Treatment of secondary CNS lymphoma using CD19-targeted chimeric antigen receptor (CAR) T cells.

BACKGROUND: Aggressive B cell lymphoma with secondary central nervous system (CNS) involvement (SCNSL) carries a dismal prognosis. Chimeric antigen receptor (CAR) T cells (CAR-T) targeting CD19 have revolutionized the treatment for B cell lymphomas; however, only single cases with CNS manifestations successfully treated with CD19 CAR-T have been reported. METHODS: We prospectively enrolled 4 patients with SCNSL into our study to assess clinical responses and monitor T cell immunity. RESULTS: Two of four SNCSL patients responded to the CD19-targeted CAR-T. Only one patient showed a substantial expansion of peripheral (PB) CAR-T cells with an almost 100-fold increase within the first week after CAR-T. The same patient also showed marked neurotoxicity and progression of the SNCSL despite continuous surface expression of CD19 on the lymphoma cells and an accumulation of CD4+ central memory-type CAR-T cells in the CNS. Our studies indicate that the local production of chemokine IP-10, possibly through its receptor CXCR3 expressed on our patient's CAR-T, could potentially have mediated the local accumulation of functionally suboptimal anti-tumor T cells. CONCLUSIONS: Our results demonstrate expansion and homing of CAR-T cells into the CNS in SNCSL patients. Local production of chemokines such as IP-10 may support CNS infiltration by CAR-T cells but also carry the potential of amplifying local toxicity. Future studies investigating numbers, phenotype, and function of CAR-T in the different body compartments of SNSCL patients receiving CAR-T will help to improve local delivery of "fit" and highly tumor-reactive CAR-T with low off-target reactivity into the CNS.

Chimeric antigen receptor (CAR) T cells for the treatment of a kidney transplant patient with post-transplant lymphoproliferative disorder (PTLD).

Post-transplant lymphoproliferative disorder (PTLD) is a potentially fatal complication following kidney transplantation, and there is a critical and unmet need for PTLD treatments associated with more pronounced and durable responses. To date, reports on the use of CD19-targeted chimeric antigen receptor (CAR) T (CAR-T) cells in patients after solid organ transplant (SOT) have been anecdotal, clinical presentations and outcomes have been heterogenous, and a longitudinal analysis of CAR-T cell expansion and persistence in PTLD patients has not been reported. Our report describes a patient with a history of renal transplant who received CD19-directed CAR-T cell therapy for the treatment of refractory PTLD, diffuse large B cell lymphoma (DLBCL)-type. We show that even with the background of prolonged immunosuppression for SOT, it is possible to generate autologous CAR-T products capable of expansion and persistence in vivo, without evidence of excess T-cell exhaustion. Our data indicate that CAR-T cells generated from a SOT recipient with PTLD can yield deep remissions without increased toxicity or renal allograft dysfunction. Future clinical studies should build on these findings to investigate CAR-T therapy, including longitudinal monitoring of CAR-T phenotype and function, for PTLD in SOT recipients.

Transference and client attachment to therapist in psychodynamic psychotherapy.

Although there are theorized connections between client transference and their attachment to their therapists (Bowlby, 1969/1982), limited empirical research exists examining their association over the course of psychotherapy. We thus examined the association between positive and negative transference and client attachment to therapist across the course of open-ended psychodynamic psychotherapy for 49 cases with doctoral student therapists and adult community clients who had at least 32 sessions. Using a Bayesian multilevel structural equation model framework, results indicated that client secure attachment increased and avoidant-fearful attachment decreased across the course of psychotherapy. For clients with higher preoccupied-merger attachment at the beginning of therapy, therapists perceived more fluctuation in negative transference over time than for clients with other attachment styles. Implications for research, practice, and therapist training are offered. (PsycInfo Database Record (c) 2023 APA, all rights reserved).

Impact of FLT3-ITD Insertion Length on Outcomes in Acute Myeloid Leukemia: A Propensity Score-Adjusted Cohort Study.

