Gabriel N. Mannis

How I treat CNS lymphomas

The pathogenesis of primary and secondary central nervous system (CNS) lymphoma poses a unique set of diagnostic, prognostic, and therapeutic challenges. During the past 10 years, there has been significant progress in the elucidation of the molecular properties of CNS lymphomas and their microenvironment, as well as evolution in the development of novel treatment strategies. Although a CNS lymphoma diagnosis was once assumed to be uniformly associated with a dismal prognosis, it is now reasonable to anticipate long-term survival, and possibly a cure, for a significant fraction of CNS lymphoma patients. The pathogenesis of CNS lymphomas affects multiple compartments within the neuroaxis, and proper treatment of the CNS lymphoma patient requires a multidisciplinary team with expertise not only in hematology/oncology but also in neurology, neuroradiology, neurosurgery, clinical neuropsychology, ophthalmology, pathology, and radiation oncology. Given the evolving principles of management and the evidence for improvements in survival, our goal is to provide an overview of current knowledge regarding the pathogenesis of CNS lymphomas and to highlight promising strategies that we believe to be most effective in establishing diagnosis, staging, and therapeutic management.

Durable Remissions with Ivosidenib in IDH1-Mutated Relapsed or Refractory AML

Background Mutations in the gene encoding isocitrate dehydrogenase 1 (IDH1) occur in 6 to 10% of patients with acute myeloid leukemia (AML). Ivosidenib (AG‐120) is an oral, targeted, small‐molecule inhibitor of mutant IDH1. Methods We conducted a phase 1 dose‐escalation and dose‐expansion study of ivosidenib monotherapy in IDH1‐mutated AML. Safety and efficacy were assessed in all treated patients. The primary efficacy population included patients with relapsed or refractory AML receiving 500 mg of ivosidenib daily with at least 6 months of follow‐up. Results Overall, 258 patients received ivosidenib and had safety outcomes assessed. Among patients with relapsed or refractory AML (179 patients), treatment‐related adverse events of grade 3 or higher that occurred in at least 3 patients were prolongation of the QT interval (in 7.8% of the patients), the IDH differentiation syndrome (in 3.9%), anemia (in 2.2%), thrombocytopenia or a decrease in the platelet count (in 3.4%), and leukocytosis (in 1.7%). In the primary efficacy population (125 patients), the rate of complete remission or complete remission with partial hematologic recovery was 30.4% (95% confidence interval [CI], 22.5 to 39.3), the rate of complete remission was 21.6% (95% CI, 14.7 to 29.8), and the overall response rate was 41.6% (95% CI, 32.9 to 50.8). The median durations of these responses were 8.2 months (95% CI, 5.5 to 12.0), 9.3 months (95% CI, 5.6 to 18.3), and 6.5 months (95% CI, 4.6 to 9.3), respectively. Transfusion independence was attained in 29 of 84 patients (35%), and patients who had a response had fewer infections and febrile neutropenia episodes than those who did not have a response. Among 34 patients who had a complete remission or complete remission with partial hematologic recovery, 7 (21%) had no residual detectable IDH1 mutations on digital polymerase‐chain‐reaction assay. No preexisting co‐occurring single gene mutation predicted clinical response or resistance to treatment. Conclusions In patients with advanced IDH1‐mutated relapsed or refractory AML, ivosidenib at a dose of 500 mg daily was associated with a low frequency of grade 3 or higher treatment‐related adverse events and with transfusion independence, durable remissions, and molecular remissions in some patients with complete remission. (Funded by Agios Pharmaceuticals; ClinicalTrials.gov number, NCT02074839.)

Risk-Reducing Salpingo-oophorectomy and Ovarian Cancer Screening in 1077 Women After BRCA Testing

