136 research outputs found
Comparison of survival in patients with T cell lymphoma after autologous and allogeneic stem cell transplantation as a frontline strategy or in relapsed disease.
We studied the roles of autologous (A) and allogeneic (allo) stem cell transplantation (SCT) in the treatment of 134 patients with T cell lymphoma (TCL) at our center. For frontline SCT, 58 patients were studied. The 4-year overall survival (OS) rates for ASCT (n = 47; median age, 49 years) and alloSCT (n = 11; median age, 55 years) groups were 76% and 54%, respectively (P \u3e .05). The 4-year OS rates for first complete remission (CR1) patients were 84% and 83%, respectively. For SCT for relapsed disease, 76 patients were studied (41 with ASCT and 35 with alloSCT). The 4-year OS rates were 50% and 36% for ASCT and alloSCT patients with chemosensitive disease, respectively (P \u3e .05). Those who were in CR2 and CR3 had 4-year OS rates of 59% and 53%, respectively. Similar results were also observed in patients with refractory disease (29% and 35%, respectively). These data suggest that a pre-SCT CR is associated with improved outcomes in TCL patients after SCT. Considering the 84% 4-year OS rates in CR1 patients and the unpredictable responses in patients with relapsed disease, we favor the use of ASCT as consolidation therapy after CR1. AlloSCT did not result in a superior outcome compared with ASCT
Association between the choice of the conditioning regimen and outcomes of allogeneic hematopoietic cell transplantation for myelofibrosis
Allogeneic hematopoietic cell transplantation (allo-HCT) remains the only curative treatment for myelofibrosis. However, the optimal conditioning regimen either with reduced intensity conditioning (RIC) or myeloablative conditioning (MAC) is not well known. Using the Center for International Blood and Marrow Transplant Research database, we identified adults aged ≥18 years with myelofibrosis undergoing allo-HCT between 2008-2019 and analyzed the outcomes separately in the RIC and MAC cohorts based on the conditioning regimens used. Among 872 eligible patients, 493 underwent allo-HCT using RIC (Fludarabine/busulfan=166, Fludarabine/melphalan=327) and 379 using MAC (Fludarabine/busulfan=247, Busulfan/cyclophosphamide=132). In multivariable analysis with RIC, Fludarabine/melphalan was associated with inferior overall survival (HR 1.80, 95% CI 1.15-2.81, p=0.009), higher early non-relapse mortality (HR 1.81, 95% CI 1.12-2.91, p=0.01) and higher acute graft versus host disease (GVHD) (grade II-IV- HR 1.45, 95% CI 1.03-2.03, p=0.03; grade III-IV HR 2.21, 95%CI 1.28-3.83, p=0.004) compared to Fludarabine/busulfan. In the MAC setting, Busulfan/cyclophosphamide was associated with a higher acute GVHD (grade II-IV HR 2.33, 95% CI 1.67-3.25, p\u3c0.001; grade III-IV HR 2.31, 95% CI 1.52-3.52, p\u3c0.001) and inferior GVHD-free relapse-free survival (GRFS) (HR 1.94, 95% CI 1.49-2.53, p\u3c0.001) as compared to Fludarabine/busulfan. Hence, our study suggests that Fludarabine/busulfan is associated with better outcomes in RIC (better overall survival, lower early non-relapse mortality, lower acute GVHD) and MAC (lower acute GVHD and better GRFS) in myelofibrosis
The Mutational Landscape in Chronic Myelomonocytic Leukemia and Its Impact on Allogeneic Hematopoietic Cell Transplantation Outcomes: A Center for Blood and Marrow Transplantation Research (CIBMTR) Analysis
Somatic mutations are recognized as an important prognostic factor in chronic myelomonocytic leukemia (CMML). However, limited data are available regarding their impact on outcomes after allogeneic hematopoietic cell transplantation (HCT). In this registry analysis conducted in collaboration with the Center for International Blood and Marrow Transplantation Registry database/sample repository, we identified 313 adult patients with CMML (median age: 64 years, range, 28- 77) who underwent allogeneic HCT during 2001-2017 and had an available biospecimen in the form of a peripheral blood sample obtained prior to the start of conditioning. In multivariate analysis, a CMML-specific prognostic scoring system (CPSS) score of intermediate-2 (HR=1.46, P=0.049) or