Background:
TA-TMA is a life-threatening complication of hematopoietic cell transplantation (HCT), usually manifested as a combination of non-immune mediated hemolytic anemia, thrombocytopenia and ...end-organ dysfunction (renal, neurologic and/or hypertension). Reported mortality rates following TA-TMA are high (50-75%; Gavriilaki et al, Bone Marrow Transplantation 2017). It is more commonly associated with allogeneic HCT, however, may infrequently occur with autologous HCT. Traditionally, treatment for TA-TMA consisted in removing possible offending agents (calcineurin inhibitors, sirolimus) and/or instituting total plasma exchange (PLEX). These approaches have not resulted in significant improvement in the natural history of TA-TMA, with complete resolution in 12-20% of pts (Mulay et al, J Clin Apher 2015).
Recent evidence of alternate complement pathway activation has been implicated in the pathophysiology of TA-TMA (Jodele et al, Blood 2013). Eculizumab (ECU) is an anti-C5 monoclonal antibody, approved for treatment of PNH and aHUS, which has been used anecdotally as treatment for TA-TMA. Most reports consist of pediatric patients. In this analysis, we evaluated consecutive cases of adult recipients of HCT who developed TA-TMA and have received ECU therapy at our institution.
Methods:
We reviewed electronic records of consecutive patients who presented with a diagnosis of TA-TMA (non-immune hemolytic anemia plus worsening thrombocytopenia and end-organ dysfunction) and were treated with ECU between 2015 and 2017 at our institution. Univariate and bivariate statistics were calculated for the sample; Fisher's exact tests and Wilcoxon rank sum tests were utilized to test for differences across groups.
Results:
Table 1 shows the baseline characteristics of these pts. A total of 15 pts were included in the analysis; 2/3 were female and the median age was 62. ECU was given according to the usual schedule for aHUS (900 mg IV weekly x 4, 1200 mg every other week starting on week 5). Median time from TA-TMA diagnosis to initiation of ECU was 2 days. All patients received prophylaxis for Neisseria meningitides with ciprofloxacin and antifungal prophylaxis at initiation of ECU. Three (20%) pts received PLEX prior to ECU. Seven (47%) patients were receiving tacrolimus at diagnosis, however, levels were not within toxic range (3.7-7.9 ng/mL). Median time post-HCT for development of TA-TMA was 135 days. Median LDH, hemoglobin, platelet count and creatinine at TA-TMA diagnosis were 1724 U/L, 7.3 g/dL, 33,000/mcL and 1.7 mg/dL, respectively. Ten (66.6%) patients had acute kidney injury and 7 (46.6%) pts had neurologic manifestations. Eight (53.3%) pts had evidence of GVHD concurrent with TA-TMA diagnosis. Ten (63.3%) pts developed systemic infections during their TA-TMA treatment. No pts developed meningitis or fungal infections.
Median follow-up was 4.5 months after initiation of ECU. Eight (53.3%) patients had complete resolution of TA-TMA (i.e. resolution of hemolytic anemia, thrombocytopenia and end-organ damage), 4 of these 8 pts were recipients of autologous HCT. Median time to resolution was 98 days and median cumulative ECU dose was 10,200 mg (range 4800-36400mg). An additional 2 pts (13%) presented clinical improvement without complete resolution of TA-TMA.
Mortality secondary to TA-TMA or its complications was 33%. Median time to death was 31 days. The most common cause of mortality were infectious complications. Median survival for the entire cohort was 130 days (range 6-833 days, Figure).
LDH >1300 U/L; more than one organ involvement, allogeneic HCT, use of tacrolimus and early (<100 days) onset of TA-TMA post-HCT were associated with lower rates of TA-TMA resolution and higher mortality. PLEX prior to ECU did not correlate with improved outcomes.
Conclusion:
To our knowledge, this is the largest reported series of adult pts with TA-TMA who were treated with ECU. Treatment with ECU for TA-TMA is associated with higher rates of resolution and lower rates of cause-specific mortality than what has been previously reported with other approaches. We hypothesize that higher cumulative doses of ECU are warranted to achieve resolution of TA-TMA. A prospective study utilizing a more intensive schedule of ECU infusions is required to confirm such hypothesis. Based on our analysis, we conclude that ECU is an appropriate - and potentially better - option in the treatment of TA-TMA.
