 6 CNV assays were evaluable after removing the variants, which were homozygous in (nearly) all samples. For sirolimus, rs2032582 (ABCB1) T-carriers versus non-T-carriers were associated with higher blood levels (P = .01), with similar results for C/D ratio. Generalized estimating equation analysis supported these findings. For tacrolimus, rs776746 CYP3A5*3/*3 and CYP3A5*3/*1 were associated with higher blood levels than CYP3A5*1/*1 (P = .002). By multivariable analysis, rs776746 CYP3A5*3/*3 and CYP3A5*3/*1 were independently associated with decreased acute GVHD compared with CYP3A5*1/*1, after adjustment for conditioning, donor type, race/ethnicity, and age. We demonstrated association of specific ADME genetic polymorphisms with blood levels of tacrolimus/sirolimus, and incidence of acute GVHD after HCT, in spite of TDM and dose adjustment. A larger ongoing study will determine whether these associations have clinical utility beyond TDM.

Impact of Additional Cytogenetic Abnormalities in Adults with Philadelphia Chromosome-Positive Acute Lymphoblastic Leukemia Undergoing Allogeneic Hematopoietic Cell Transplantation.

The occurrence of additional cytogenetic abnormalities (ACAs) is common in Philadelphia chromosome-positive acute lymphoblastic leukemia (Ph+ ALL) but is of unknown significance in the tyrosine kinase inhibitor (TKI) era. We retrospectively analyzed data from a consecutive case series of adults with Ph+ ALL who had undergone allogeneic hematopoietic cell transplantation (alloHCT) at City of Hope between 2003 and 2014. Among 130 adults with Ph+ ALL who had TKI therapy before alloHCT, 78 patients had available data on conventional cytogenetics at diagnosis and were eligible for outcomes analysis. ACAs were observed in 41 patients (53%). There were no statistically significant differences in median age, median initial WBC count, post-HCT TKI maintenance, or disease status at the time of transplant between the Ph-only and ACA cohorts; however, the Ph-only cohort had a higher rate of minimal residual disease positivity at the time of HCT. Three-year leukemia-free survival (79.8% versus 39.5%, P = .01) and 3-year overall survival (83% versus 45.6%, P = .02) were superior in the Ph-only cohort compared with the ACA cohort, respectively. Monosomy 7 was the most common additional aberration observed in our ACA cohort (n = 12). Thus, when TKI therapy and alloHCT are used as part of adult Ph+ ALL therapy, the presence of ACAs appears to have a significant deleterious effect on outcomes post-HCT.

PSCA-CAR T cell therapy in metastatic castration-resistant prostate cancer: a phase 1 trial.

Despite recent therapeutic advances, metastatic castration-resistant prostate cancer (mCRPC) remains lethal. Chimeric antigen receptor (CAR) T cell therapies have demonstrated durable remissions in hematological malignancies. We report results from a phase 1, first-in-human study of prostate stem cell antigen (PSCA)-directed CAR T cells in men with mCRPC. The starting dose level (DL) was 100 million (M) CAR T cells without lymphodepletion (LD), followed by incorporation of LD. The primary end points were safety and dose-limiting toxicities (DLTs). No DLTs were observed at DL1, with a DLT of grade 3 cystitis encountered at DL2, resulting in addition of a new cohort using a reduced LD regimen + 100 M CAR T cells (DL3). No DLTs were observed in DL3. Cytokine release syndrome of grade 1 or 2 occurred in 5 of 14 treated patients. Prostate-specific antigen declines (>30%) occurred in 4 of 14 patients, as well as radiographic improvements. Dynamic changes indicating activation of peripheral blood endogenous and CAR T cell subsets, TCR repertoire diversity and changes in the tumor immune microenvironment were observed in a subset of patients. Limited persistence of CAR T cells was observed beyond 28 days post-infusion. These results support future clinical studies to optimize dosing and combination strategies to improve durable therapeutic outcomes. ClinicalTrials.gov identifier NCT03873805 .

Thrombotic microangiopathy associated with sirolimus level after allogeneic hematopoietic cell transplantation with tacrolimus/sirolimus-based graft-versus-host disease prophylaxis.