high (HR=3.22, P=0.0004) correlated significantly with overall survival. When the molecularly informed CPSS-Mol prognostic model was applied, a high CPSS-Mol score (HR=2 P=0.0079) correlated significantly with overall survival. The most common somatic mutations were in ASXL1 (62%), TET2 (35%), KRAS/NRAS (33% combined), and SRSF2 (31%). DNMT3A and TP53 mutations were associated with decreased overall survival (HR=1.70 [95% CI: 1.11-2.60], P=0.0147 and HR=2.72 [95% CI: 1.37-5.39], P=0.0042, respectively) while DNMT3A, JAK2, and TP53 mutations were associated with decreased disease-free survival (HR=1.66 [95% CI: 1.11-2.49], P=0.0138, HR=1.79 [95% CI: 1.06-3.03], P=0.0293, and HR=2.94 [95% CI: 1.50-5.79], P=0.0018, respectively). The only mutation associated with increased relapse was TP53 (HR=2.94, P=0.0201). Nonetheless, the impact of TP53 mutations specifically should be interpreted cautiously given their rarity in CMML. We calculated the goodness of fit measured by Harrell\u27s C-index for both the CPSS and CPSS-Mol, which were very similar. In summary, via registry data we have determined the mutational landscape in patients with CMML who underwent allogeneic HCT, and demonstrated an association between CPSS-Mol and transplant outcomes although without major improvement in the risk prediction beyond that provided by the CPSS
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Outcomes of haploidentical vs matched sibling transplantation for acute myeloid leukemia in first complete remission.
HLA-haploidentical hematopoietic cell transplantation (Haplo-HCT) using posttransplantation cyclophosphamide (PT-Cy) has improved donor availability. However, a matched sibling donor (MSD) is still considered the optimal donor. Using the Center for International Blood and Marrow Transplant Research database, we compared outcomes after Haplo-HCT vs MSD in patients with acute myeloid leukemia (AML) in first complete remission (CR1). Data from 1205 adult CR1 AML patients (2008-2015) were analyzed. A total of 336 patients underwent PT-Cy–based Haplo-HCT and 869 underwent MSD using calcineurin inhibitor–based graft-versus-host disease (GVHD) prophylaxis. The Haplo-HCT group included more reduced-intensity conditioning (65% vs 30%) and bone marrow grafts (62% vs 7%), consistent with current practice. In multivariable analysis, Haplo-HCT and MSD groups were not different with regard to overall survival (P 5 .15), leukemia-free survival (P 5 .50), nonrelapse mortality (P 5 .16), relapse (P 5 .90), or grade II-IV acute GVHD (P 5 .98). However, the Haplo-HCT group had a significantly lower rate of chronic GVHD (hazard ratio, 0.38; 95% confidence interval, 0.30-0.48; P, .001). Results of subgroup analyses by conditioning intensity and graft source suggested that the reduced incidence of chronic GVHD in Haplo-HCT is not limited to a specific graft source or conditioning intensity. Center effect and minimal residual disease–donor type interaction were not predictors of outcome. Our results indicate a lower rate of chronic GVHD after PT-Cy–based Haplo-HCT vs MSD using calcineurin inhibitor–based GVHD prophylaxis, but similar other outcomes, in patients with AML in CR1. Haplo-HCT is a viable alternative to MSD in these patients. © 2019 American Society of Hematology. All rights reserved
Allogeneic Hematopoietic Cell Transplantation for Blastic Plasmacytoid Dendritic Cell Neoplasm: A CIBMTR Analysis
Blastic plasmacytoid dendritic cell neoplasm (BPDCN) is a rare hematological malignancy with a poor prognosis and considered incurable with conventional chemotherapy. Small observational studies reported allogeneic hematopoietic cell transplantation (allo-HCT) offers durable remissions in patients with BPDCN. We report an analysis of patients with BPDCN who received an allo-HCT, using data reported to the Center for International Blood and Marrow Transplant Research (CIBMTR). We identified 164 patients with BPDCN from 78 centers who underwent allo-HCT between 2007 and 2018. The 5-year overall survival (OS), disease-free survival (DFS), relapse, and nonrelapse mortality (NRM) rates were 51.2% (95% confidence interval [CI], 42.5-59.8), 