The prognostic significance of the length of internal tandem duplication (ITD) insertions in mutant FLT3 genes in acute myeloid leukemia (AML) is controversial. We conducted a retrospective study to evaluate the correlation between the ITD base-pair (bp) insertion length and clinical outcomes. The mutational status of the FLT3 gene was evaluated in 402 of 467 consecutive AML patients treated at the University of Maryland Greenebaum Comprehensive Cancer Center between 2013 and 2020; 77 had FLT3-ITD mutations. Patients were divided into three cohorts based on bp insertion length (<30 (0−33rd percentile), 30−53 (34th−66th percentile),and >53 (>66th percentile)). The median overall survival (OS) of patients was 16.5 months (confidence interval (CI) 7.3-NA), 18.5 months (CI 7.3-NA), and 21.9 months (CI 19.1-NA) (p = 0.03) for the <30, 30−53, and >53 bp insertion length cohorts, respectively. The adjusted median event-free survival (EFS) for the ITD insertion lengths >30, 30−53, and >53 bp was 11.1 months (CI 2.8−16.5), 5.2 months (CI 2.9−12.6), and 9.1 months (CI 5.4-NA) (p = 0.5), respectively. Complete remission (CR) rates were 64% (<30 inserted bp), 55% (30−53 inserted bp), and 79% (>53 inserted bp) (p = 0.23). For patients treated with gilteritinib and midostaurin, the unadjusted median OS was not statistically significantly different between cohorts.

Outcomes of Newly Diagnosed Acute Myeloid Leukemia Patients Treated With Hypomethylating Agents With or Without Venetoclax: A Propensity Score-Adjusted Cohort Study.

There is a deficiency of real-world data on the impact of combining venetoclax (VEN) with hypomethylating agents (HMAs) in newly diagnosed acute myeloid leukemia (AML) patients. We conducted a single-center, propensity-adjusted retrospective cohort study to compare composite complete remission (CCR) rates, median overall survival (m-OS) and median event-free survival (m-EFS). A total of 170 adult AML patients were treated with first-line azacitidine (AZA) or decitabine (DEC) +/- VEN. Median age was 71 years and 99 (58%) were male. Median follow-up in HMA and HMA-VEN groups was 79 and 21 months. Treatments included AZA alone (n=35, 21%), DEC alone (n=84, 49%), AZA-VEN (n=24, 14%) and DEC-VEN (n=27, 16%). VEN improved CCR rates to HMAs overall (52% vs. 27%, P<0.05) and to AZA (54% vs. 10%, P<0.05), but not to DEC (43% vs. 32%, P=0.35); it did not improve OS, and only improved EFS for AZA (10.5 vs. 3.8 months, P<0.05). CCR rates were lower with AZA than with DEC (13% vs. 33%, P<0.05), but OS and EFS were not different statistically. CCR rates did not differ for AZA-VEN vs. DEC-VEN (CCR: 58% vs. 52%, P=0.66), but OS and EFS were longer for AZA-VEN (m-OS: 12.3 vs. 2.2 months, P<0.05; m-EFS: 9.2 vs. 2.1 months, P<0.05). Our analysis showed that combining VEN with AZA in newly diagnosed AML patients improved outcomes, but combining VEN with DEC did not. AZA-VEN was associated with improved outcomes compared to DEC-VEN. Further studies are needed to test the benefit of combining VEN with DEC.

Impact of IDH1 c.315C>T SNP on Outcomes in Acute Myeloid Leukemia: A Propensity Score-Adjusted Cohort Study.

Acute myeloid leukemia (AML) is the common type of acute leukemia in adults. Definitive prognostic significance of variants of unknown significance lacks for many commonly mutated genes, including the isocitrate dehydrogenase 1 (IDH1) synonymous single nucleotide polymorphism (SNP) variant c.315C>T. In this retrospective cohort study of 248 AML patients at the University of Maryland Greenebaum Comprehensive Cancer Center, we show that the IDH1 c.315C>T SNP, previously reported to be associated with poor prognosis by other studies with conflicting data, does not confer worse prognosis, with a median overall survival (OS) of 17.1 months compared to 15.1 months for patients without this SNP (P=0.57). The lack of negative effect on prognosis by IDH1 SNP c.315C>T is consistent with the absence of amino acid alteration (p.Gly105Gly).

The triadic effect: Associations among the supervisory working alliance, therapeutic working alliance, and therapy session evaluation.