Posttransplantation thrombotic microangiopathy (TMA) is a multifactorial complication of allogeneic hematopoietic cell transplantation (allo-HCT) whose incidence is increased with the use of a sirolimus plus tacrolimus (SIR/TAC) regimen for acute graft-versus-host disease (aGVHD) prophylaxis. We evaluated the incidence and possible risk factors for TMA in a case series of 177 patients who received allo-HCT using SIR/TAC-based GVHD prophylaxis. The patients received either a sibling donor graft (n = 82) or a matched unrelated donor graft (n = 95). Within the first 100 days post-HCT, 30 patients (17%) were diagnosed with TMA, and an additional 9 patients (5%) were classified as probable TMA cases. The median time to onset of TMA was 4.6 weeks (range, 1.6-10.6 weeks). Thirty-four patients developed both TMA and aGVHD, with the majority (81%) developing aGVHD first. Multivariate analysis identified the following factors as associated with increased risk of TMA: day 14 serum sirolimus level ≥9.9 ng/mL (hazard ratio [HR], 2.19; 95% confidence interval [CI], 1.13-4.27; P = .02), presence of previous aGVHD grade II-IV (HR, 3.04; 95% CI, 1.38-6.71; P < .01), and fully myeloablative conditioning (HR, 3.47; 95% CI, 1.60-7.53; P < .01). These risk factors for TMA suggest that when using a SIR/TAC regimen for GVHD prophylaxis, careful monitoring and adjustment of the sirolimus dosage is critical, particularly in patients with active aGVHD.

Expansion of endogenous T cells in CSF of pediatric CNS tumor patients undergoing locoregional delivery of IL13R〿2-targeting CAR T cells: an interim analysis.

Outcomes for pediatric brain tumor patients remain poor, and there is optimism that chimeric antigen receptor (CAR) T cell therapy can improve prognosis. Here, we present interim results from the first six pediatric patients treated on an ongoing phase I clinical trial (NCT04510051) of IL13BBζ-CAR T cells delivered weekly into the lateral cerebral ventricles, identifying clonal expansion of endogenous CAR-negative CD8+ T cells in the cerebrospinal fluid (CSF) over time. Additionally, of the five patients evaluable for disease response, three experienced transient radiographic and/or clinical benefit not meeting protocol criteria for response. The first three patients received CAR T cells alone; later patients received lymphodepletion before the first infusion. There were no dose limiting toxicities (DLTs). Aside from expected cytopenias in patients receiving lymphodepletion, serious adverse events possibly attributed to CAR T cell infusion were limited to one episode of headache and one of liver enzyme elevation. One patient withdrew from treatment during the DLT period due to a Grade 3 catheter-related infection and was not evaluable for disease response, although this was not attributed to CAR T cell infusion. Importantly, scRNA- and scTCR-sequence analyses provided insights into CAR T cell interaction with the endogenous immune system. In particular, clonally expanded endogenous CAR- T cells were recovered from the CSF, but not the peripheral blood, of patients who received intraventricular IL13BBζ-CAR T cell therapy. Additionally, although immune infiltrates in CSF and post-therapy tumor did not generally correlate, a fraction of expanded T cell receptors (TCRs) was seen to overlap between CSF and tumor. This has important implications for what samples are collected on these trials and how they are analyzed. These initial findings provide support for continued investigation into locoregionally-delivered IL13BBζ-CAR T cells for children with brain tumors.

Peritransplantation ruxolitinib administration is safe and effective in patients with myelofibrosis: a pilot open-label study.

We report results of our prospective pilot trial evaluating safety/feasibility of peritransplantation ruxolitinib for myelofibrosis treatment. Primary objectives were to determine safety and maximum tolerated dose (MTD) of ruxolitinib. Ruxolitinib was administered at 2 dose levels (DLs) of 5 and 10 mg twice daily, with fludarabine/melphalan conditioning regimen and tacrolimus/sirolimus graft-versus-host disease (GVHD) prophylaxis. We enrolled 6 and 12 patients at DL1 and DL2, respectively. Median age at transplantation was 65 years (range, 25-73). Per Dynamic International Prognostic Scoring System, 4 patients were high and 14 intermediate risk. Peripheral blood stem cells were graft source from matched sibling (n = 5) or unrelated (n = 13) donor. At each DL, 1 patient developed dose-limiting toxicities (DLTs): grade 3 cardiac and gastrointestinal with grade 4 pulmonary DLTs in DL1, and grade 3 kidney injury in DL2. All patients achieved engraftment. Grade 2 to 4 and 3 to 4 acute GVHD cumulative incidence was 17% (95% confidence interval [CI], 6-47) and 11% (95% CI, 3-41), respectively. Cumulative incidence of 1-year chronic GVHD was 42% (95% CI, 24-74). With 22.6-month (range, 6.2-25.8) median follow-up in surviving patients, 1-year overall and progression-free survival were 77% (95% CI, 50-91) and 71% (95% CI, 44-87), respectively. Causes of death (n = 4) were cardiac arrest, GVHD, respiratory failure, and refractory GVHD of liver. Our results show peritransplantation ruxolitinib is safe and well tolerated at MTD of 10 mg twice daily and associated with dose-dependent pharmacokinetic and cytokine profile. Early efficacy data are highly promising in high-risk older patients with myelofibrosis. This trial was registered at www.clinicaltrials.gov as #NCT02917096.