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Skarbnik:Seattle Genetics: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Jazz Pharmaceuticals: Honoraria, Speakers Bureau; Genentech: Honoraria, Speakers Bureau; Abbvie: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Pharmacyclics: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Novartis: Honoraria, Speakers Bureau; Gilead Sciences: Honoraria, Speakers Bureau.
Background: Allogeneic stem cell transplantation (SCT) remains the only curative option for CLL, in part due to allogeneic graft-vs-leukemia effect (GVL), which can lead to complete suppression of ...the CLL clone (Schetelig et al, JCO 2003). Management of post-SCT relapse remains challenging, and DLI has been successfully used as salvage, due to its potential to induce GVL (Delgado et al, Blood 2009). We evaluated outcomes of SCT for patients (pts) with a diagnosis of CLL transplanted at our center.
Methods: 36 consecutive pts transplanted between 2004 and 2015 were reviewed. Kaplan Meier survival curves were produced to examine overall survival (OS), time to progression (TTP) and post-DLI survival. Univariate Cox Proportionate hazard models were also estimated to assess the impact of pt characteristics on the risk of survival and progression. Bivariate frequencies with Fisher exact tests, correlation analysis, and independent samples t-tests were performed to test associations across outcomes.
Results: Sample was 72% male. Median age at time of SCT was 57 yo (range 42-74). Pts had a median time of 70 months (mos) between diagnosis (Dx) of CLL and SCT. Median follow-up post-SCT was 32 mos (range 1-118). Of the 30 pts with known disease status at the time of SCT, 16.7% were in complete remission (CR), 20% had stable disease (SD), 50% were in partial remission (PR) and 13.3% had progressive disease (PD). Median number of lines of therapy pre-SCT was 3 (range 1-8). Thirteen pts (36%) were refractory to their first line of therapy. 10 pts (27.8%) had del(17p), 11 pts (30.6%) had del(11q) and 8 pts (22.2%) had complex cytogenetics. Most patients (72%) received pre-SCT conditioning with FCR (Khouri et al, Exp Hematol 2004). 16 pts (44.4%) received rATG as part of their conditioning regimen. Graft-vs-host disease (GVHD) prophylaxis consisted of methotrexate and tacrolimus. 20 (55.6%) pts had acute GVHD and 19 (52.8%) had chronic GVHD. 5 (13.8%) pts had grade 3/4 acute GVHD and 1 (2.7%) had extensive chronic GVHD. When comparing pts who received SCT from unrelated donors (MUD, 24 pts) vs sibling donors (sib, 10 pts) there were no differences in rates of GVHD, disease progression or overall survival.
Twenty-seven pts (75%) were in CR at first disease evaluation after SCT (CR conversion rate of 58.3%) and 2 pts (5.5%) had PD. On follow-up, another 15 pts (41.7%) presented PD. Median TTP was 14 months, with only 3 pts relapsing after 2 years from SCT. Eight pts who had PD and one patient who had a PR post-SCT received short-term anti-CLL therapy for disease debulking, followed by DLI. Six (66.6%) out of the 9 pts who received DLI achieved CR and are currently alive and in CR. Median follow-up post-DLI was 43 months and median duration of response to DLI was 47 mos (range 6-85 mos).
Ultimately, 13 (36.1%) pts died, 8 (22.2%) were lost to follow-up, and 15 (41.7%) were alive at last contact. Disease progression was the most common cause of death (5 pts, 13.9%). Transplant-related mortality (TRM) was 13.9% (3 deaths due to infection, 2 deaths due to chronic GVHD). Only 2 deaths (5.5%) occurred during the first 100 days post-SCT, both due to infection. No deaths occurred due to acute GVHD.
Median OS was 84 months. PFS (not accounting for pts who relapsed post-SCT but achieved CR with DLI) was 58% in the first year and 25% at five years. The median PFS was 19 months.
Univariate and multivariate analysis of pre-SCT pt characteristics (age, time from Dx to SCT, number of therapies, stage, presence of adenopathy, MUD vs sib donor, cytogenetic abnormalities, ABO mismatch, disease status at SCT) did not show any statistically significant correlation with OS, PFS or GVHD rates.