Several theorists (Bandura, 1969; Hackney & Goodyear, 1984; Searles, 1955) suggest parallels between the relationship in supervision and the relationship in therapy. We examined supervisor and therapist trainee ratings of supervisory working alliance (SWA) in 1 week predicting client-rated therapeutic working alliance (TWA) and client-rated therapy session evaluation (TSE) in the following week as well as TWA and TSE ratings in 1 week predicting SWA ratings in the following week. Our data included 663 weeks of therapy nested within 28 trainees nested within 15 supervisors, disaggregated into differences between supervisors, differences within supervisors, and differences within trainees. At the between-supervisor level, when supervisors' trainees rated the SWA higher on average compared with other supervisors' trainees' average SWA ratings, their clients' average TWA rating was higher. In contrast, when supervisors rated the SWA higher on average compared with other supervisors' average SWA ratings, their trainees' clients' average TSE rating was higher but the average TWA rating was lower. At the within-supervisor level, when trainees rated a higher SWA on average compared with other trainees' average SWA ratings with the same supervisor, their clients' average TSE rating was higher. The theoretical prediction of parallel relationships in supervision and therapy was supported, but only for between-supervisor and within-supervisor differences in SWA. We found no evidence that week-to-week changes in SWA or client-rated TWA or TSE reflected parallel relationships. We provide suggestions for further research, including exploring the mechanisms through which supervision relates to the therapy process and outcome. (PsycInfo Database Record (c) 2022 APA, all rights reserved).

Some directions for research and theory on countertransference.

The topic of countertransference (CT) has been a controversial one over the decades, and its various, often conflicting, definitions have made it difficult to gather clear and consistent empirical evidence about the phenomenon. The growing awareness that CT occurs across theoretical orientations has fueled the need for research on CT, its effects, how it emerges in treatment, and how it can be used to enhance psychotherapy. In this paper, we reflect on three studies published in the special section on CT that we believe advance the field of CT research. We also provide future directions for CT theory and research, including attending to CT definitions and their rationale in empirical studies, striving for methodological diversity, differentiating acute and chronic CT, and continuing to investigate CT management.

Acute Lymphoblastic Leukemia and Acute Lymphoblastic Lymphoma: Same Disease Spectrum but Two Distinct Diagnoses.

PURPOSE OF REVIEW: Rare malignancies developing from lymphocyte precursor cells, lymphoblastic leukemia (LBL), and acute lymphoblastic lymphoma (ALL) have historically been viewed as different manifestations of the same disease process. This review examines data on their epidemiology, genetics, clinical presentation, and response to treatment while highlighting areas of similarity and divergence between these two clinical entities. RECENT FINDINGS: Pediatric-type ALL chemotherapy regimens, compared to both lymphoma-type chemotherapy and adult-type ALL regimens, have led to improved outcomes for children, adolescents, and young adults with ALL. BCR-ABL-targeting tyrosine kinase inhibitors (TKIs) have improved outcomes in Philadelphia chromosome-positive (Ph +) ALL and in rare cases of Ph + LBL. Newer therapies including blinatumomab, inotuzumab, CAR-T therapy, and nelarabine have improved outcomes in selected cases of ALL and have an emerging role in the management of LBL. Better understanding of ALL and LBL biology allows for the development of therapies that target immunophenotypic or genetic features found in subsets of both diseases. Novel therapies are leading to improved outcomes in Ph + and relapsed and refractory disease.

A follow-up of undergraduate students five years after helping skills training.

In a 5-year follow-up assessment, 33 students who had taken an undergraduate helping skills course indicated that they had continued to use the helping skills in both their professional lives and personal relationships. On average, there were no significant changes from pretraining to follow-up on empathy, natural helping ability, or facilitative interpersonal skills. Furthermore, although students had increased in self-efficacy for using the skills during training, on average they maintained their self-efficacy levels at the follow-up. The 15 participants who had further mental health education, however, scored higher at follow-up on empathy, natural helping ability, self-efficacy for using the skills, and facilitative interpersonal skills compared with the 18 participants who had no further mental health education (controlling for pretraining levels), suggesting that continued exposure to and practice using the skills helped them continue to improve their helping abilities. Qualitative data indicated that participants typically had positive experiences in the helping skills course. Implications for training and research are provided. (PsycInfo Database Record (c) 2020 APA, all rights reserved).

Facilitating client collaboration and insight through interpretations and probes for insight in psychodynamic psychotherapy: A case study of one client with three successive therapists.

We investigated therapist interpretations (Ints) and probes for insight (PIs) in relation to changes in client collaboration and insight for 1 male client paired with 3 successive doctoral student therapists in psychodynamic psychotherapy for 192 sessions over 5 years. Judges coded client collaboration and insight in the antecedent and subsequent 3 min for all Ints and PIs in each of 6 middle sessions for each treatment. Qualitative analyses showed that PIs were more helpful than Ints for this defended client. More gains in collaboration were found when antecedent client collaboration was high, antecedent client insight was low, and therapists gave PIs instead of Ints, but no differences were found among therapists. More gains in insight were found when antecedent insight in a given session was higher than in other sessions with the same therapist, with Therapist 3 facilitating more insight than Therapist 1; no differences were found between Ints and PIs. (PsycInfo Database Record (c) 2020 APA, all rights reserved).