BACKGROUND For women at potentially increased risk for ovarian cancer, data regarding screening and risk reduction are limited. Previous studies have reported on the behaviors of BRCA mutation carriers, but less is known about the behaviors of non- BRCA carriers. We surveyed a large cohort of women after BRCA testing to identify the prevalence and posttest predictors of risk-reducing and screening interventions. METHODS A median of 3.7 years after BRCA testing, 1447 women who received genetic counseling and BRCA testing at 2 hospital sites were surveyed, with a 77.6% response rate. We analyzed data from 1077 survey respondents. We performed univariate and multivariate logistic regression analyses to identify predictors of risk-reducing salpingo-oophorectomy (RRSO), screening transvaginal ultrasonography (TVUS), and screening serum cancer antigen 125 (CA-125). RESULTS Among the respondents, 201 women (18.7%) received positive test results for a deleterious mutation, 103 women (9.6%) received true-negative results, and 773 women (71.8%) received uninformative results. Overall, 19.1% of eligible women underwent RRSO and 39.6% used screening procedures. A positive BRCA result predicted RRSO (odds ratio [OR], 28.1; 95% CI, 16.2-48.6), TVUS (9.5 [4.3-21.0]), and serum CA-125 (13.0 [5.5-29.0]). Similarly, a true-negative BRCA result reduced the OR for RRSO (0.1 [0.0-0.6]), TVUS (0.2 [0.1-0.5]), and serum CA-125 (0.3 [0.1-0.7]). Of the 71.8% of women who received uninformative results after BRCA testing, 12.3% subsequently underwent RRSO, 33.8% reported ever having undergone screening serum CA-125 since BRCA testing, and 37.3% reported ever having undergone screening TVUS since BRCA testing. CONCLUSIONS Results of BRCA testing strongly predict RRSO and ovarian cancer screening. Use of RRSO and ovarian screening was reported in a sizable percentage of non- BRCA carriers despite insufficient data to determine the effectiveness of these interventions.

Delayed hematopoietic recovery after auto-SCT in patients receiving arsenic trioxide-based therapy for acute promyelocytic leukemia: a multi-center analysis.

A potential link between arsenic (ATO)-based therapy and delayed hematopoietic recovery after autologous hematopoietic SCT (HSCT) for acute promyelocytic leukemia (APL) has previously been reported. We retrospectively reviewed the clinical histories of 58 patients undergoing autologous HSCT for APL at 21 institutions in the United States and Japan. Thirty-three (56%) of the patients received ATO-based therapy prior to stem cell collection. Delayed neutrophil engraftment occurred in 10 patients (17%): 9 of the 10 patients (90%) received prior ATO (representing 27% of all ATO-treated patients), compared with 1 of the 10 patients (10%) not previously treated with ATO (representing 4% of all ATO-naïve patients; P<0.001). Compared with ATO-naïve patients, ATO-treated patients experienced significantly longer times to ANC recovery (median 12 days vs 9 days, P<0.001). In multivariate analysis, the only significant independent predictor of delayed neutrophil engraftment was prior treatment with ATO (hazard ratio 4.87; P<0.001). Of the available stem cell aliquots from APL patients, the median viable post-thaw CD34+ cell recovery was significantly lower than that of cryopreserved autologous stem cell products from patients with non-APL AML. Our findings suggest that ATO exposure prior to CD34+ cell harvest has deleterious effects on hematopoietic recovery after autologous HSCT.

Long-term survival in AIDS-related primary central nervous system lymphoma

Background. The optimal therapeutic approach for patients with AIDS-related primary central nervous system lymphoma (AR-PCNSL) remains undefined. While its incidence declined substantially with combination antiretroviral therapy (cART), AR-PCNSL remains a highly aggressive neoplasm for which whole brain radiotherapy (WBRT) is considered a standard first-line intervention. Methods. To identify therapy-related factors associated with favorable survival, we first retrospectively analyzed outcomes of AR-PCNSL patients treated at San Francisco General Hospital, a public hospital with a long history of dedicated care for patients with HIV and AIDS-related malignancies. Results were validated in a retrospective, multicenter analysis that evaluated all newly diagnosed patients with AR-PCNSL treated with cART plus high-dose methotrexate (HD-MTX). Results. We provide evidence that CD4+ reconstitution with cART administered during HD-MTX correlates with long-term survival among patients with CD4 <100. This was confirmed in a multicenter analysis which demonstrated that integration of cART regimens with HD-MTX was generally well tolerated and resulted in longer progression-free survival than other treatments. No profound differences in immunophenotype were identified in an analysis of AR-PCNSL tumors that arose in the pre- versus post-cART eras. However, we detected evidence for a demographic shift, as the proportion of minority patients with AR-PCNSL increased since advent of cART. Conclusion. Long-term disease-free survival can be achieved in AR-PCNSL, even among those with histories of opportunistic infections, limited access to health care, and medical non-adherence. Given this, as well as the long-term toxicities of WBRT, we recommend that integration of cART plus first-line HD-MTX be considered for all patients with AR-PCNSL.