Conclusion: SCT remains the only curative option for CLL. Our experience shows that pts may achieve long-term survival with this approach. TRM was low (13.8%) and rates of acute and chronic GVHD were compatible with previous reports (Sorror et al, JCO 2005; Dreger et al, Blood 2010). Type of donor (MUD vs sib) did not impact outcomes, suggesting that patients without a matched sibling should not be denied transplantation if a MUD is available. Although 47% of the patients eventually progressed after transplantation, 66% of patients who received DLI for salvage were able to achieve CR and remain progression-free for a prolonged period of time, underlining the importance of the GVL effect. Most relapses occurred within the first 2 years post SCT and late relapses were rare.
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Skarbnik:Gilead Sciences: Speakers Bureau; Seattle Genetics: Speakers Bureau; Genentech: Speakers Bureau; Abbvie: Consultancy; Pharmacyclics: Consultancy. Vesole:Celgene: Speakers Bureau; Takeda: Speakers Bureau; Janssen: Speakers Bureau; Amgen: Speakers Bureau; Novartis: Speakers Bureau. Goy:Pharmacyclics: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Takeda: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Writing support, Speakers Bureau; Celgene: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Genentech: Research Funding; Janssen: Consultancy, Honoraria, Research Funding, Speakers Bureau; Infinity: Consultancy, Membership on an entity's Board of Directors or advisory committees; Acerta: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees. Feldman:Pharmacyclics: Speakers Bureau; Celgene: Speakers Bureau; Seattle Genetics: Consultancy, Speakers Bureau; Abbvie: Consultancy, Speakers Bureau. Leslie:Seattle Genetics: Speakers Bureau; Celgene: Speakers Bureau. Leslie:Seattle Genetics: Speakers Bureau; Celgene: Speakers Bureau.
The use of ASCT is highly established as consolidation or salvage for multiple myeloma (MM) and post salvage therapy in non-Hodgkin Lymphomas (NHL), particularly diffuse large B-cell lymphoma (DLBCL) ...with chemosensitive disease, as well as upfront consolidation in PTCL given poor outcomes after standard therapy (Philip et al., NEJM 1995, Kewalramani et al., Br J Haematol 2006, Gisselbrecht et al., J Clin Oncol 2010, Kumar et al., Leukemia 2012). Although a significant number of pts experience long-term disease-free survival following ASCT, those with high-risk disease (i.e.high-risk cytogenetics in MM, primary refractory DLBCL) are likely to present early relapses, particularly in the first 18 months post-ASCT, illustrating the need for better disease control strategies following ASCT. The rapidly rising impact of checkpoint inhibitors in oncology provides an opportunity for its usage as post-ASCT consolidation, especially given the favorable immunologic milieu found in the immediate post-ASCT setting (i.e. decreased T-regs, increased effector T-cells) and minimal expected tumor burden at that time. Here, we report preliminary safety and efficacy data of a Phase I trial evaluating I and N as post-ASCT consolidation.
Pts with the following malignancies were eligible, if they presented at least stable disease after most recent line of therapy: DLBCL: primary refractory or relapsed, PTCL: de novo stage III/IV or relapsed, MM: transplant-naïve with high-risk cytogenetics or relapse within 3 years of upfront ASCT.
Pts were enrolled prior to ASCT, starting in July 2016. Total accrual goal is 42 patients. All pts with DLBCL/PTCL received BEAM (carmustine 300 mg/m2 day -6, etoposide 200 mg/m2 and cytarabine 200 mg/m2 days -5 to -2, melphalan 140 mg/m2 day -1) as conditioning regimen for ASCT, all pts with MM received melphalan 200 mg/m2 on day -1.
For pts who achieved appropriate hematologic recovery (ANC >800/mm3 and platelets > 20,000/mm3), I/N were started between days 14 and 28 post ASCT. The infusion schedule was:
• I: 1 mg/kg; 6 doses Weeks 1, 4, 7, 10, 16, 22
• N: 3 mg/kg; 12 doses Weeks 1, 4, 7, 10, 12, 14, 16, 18, 20, 22, 24, 26
At this time, 25 patients have been enrolled and received at least one dose of I/N. Additional pts are in screening and results will be updated.