CD19-directed CAR T-cell therapy for treatment of primary CNS lymphoma.

CD19-directed chimeric antigen receptor (CD19CAR) T-cell therapy has been successful in treating several B-cell lineage malignancies, including B-cell non-Hodgkin lymphoma (NHL). This modality has not yet been extended to NHL manifesting in the central nervous system (CNS), primarily as a result of concerns for potential toxicity. CD19CAR T cells administered IV are detectable in cerebrospinal fluid (CSF), suggesting that chimeric antigen receptor (CAR) T cells can migrate from the periphery into the CNS, where they can potentially mediate antilymphoma activity. Here, we report the outcome of a subset of patients with primary CNS lymphoma (PCNSL; n = 5) who were treated with CD19CAR T cells in our ongoing phase 1 clinical trial. All patients developed grade ≥ 1 cytokine release syndrome and neurotoxicity post-CAR T-cell infusion; toxicities were reversible and tolerable, and there were no treatment-related deaths. At initial disease response, 3 of 5 patients (60%; 90% confidence interval, 19-92%) seemed to achieve complete remission, as indicated by resolution of enhancing brain lesions; the remaining 2 patients had stable disease. Although the study cohort was small, we demonstrate that using CD19CAR T cells to treat PCNSL can be safe and feasible. This trial was registered at www.clinicaltrials.gov as #NCT02153580.

Phase II study of neratinib in older adults with HER2 amplified or HER2/3 mutated metastatic breast cancer.

OBJECTIVE: The tolerability and efficacy of targeted therapy in older adults with cancer has not been adequately studied. Neratinib is a novel HER1, HER2, HER4 tyrosine kinase inhibitor that has recently been granted FDA approval for treatment of breast cancer. The major toxicity of neratinib is diarrhea, which affects up to 90% of patients. This phase II trial evaluates the safety and tolerability of neratinib in adults ≥60. METHODS: Patients aged 60 or older with histologically proven metastatic breast cancer and HER2 amplification (defined by ASCO/CAP guideline) or HER2/HER3 activating mutation were enrolled to receive neratinib at 240 mg daily in 28-day cycles. The association between tolerability, defined as dose reduction and number of completed courses, and log2 Cancer and Aging Research Group (CARG) toxicity risk score was assessed using a Student's t-test and linear regression, respectively. Response rate, progression free survival, and overall survival were also evaluated. RESULTS: 25 patients were enrolled with median age of 66 (range 60-79). Seventy-six percent of patients were white, 16% Asian, and 8% African-American. Seventy-six percent were patients with hormone receptor (HR) positive metastatic breast cancer (MBC) and 24% were patients with HR negative MBC. Median number of prior lines of metastatic therapy were 3 (range 0-11). 20/25 (80%) had worst grade toxicities ≥2. A total of 9/25 (36%) had grade 3 toxicities including 5/20 (20%) diarrhea, 2/20 (8%) vomiting, and 2/20 (8%) abdominal pain. There were no grade 4 or 5 toxicities. A total of 9/25 (36%) had dose reduction, and 2/25 (8%) discontinued therapy due to toxicity. The association between dose reductions and CARG toxicity score reached borderline statistical significance suggesting a trend with participants with higher CARG toxicity risk scores being more likely to require a dose modification (p = 0.054). 1/25 (4%) had a partial response, 11/25 (44%) had stable disease, 12/25 (48%) had progression of disease, and 1/25 (4%) was not assessed. Median progression free survival (PFS) was 2.6 months (95% CI [2.56-5.26]), and median overall survival (OS) was 17.4 months (95% CI [10.3, NA]). CONCLUSIONS: Neratinib was safe in this population of older adults with HER2 amplified or HER2/3 mutated metastatic breast cancer (BC). Higher CARG toxicity risk score may be associated with greater need for dose adjustments. Future studies are needed to confirm this finding.

Conditional Survival, Cause-Specific Mortality, and Risk Factors of Late Mortality After Allogeneic Hematopoietic Cell Transplantation.