Ibrutinib rash in a patient with 17p del chronic lymphocytic leukemia

A 67-year-old man with chronic lymphocytic leukemia (CLL) and deletion of chromosome 17p presented to clinic for evaluation of leukocytosis (total white blood cell count 149,000/mm3, absolute lymphocyte count 144,000/mm3) associated with fatigue, drenching night sweats, and recurrent viral infections. He had been treated previously with a combination of rituximab, cyclophosphamide, vincristine, and prednisone as well as rituximab and bendamustine (B-R), with the most recent therapy 3 years prior to his clinic visit. He had previously declined referral for hematopoietic stem cell evaluation. He was started on ibrutinib 420 mg PO daily in combination with allopurinol 300 mg PO daily for prophylaxis against tumor lysis syndrome. Two weeks after beginning therapy, he developed a painless, non-pruritic, rash that began on his wrists and then spread to his entire body (Image 1). The rash was characterized by a diffuse distribution of bright red edematous papules, ranging from 0.5 to 1 cm in diameter, with sparing of his palms and soles. He was evaluated in the Emergency Department and both allopurinol and ibrutinib were held. His absolute eosinophil count at the time was within the normal range (100/mm3). Within several days his rash had completely resolved, and given consideration for allopurinol as the etiology of his rash, he was restarted on dose-reduced ibrutinib (140 mg PO daily) without allopurinol. After a single dose, he developed recrudescence of his full-body rash and ibrutinib was once again discontinued. The rash again resolved within several days of discontinuing ibrutinib. Image 1 Painless, non-pruritic edematous papules on the trunk of a patient who developed an ibrutinib-related rash. Lesions began on the wrists and arms and subsequently generalized to the entire body. Ibrutinib (Imbruvica, Pharmacyclics/Janssen Biotech), an oral Brutons tyrosine kinase inhibitor, was approved in February 2014 by the Federal Drug Administration for the treatment of CLL patients who have received at least one prior therapy. Ibrutinib is generally very well-tolerated, with few Grade 3 or higher adverse events [1–3]. In published studies, rash occurs at a frequency of 15–27%, although no identifying characteristics have been reported. In this case, clinical features distinguishing the rash from a classic allopurinol-mediated rash included its presentation with edematous papules (versus the morbilliform rash commonly associated with allopurinol) and its peripheral-to-central pattern of spread.

Long-term outcomes of patients with intermediate-risk acute myeloid leukemia treated with autologous hematopoietic cell transplant in first complete remission

Abstract In 2014, autologous hematopoietic cell transplant (autoHCT) was removed from the National Comprehensive Cancer Network guidelines as a recommended treatment for patients with intermediate-risk AML in first complete remission (CR1). We reviewed the outcomes of all patients with intermediate-risk AML treated with autoHCT in CR1 at our institution. Of 334 patients who underwent autoHCT for AML between 1988 and 2013, 133 patients with intermediate-risk AML in CR1 were identified. Cytogenetics were diploid in 97 (73%). With a median follow-up of 4.1 years (range 0.1–17), median overall survival (OS) is 6.7 years; at 5 years post-transplant, 59% of patients remain alive and 43% remain relapse-free. Forty-eight percent of relapsing patients proceeded to salvage alloHCT. Our findings demonstrate that nearly half of patients with intermediate-risk AML in CR1 achieve sustained remissions, and that salvage alloHCT is feasible in those who relapse. AutoHCT therefore remains a reasonable option for intermediate-risk patients with AML in CR1.

The transfusion tether: Bridging the gap between end-stage hematologic malignancies and optimal end-of-life care