Median follow-up from time of first I/N infusion is 24 weeks (range 2-49). Adverse events (AEs) were documented starting week 1, day 1 of I/N infusion. AEs deemed at least possibly related to I and/or N were termed immune-related (irAEs) with 80% of pts developing irAEs of any grade (table 1). Treatment-related AEs of any grade that led to discontinuation of I/N occurred in 6 pts (24% total: colitis 12%, pneumonitis 4%, adrenal crisis 4% and hepatotoxicity 4%). One death attributable to I/N occurred (due to recurrent pneumonitis complicated by parainfluenza). Therapy with systemic steroids for management of irAEs was required for 19 pts (76%). 70% of irAEs improved within one week and 65% resolved within 2 weeks of initiation of steroids. Median time on treatment with I/N for development of irAEs was 9 weeks (range 2-25). For pts who discontinued treatment due to toxicity, the median time on I/N was 5 weeks (range 3-14). Incidence of irAEs was similar across disease groups.
With a median follow-up of 24 weeks, OS is 92% and PFS is 88% for the entire cohort. 100% of the pts with relapsed MM after first ASCT (50% of whom had less than CR to 1st ASCT) are now in stringent complete remission (sCR). 100% of pts with primary refractory DLBCL are in CR (table 2).
The toxicity profile of consolidation with I/N following ASCT was within expectations. Although there has been a significant number of irAEs (80%) given the mechanism of action of these drugs, this rate is not higher than what has been previously reported with I/N combination in other disease settings (Larkin et al., NEJM 2015, Postow et al., NEJM 2015) and all patients except 1 had resolution of irAEs with the use of systemic steroids . With a median follow-up of 6 months, 84% of pts across disease groups are in complete remission. Interestingly, 5 of 6 patients who had early discontinuation due to AEs, presented sustained remission. Correlative studies evaluating blood immunophenotype are being reported in a separate abstract.
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Skarbnik:Novartis: Speakers Bureau; Genentech: Speakers Bureau; Gilead: Speakers Bureau; Abbvie: Other: Ad board, Speakers Bureau; Seattle Genetics: Speakers Bureau. Goy:Seattle Genetics: Membership on an entity's Board of Directors or advisory committees, Research Funding; Acerta: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Celgene: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Genentech: Research Funding; Takeda: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Pharmacyclics / J&J: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau. Siegel:Merck: Consultancy; Celgene, Takeda, Amgen Inc, Novartis and BMS: Consultancy, Speakers Bureau. Biran:Takeda: Speakers Bureau; Celgene, Amgen: Consultancy, Speakers Bureau. Richter:Janssen: Speakers Bureau; Takeda: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; BMS: Speakers Bureau; Amgen: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Celgene: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau. Feldman:Kite Pharma: Speakers Bureau; Seattle Genetics: Honoraria, Research Funding, Speakers Bureau; Celgene: Speakers Bureau; Pharmacyclics: Speakers Bureau; Janssen: Speakers Bureau; Bristol-Myers Squibb: Consultancy; AbbVie: Speakers Bureau. Leslie:seattle genetics: Speakers Bureau; KITE pharma: Speakers Bureau; celgene: Speakers Bureau. McKiernan:Novartis: Speakers Bureau. McNeill:pharmacyclics: Speakers Bureau; celgene: Speakers Bureau; seattle genetics: Speakers Bureau. Pecora:Caladrius Biosciences: Equity Ownership, Membership on an entity's Board of Directors or advisory committees; COTA: Equity Ownership, Membership on an entity's Board of Directors or advisory committees, Patents & Royalties.