Testing a mediation model of psychotherapy process and outcome in psychodynamic psychotherapy: Previous client distress, psychodynamic techniques, dyadic working alliance, and current client distress.

To test a sequential model of psychotherapy process and outcome, we included previous client distress, therapist psychodynamic techniques, dyadic working alliance, and current client distress. For 114 sets of eight-session segments in 40 cases of psychodynamic psychotherapy, clients completed the Outcome Questionnaire-45 and Inventory of Interpersonal Problems-32 after the first and final session, judges reliably coded one middle sessions on the Psychodynamic subscale of the Multitheoretical List of Therapeutic Interventions, and clients and therapists completed the Working Alliance Inventory after every session. Results indicated that higher use of psychodynamic techniques was associated with higher levels of the working alliance, which in turn was associated decreased client distress; and working alliance was higher later in psychotherapy. There was a significant indirect effect of psychodynamic techniques on decreases in distress mediated by the working alliance. Implications for theory, practice, and research are provided. Clinical or methodological significance of this article: Conducted a longitudinal, latent variable examination of the relationships of psychodynamic techniques and working alliance on client distress. Psychodynamic techniques have an indirect effect on decreases in client distress through the dyadic working alliance.

The sister concepts of the working alliance and the real relationship: on their development, rupture, and repair.

Jeremy Safran has presented seminal and widely applicable clinical theory and research around the therapeutic alliance and ruptures in the alliance. We explore areas of agreement with and departure from some of Safran's key conceptualizations on these topics, focusing on overlap and distinctions between two constructs theorized to be fundamentally significant elements of all therapeutic relationships: the working alliance and the real relationship. We share Safran's view that the alliance centrally implicates an emotional bond between patient and therapist, as well as an agreement about the goals of treatment and the tasks needed to attain those goals. We depart from Safran, however, in his belief that the real relationship should be seen as part of the emotional bond of the working alliance. Instead, we argue that the real relationship and the working alliance (including the bond aspect of the alliance) are best viewed as highly interrelated but distinct aspects of the therapeutic relationship. In addition, a distinction is made between the working bond (part of the working alliance) and the personal bond (part of the real relationship). Hence, we examine the concept of rupture in the working alliance, and in the real relationship as well. The nature of ruptures is discussed, as well as what therapists can do to repair them. A more limited definition of ruptures than the broader conception that has evolved in recent years is proposed. It is suggested that, whereas ruptures in the working alliance generally can be repaired to the benefit of the work, ruptures in the real relationship are likely to be more damaging to the treatment.

Silence is golden: A mixed methods investigation of silence in one case of psychodynamic psychotherapy.

We investigated the antecedents, occurrences, and consequences of 183 silence events in the first 5 and last 5 sessions of a 73-session case of successful psychodynamic psychotherapy. Silences generally occurred within client speaking turns, such that the client often paused to reflect while speaking. In the last 5 sessions, as compared with the first 5 sessions, the client was more collaborative before and after silences, silences were shorter, the therapist was more connectional during silences (e.g., shared emotion and meaning with client), and the client was more emotional after silences. Antecedent client collaboration, duration of the silence, therapist behavior during silence events, client behavior during silence events, and who broke the silence all related to change in collaboration from before to after the silence events. We concluded that silence was helpful in this case because of client factors (the client naturally paused a lot during discussion, the client was quite reflective and insightful), therapist factors (the therapist was comfortable with and believed in silence), and relationship factors (there was a strong therapeutic relationship). (PsycINFO Database Record (c) 2019 APA, all rights reserved).

Centro SOL: A Community-Academic Partnership to Care for Undocumented Immigrants in an Emerging Latino Area.