Two patients with refractory acute myeloid leukemia (AML) were recently treated at our institution. Patient 1 was a fit 72-year-old gentleman who failed to remit after high-intensity induction chemotherapy. Despite a second induction, his leukemia persisted. Although his functional status remained excellent, he eventually developed platelet-directed antibodies and required outpatient transfusion of HLA-matched platelets several times per week. When his leukemia eventually progressed, he suffered a stroke, leaving him unable to care for himself at home. Reluctant to forego lifeprolonging transfusion support, he refused to be discharged from the hospital unless he could continue to receive a similar level of transfusion support as he had been receiving. He remained hospitalized for 36 days while awaiting identification of a facility that was willing to continue transfusions. Patient 2 was a 79-year-old gentleman whose leukemia had been controlled for more than a year on various low-intensity, outpatient-based regimens. Like Patient 1, he too developed progressive transfusion dependence, requiring either blood and/or platelets multiple times per week. He had a long history of cardiovascular disease, and severe anemia typically precipitated dyspnea and angina, both of which resolved with transfusion. Unfortunately, his performance status steadily declined, and at his final clinic visit he felt so poorly that he requested to be “euthanized.” He was transferred from clinic directly to an inpatient hospice unit, where he died less than 24 hours later. Patients 1 and 2 illustrate one of the unique challenges faced by the practitioners who care for patients with advanced hematologic malignancies—the “transfusion tether.” Unlike many costly “breakthrough” treatments for solid tumors—typically lauded for providing modest gains in progression-free survival—many patients with terminal hematologic malignancies can live equally long and can feel better with intensive transfusion support alone. While recent studies suggest a benefit in terms of both quality of life and even overall survival in patients with solid tumors who receive early integration of palliative care, palliative care and hospice utilization for patients with hematologic malignancies remains low [1,2]. This is, in part, because no such data are yet available specific to these patients. Nonetheless, it seems reasonable to extrapolate that improvements in symptom management and end-of-life transitions might translate into similar gains for patients with liquid tumors. Interestingly, however, the very benefits afforded by transfusion support can paradoxically prevent patients with end-stage hematologic malignancies from receiving the more comprehensive palliative support provided by hospice care. A recent meta-analysis demonstrated that patients with hematologic malignancies were significantly less likely to receive specialist palliative care or hospice services compared to patients with solid tumors (RR 0.46, 95% CI 0.42–0.50) [3]. In another retrospective cohort of nearly 350 patients referred to the palliative care program at M.D. Anderson Cancer Center, the median time from palliative care referral to death was 0.6 months for patients with hematologic malignancies versus 2 months for patients with solid tumors (P< 0.001) [4]. At Massachusetts General Hospital and the Dana-Farber Cancer Institute, end-of-life health care utilization was specifically studied in older patients with AML, with only 47 of 330 patients (14.2%) ever receiving a palliative care consultation, and a median time from palliative care consultation to death of 7 days [5]. In our practice, reluctance to discontinue transfusion support at the end of life—whether patient-driven, physician-driven, or both—is one of the principal barriers to optimizing end-of-life care for our patients. While not explicitly contraindicated in the eligibility criteria for Medicare’s hospice benefit, hospice organizations frequently opt to exclude patients who wish to receive ongoing transfusions. A survey of 591 hospices in the United States found that 40% of hospices refused to allow transfusion support for their patients [6]. It is likely that a much higher percentage of hospices would have excluded patients with end-stage hematologic malignancies, whose transfusion needs are typically much higher than for the average terminally ill patient. The “palliative” benefit of transfusion support to reduce dyspnea, fatigue, bleeding, and weakness is relatively well-documented [7]. But in addition to receiving symptomatic relief, it is clear that many patients who continue transfusions also derive benefit from the regular interactions with the medical assistants, nurses, and physicians with whom they have formed strong personal connections over the course of their treatment. When patients cease to be able to receive transfusions, this network of support is severed. The obvious and not inconsequential impact of intensive transfusion support for patients with terminal disease is the financial burden placed on the healthcare system. Medicare hospice benefits pay a fixed, per patient, per day benefit to hospice organizations, regardless of the services

A phase I study of targeted, dose-escalated intravenous busulfan in combination with etoposide as myeloablative therapy for autologous stem cell transplantation in acute myeloid leukemia.

BACKGROUND Busulfan and etoposide have been used as myeloablative therapy for autologous hematopoietic stem cell transplantation (HSCT) in adults with acute myeloid leukemia (AML) for > 20 years. The use of targeted intravenous (I.V.) busulfan has significantly improved the tolerability and efficacy of this regimen. We designed a dose-escalation study to examine the maximum tolerated dose (MTD) of targeted I.V. busulfan with bolus etoposide as preparative therapy for autologous HSCT in AML. PATIENTS AND METHODS In this single-center, phase I study, adult AML patients received I.V. busulfan targeted to either an area under the curve (AUC) of 1250 (cohort 1) or 1400 (cohort 2) μmol/min over 16 doses. Dose adjustments based on plasma pharmacokinetics occurred before doses 2 and 11. Etoposide 60 mg/kg I.V. was administered 24 hours after the last busulfan dose and 3 days before stem cell infusion. RESULTS Twelve patients with intermediate-risk AML in first complete remission were treated. All patients in cohort 1 and 5 patients (83%) in cohort 2 were within 10% of the target AUC. The MTD was not reached, although Grade ≥ 3 mucositis occurred in 3 patients (50%) in cohort 1 and in 4 patients (66%) in cohort 2, limiting further dose escalation. Two-year relapse-free survival was 33% in cohort 1 versus 67% in cohort 2 (P = .08). CONCLUSION Etoposide and targeted, dose-escalated I.V. busulfan as myeloablative therapy for autologous HSCT in AML is safe, with mucositis being the most significant toxicity. A phase II study is warranted to further evaluate the activity and safety of busulfan targeted to AUC 1400 μmol/min.

Advance care planning and end-of-life care for patients with hematologic malignancies who die after hematopoietic cell transplant

Advance care planning and end-of-life care for patients with hematologic malignancies who die after hematopoietic cell transplant