We have developed an autologous whole cell leukemia vaccine, whereby patient derived leukemic blasts are fused to ex-vivo generated dendritic cells. In this way, a broad array of leukemia-associated ...antigens are presented in the context of DC mediated co-stimulation, resulting in the expansion of a polyclonal anti-leukemia immune response. We are conducting a clinical trial in which AML patients who are not candidates for allogeneic transplantation undergo vaccination with DC/AML fusion cells after achieving a complete remission. 56 patients underwent collection of AML cells for vaccine generation from either a bone marrow aspirate (N=38), 20cc of peripheral blood (N=15) or a leukapheresis product (N=3) at presentation with newly diagnosed (N=55) or first relapsed (N=1) AML. The mean yield of AML cells was 692 x 106 cells with a mean viability of 99%. Patients who did not achieve remission or who underwent allogeneic transplant in first remission came off study and did not complete vaccine generation. Eligible patients achieving CR who did not proceed to allogeneic transplant (N=21) underwent leukapheresis for DC generation and vaccine preparation. Adherent peripheral blood mononuclear cells were cultured in the presence of GM-CSF and IL-4 for 5-7 days, and exposed to TNFα for 48-72 hours to generate mature DCs. Fusion cells were generated by co-culture of DCs with AML cells in the presence of 50% polyethylene glycol and identified as cells co-expressing antigens that were unique to the DC and tumor population. Mean fusion efficiency and viability was 42% and 87%, respectively. Vaccination with DC/leukemia fusion cells was initiated within 12 weeks from count recovery following the final cycle of post-remission therapy. 16 patients (median age 60) have received at least two monthly vaccinations at a dose of 5x106 fusion cells. Remission induction therapy consisted of 7+3 in 13 patients, 7+3 followed by 5+2 re-induction in 1 patient, MEC in one patient, and decitabine in 1 patient. 9 patients had intermediate risk cytogenetics, 2 patients had good risk cytogenetics, and 5 patients had poor cytogenetic risk disease. Vaccination was well tolerated, and importantly, was not associated with clinically significant auto-immunity. Possibly related adverse events were transient and of grade 1-2 intensity, including vaccine site reactions, pruritis, arthalgias, myalgias, eosinophilia, leukopenia, thrombocytopenia. Biopsy of vaccine site reactions demonstrated a dense infiltrate of CD4 and CD8 T cells consistent with recruitment of reactive T cell populations to the vaccine bed. To date, 12 of 16 evaluable patients remain in remission (75%), with a median follow up of 45 months. Notably, no patient has relapsed later than 1 year from completing chemotherapy and the patient who was treated in CR2 remains in remission with 51 months of follow up, after having relapsed within a year of CR1. Vaccination resulted in the potent induction of leukemia specific immunity as measured by a mean fold increase of 4.9 CD8 T cells expressing IFNγ in response to ex vivo exposure to autologous leukemia cell lysates (n=14). In a subset of patients who are HLA2.1+, vaccination resulted in the expansion of T cells recognizing MUC1 (4.4 fold increase), WT1 (2.7 fold increase), NY-ESO (3.8 fold increase) tumor antigens by pentamer analysis. In conclusion, DC/AML fusion cell vaccination administered to patients who achieve complete remission results in the potent expansion of leukemia reactive T cells, and durable remissions. A second cohort is planned in which patients will be treated with DC/AML fusion cell vaccination in conjunction with immune checkpoint blockade.
Stone:Karyopharm: Consultancy; Roche/Genetech: Consultancy; Merck: Consultancy; Novartis: Research Funding; Celgene: Consultancy; Pfizer: Consultancy; Agios: Consultancy; Sunesis: Consultancy, Other: DSMB for clinical trial; Amgen: Consultancy; Abbvie: Consultancy; Celator: Consultancy; AROG: Consultancy; Juno: Consultancy. Steensma:Celgene: Consultancy; Amgen: Consultancy; Incyte: Consultancy; Onconova: Consultancy. DeAngelo:Incyte: Consultancy; Celgene: Consultancy; Agios: Consultancy; Novartis: Consultancy; Ariad: Consultancy; Bristol Myers Squibb: Consultancy; Amgen: Consultancy; Pfizer: Consultancy. Kufe:Genus Oncology: Consultancy, Equity Ownership.
Autologous stem cell transplantation (ASCT) for multiple myeloma (MM) offers a unique setting to incorporate immunotherapy in an effort to target residual disease. Our group has developed a cancer ...vaccine in which dendritic cells (DCs) are fused to autologous tumor cells resulting in the presentation of multiple tumor antigens with the capacity to elicit a broad anti-tumor response. A fundamental challenge to developing a more effective tumor vaccine is overcoming the immunosuppressive milieu by which tumor cells evade host immunity. Up-regulation of the PD-1/PDL1 pathway represents a key element contributing to tumor-mediated tolerance, and potentially muting response to vaccination. We are conducting a clinical trial in which patients with MM are treated with an anti-PD1 antibody (Pidilizumab, MDV9300) in combination with a dendritic cell/myeloma fusion cell vaccine following autologous transplantation. 