BACKGROUND: Long-term mortality after hematopoietic cell transplantation (HCT) is conventionally calculated from the time of HCT, ignoring temporal changes in survivors' mortality risks. Conditional survival rates, accounting for time already survived, are relevant for optimal delivery of survivorship care but have not been widely quantified. We estimated conditional survival by elapsed survival time in allogeneic HCT patients and examined cause-specific mortality. METHODS: We calculated conditional survival rates and standardized mortality ratio for overall and cause-specific mortality in 4485 patients who underwent HCT for malignant hematologic diseases at a large transplant center during 1976-2014. Statistical tests were two-sided. RESULTS: The 5-year survival rate from HCT was 48.6%. After surviving 1, 2, 5, 10, and 15 years, the subsequent 5-year survival rates were 71.2%, 78.7%, 87.4%, 93.5%, and 86.2%, respectively. The standardized mortality ratio was 30.3 (95% confidence interval [CI] = 29.2 to 35.5). Although the standardized mortality ratio declined in longer surviving patients, it was still elevated by 3.6-fold in survivors of 15 years or more (95% CI = 3.0 to 4.1). Primary disease accounted for 50% of deaths in the overall cohort and only 10% in 15-year survivors; the leading causes of nondisease-related mortality were subsequent malignancy (26.1%) and cardiopulmonary diseases (20.2%). We also identified the risk factors for nondisease-related mortality in 1- and 5-year survivors. CONCLUSION: Survival probability improves the longer patients survive after HCT. However, HCT recipients surviving 15 years or more remain at elevated mortality risk, largely because of health conditions other than their primary disease. Our study findings help inform preventive and interventional strategies to improve long-term outcomes after allogeneic HCT.

Protective effect of HLA-DPB1 mismatch remains valid in reduced-intensity conditioning unrelated donor hematopoietic cell transplantation.

A mismatch at HLA-DPB1 locus is associated with higher acute GVHD and lower relapse rate after myeloablative (MAC) allogeneic hematopoietic cell transplantation (alloHCT). Also, in MAC setting, mismatch permissiveness and expression level impact alloHCT outcomes. However, in reduced intensity conditioning (RIC), DP mismatch effect on transplant outcomes is unknown. We retrospectively evaluated DP mismatch influence (number, permissiveness, and expression) on HCT outcomes in 310 patients with high-resolution typing (HLA-A, -B, -C, -DRB1, -DQB1, and -DPB1), who underwent RIC HCT. By multivariable analysis, 11/12 had better overall survival (OS) and relapse vs. 12/12 (HR = 1.61 and 2.02; p = 0.04 and 0.01, respectively) and better OS vs. 10/12 (HR = 1.68; p = 0.02). Within the 11/12, nonpermissive (NoPR) mismatch was associated with higher risk of grade II-IV acute GVHD (HR = 1.97; p = 0.005) and nonrelapse mortality (HR = 2.13; p = 0.02) vs. permissive (PR). Grouping 11/12 based on the DP expression conferred higher mortality (HR = 3.78; p = 0.003) when low expressers received a graft from high expressers (AG) vs. low expressers (AA). Better OS was achieved in PR 11/12, when expression was low in patient and donor (AA) vs. all other combinations. Therefore, in RIC HCT, a single-DP mismatch has a protective role, especially in permissive setting, when donor and recipient are low expressers.

Acute lymphoblastic leukemia as a clonally unrelated second primary malignancy after multiple myeloma.

Multiple myeloma (MM) patients have an 11-fold increased risk of developing myeloid neoplasms compared to the general population; however, acute lymphoblastic leukemia (ALL) is rarely observed. Given that both MM and the majority of ALL are of B cell origin, this raises the question of whether ALL in patients with MM arises from the same clone. We report 13 cases of B-cell ALL following therapy for MM. The interval from MM diagnosis to ALL onset was 5.4 years (range 3.3-10). The median age at the time of ALL diagnosis was 60 years (range 43-67). MM therapy included immunomodulatory agents in all patients and autologous hematopoietic cell transplantation in 10 (77%) patients preceding ALL diagnosis. ALL genetics showed a normal karyotype, TP53 mutation/deletion, and monosomy 7 or 7q deletion in 5, 3, and 2 cases, respectively. Analysis of paired samples of MM and ALL using whole exome sequencing demonstrated that the malignancies arose from different clones. Thus, ALL as a second primary malignancy following MM is not clonally related but could potentially represent a therapy-related leukemia.