PROBLEM: From 2000 to 2014, the Latino population in Baltimore city, an emerging Latino settlement area, experienced rapid growth. Many of these individuals are undocumented and not eligible for coverage. Academic medical centers often lead the way in addressing the health needs of undocumented immigrants; however, examples from emerging immigrant areas are limited. APPROACH: In October 2013, Johns Hopkins Medicine clinicians established the Center for Salud/Health and Opportunities for Latinos (Centro SOL) to better address the health needs of Baltimore's growing Latino community. Centro SOL's mission focuses on four core activities: clinical services; advocacy and community engagement efforts; pipeline/education opportunities; and research consultations. Progress is measured through a scorecard reviewed annually by Centro SOL leadership. OUTCOMES: Centro SOL's program has expanded health care access for undocumented immigrants, patient safety and quality of service/care programs for patients with limited English proficiency, and pipeline opportunities for Latino youth. In 2017, 2,763 uninsured patients received primary or specialty care and 290 people received group therapy to address stress-related conditions. In addition, 49 Latino students (ranging from high school to postgraduate students) received mentorship at Centro SOL. NEXT STEPS: In the next five years, Centro SOL plans to expand the pipeline for Latinos interested in health professions fields and to further improve access to health services for Latino families through both advocacy efforts and enhanced clinical services.

Ruptures in psychotherapy: Experiences of therapist trainees.

Method: We used consensual qualitative research (CQR) to investigate the experiences of therapist trainees who had a rupture with a client. Results: Of 21 trainees who were tracked weekly, 14 experienced a rupture and were interviewed 1 week after the rupture and again 2 weeks later about antecedents, repair attempts, and consequences. Trainees typically reported experiencing tension at the beginning of the rupture session and difficult emotions during the rupture (e.g., anger, depleted self-efficacy). Conclusion: Trainees typically tried to repair the rupture by using immediacy or facilitating exploration about the conflict. Trainees typically reported both negative (e.g., strained therapeutic relationship) and positive consequences (e.g., therapeutic work became more productive). Trainees seemed to be less aware of withdrawal than confrontational ruptures. Implications are that trainees could benefit from learning more about ruptures including how to regulate negative emotions toward clients and acquiring more rupture-repair tools, as well as realizing that ruptures can have some positive as well as negative aspects.

Congruence and discrepancy between working alliance and real relationship: Variance decomposition and response surface analyses.

We examined how congruence and discrepancy in clients' and therapists' ratings of the working alliance (WA) and real relationship (RR) were related to client-rated session quality (SES; Session Evaluation Scale). Ratings for 2517 sessions of 144 clients and 23 therapists were partitioned into therapist-level, client-level, and session-level components and then analyzed using multilevel, polynomial regression and response surface analysis. For both clients and therapists, at all levels of analysis (except the therapist level for therapist ratings), SES was highest when combined WA and RR ratings were high, and lowest when combined ratings were low. For client ratings, discrepancy between WA and RR, at the client and session levels, was associated with greater session quality. Some clients perceived greater session quality when, across all sessions, WA was stronger than RR and other clients perceived greater session quality when RR was stronger than WA. Within clients, session quality was highest when some sessions had a stronger WA than RR whereas other sessions had a stronger RR than WA. These findings are compatible with a responsiveness framework, therapists varied the balance of WA and RR to suit situational demands or needs of different clients. When therapists rated WA and RR the opposite pattern of results emerged; clients perceived greater session quality when therapists' WA and RR ratings, for a session were high and consistent (i.e., no discrepancy between WA and RR). In addition, across all sessions, clients perceived greater session quality when WA and RR ratings were high and consistent. (PsycINFO Database Record

Are you in the mood? Therapist affect and psychotherapy process.

Studies on therapist factors have mostly focused on therapist traits rather than states such as affect. Research related to therapist affect has often looked at therapist baseline well-being or therapist reactions, but not both. Fifteen therapists and 51 clients rated pre- and postsession affect, as well as postsession working alliance and session quality, for 1,172 sessions of individual psychotherapy at a community clinic. Therapists' affect became more positive when clients were initially positive and when clients became more positive over the session, and became more negative when clients were initially negative and when clients became more negative over the session. Furthermore, when therapists were initially positive in affect and when therapists became more positive over the session, clients rated the session quality to be high. Conversely, when therapists were initially negative in affect and when therapists became more negative over the session, clients rated the session quality and working alliance low. On open-ended questions, therapists reported mood shifts in 67% of sessions (63% positive, 50% negative). Positive affect change was attributed to collaborating with the client, perceiving the client to be engaged, or being a good therapist. Negative affect change was attributed to having a difficult client, perceiving the client to be in distress, or being a poor therapist. Thus, therapist state affect at presession and change in affect across a session may independently contribute to the process and outcome of therapy sessions. The examination of within-therapist variables over the course of therapy may further our understanding of therapist factors. (PsycINFO Database Record