22 patients have been treated with post-transplant immunotherapy. Mean age was 64. MM cells were isolated from bone marrow and were identified by expression of CD38 or CD138. Mean tumor cell yield was 118x106 cells. Adherent mononuclear cells were isolated from leukapheresis collections and cultured with GM-CSF and IL-4 for 5-7 days, then exposed to TNFα for 48-72 hours to generate mature DCs. DCs expressed co-stimulatory (mean CD86 75%) and maturation markers (mean CD83 50%). DC and MM cells were co-cultured with PEG and fusion cells were quantified by determining the percentage of cells that co-express unique DC and myeloma antigens. Mean fusion efficiency was 41% and the mean cell dose generated was 4 x 106 fusion cells. Mean viability of the DC, myeloma, and fusion preparations was 92%, 89%, and 85%, respectively. As a measure of their potency as antigen presenting cells, DC/MM fusions potently stimulate allogeneic T cell proliferation ex-vivo (Mean stimulation index of 1.9, 9.2 and 7.1 for tumor, DC and DC/myeloma fusions respectively, n=21) Post-transplant immunotherapy was initiated after recovery from transplant-related toxicities. Median time from transplant to initiation of post-transplant immunotherapy was 80 days. Patients received 3 doses of Pidilizumab at 6-week intervals. DC/myeloma fusion cells vaccination is administered 1 week before each dose of Pidilizumab. To date, 22 patients have completed vaccinations and Pidilizumab. Adverse events judged to be potentially treatment related included grade 1-2 diarrhea, arthralgias, myalgias, fatigue, headache, nausea, chills, transaminitis, cytopenia, elevated TSH, and vaccine site reactions. A significant increase in circulatingtumor reactive lymphocytes was noted following post-transplant immunotherapy, as determined by T cell expressionof IFN-γ by CD8 cells following ex-vivo co-culture withautologous myeloma cell lysate. Mean percentage of tumor reactiveCD8 cells increased from 1.8% post-transplant to a peak of 9.16% following immunotherapy. In the post-transplant period, regulatory T cells fell to minimal levels and remained low throughout the period of immunotherapy. 6 patients achieved a best response of VGPR, 6 patients have achieved a nCR/CR, including 3 who converted to CR following immunotherapy. Median PFS from transplant is 19 months with ongoing follow up. In summary, DC/MM fusion cell vaccination in conjunction with PD1 blockade following ASCT was well tolerated, potently induced anti-tumor immunity, and in a subset of patients, resulted in the eradication of post-transplant measurable disease.
Richardson:Gentium S.p.A.: Membership on an entity's Board of Directors or advisory committees, Research Funding; Jazz Pharmaceuticals: Membership on an entity's Board of Directors or advisory committees, Research Funding; Millennium Takeda: Membership on an entity's Board of Directors or advisory committees; Novartis: Membership on an entity's Board of Directors or advisory committees; Celgene Corporation: Membership on an entity's Board of Directors or advisory committees. Laubach:Novartis: Research Funding; Onyx: Research Funding; Celgene: Research Funding; Millennium: Research Funding. Anderson:Celgene: Consultancy; Millennium: Consultancy; BMS: Consultancy; Gilead: Consultancy; Oncopep: Equity Ownership; Acetylon: Equity Ownership. Rowe:BioSight Ltd.: Consultancy, Membership on an entity's Board of Directors or advisory committees; Amgen: Consultancy; BioLineRx Ltd.: Consultancy. Kufe:Genus Oncology: Consultancy, Equity Ownership.
To establish the efficacy of a temperature-based pacemaker control algorithm, right ventricular temperature and heart rate were measured for 12-70 hours in eight patients (51 +/- 17 years) and in one ...normal volunteer (28 years) during a variety of activities including exercise, rest, sleeping, eating, drinking, and bathing. A diurnal variation in heart rate and temperature was observed. Drinking caused transient temperature changes (less than one minute); during eating, increases of 0.07-0.36 degrees C over 3-12 minutes were observed. An increase of 0.24 degrees C over 8.5 minutes was observed in one patient during bathing. An abrupt drop in temperature was typically observed at the onset of exercise, followed by a steady temperature rise. During treadmill exercise, after a drop (0.13-0.48 degrees C, Bruce n = 4; 0.16-0.34 degrees C, Naughton, n = 3) during the first 1-2 minutes, temperature rose steadily through the end of peak exercise (0.45-1.01 degrees C, Bruce; 0.28-0.47 degrees C, Naughton). A temperature dip was also observed when a patient was told exercise would start but the treadmill failed to turn on. The dip is probably secondary to changes in blood flow from the peripheral circulation to the central system at the onset of exercise. Repeated exercise separated by short rests caused progressive blunting of the initial dip. Right ventricular temperature changes in a predictable manner with daily activity, allowing a temperature algorithm to detect rest and exercise.
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