44.4% (95% CI, 36.2-52.8), 32.2% (95% CI, 24.7-40.3), and 23.3% (95% CI, 16.9-30.4), respectively. Disease relapse was the most common cause of death. On multivariate analyses, age of ≥60 years was predictive for inferior OS (hazard ratio [HR], 2.16; 95% CI, 1.35-3.46; P = .001), and higher NRM (HR, 2.19; 95% CI, 1.13-4.22; P = .02). Remission status at time of allo-HCT (CR2/primary induction failure/relapse vs CR1) was predictive of inferior OS (HR, 1.87; 95% CI, 1.14-3.06; P = .01) and DFS (HR, 1.75; 95% CI, 1.11-2.76; P = .02). Use of myeloablative conditioning with total body irradiation (MAC-TBI) was predictive of improved DFS and reduced relapse risk. Allo-HCT is effective in providing durable remissions and long-term survival in BPDCN. Younger age and allo-HCT in CR1 predicted for improved survival, whereas MAC-TBI predicted for less relapse and improved DFS. Novel strategies incorporating allo-HCT are needed to further improve outcomes
Risk Factors for Graft-versus-Host Disease in Haploidentical Hematopoietic Cell Transplantation Using Post-Transplant Cyclophosphamide
Post-transplant cyclophosphamide (PTCy) has significantly increased the successful use of haploidentical donors with a relatively low incidence of graft-versus-host disease (GVHD). Given its increasing use, we sought to determine risk factors for GVHD after haploidentical hematopoietic cell transplantation (haplo-HCT) using PTCy. Data from the Center for International Blood and Marrow Transplant Research on adult patients with acute myeloid leukemia, acute lymphoblastic leukemia, myelodysplastic syndrome, or chronic myeloid leukemia who underwent PTCy-based haplo-HCT (2013 to 2016) were analyzed and categorized into 4 groups based on myeloablative (MA) or reduced-intensity conditioning (RIC) and bone marrow (BM) or peripheral blood (PB) graft source. In total, 646 patients were identified (MA-BM = 79, MA-PB = 183, RIC-BM = 192, RIC-PB = 192). The incidence of grade 2 to 4 acute GVHD at 6 months was highest in MA-PB (44%), followed by RIC-PB (36%), MA-BM (36%), and RIC-BM (30%) (P = .002). The incidence of chronic GVHD at 1 year was 40%, 34%, 24%, and 20%, respectively (P < .001). In multivariable analysis, there was no impact of stem cell source or conditioning regimen on grade 2 to 4 acute GVHD; however, older donor age (30 to 49 versus <29 years) was significantly associated with higher rates of grade 2 to 4 acute GVHD (hazard ratio [HR], 1.53; 95% confidence interval [CI], 1.11 to 2.12; P = .01). In contrast, PB compared to BM as a stem cell source was a significant risk factor for the development of chronic GVHD (HR, 1.70; 95% CI, 1.11 to 2.62; P = .01) in the RIC setting. There were no differences in relapse or overall survival between groups. Donor age and graft source are risk factors for acute and chronic GVHD, respectively, after PTCy-based haplo-HCT. Our results indicate that in RIC haplo-HCT, the risk of chronic GVHD is higher with PB stem cells, without any difference in relapse or overall survival
Toxic Leukoencephalopathy following Fludarabine-Associated Hematopoietic Cell Transplantation
Toxic leukoencephalopathy has been more thoroughly investigated during the last decade because of the advance of magnetic resonance imaging (MRI) techniques. We analyzed fludarabine (Flu)-associated hematopoietic cell transplantation (HCT), resulting in severe leukoencephalopathy (n = 39/1596, 2.4%), and describe 3 clinical syndromes with unique clinical and radiographic characteristics. Posterior reversible encephalopathy syndrome (PRES) presents predominantly with seizures, persistent headache, and vision changes, along with variable mental status alterations. PRES is likely to be reversible, particularly after withholding cyclosporine (CsA). Acute toxic leukoencephalopathy (ATL) presents with cognitive dysfunction, decreased levels of consciousness, and vision changes. Other leukoencephalopathy (OLE) includes patients who behave similar to the ATL group, but with less prominent deep white matter changes on MRI. ATL and OLE are less likely to be reversible. The neurologic syndromes correlate with different MRI patterns. In PRES, subcortical and cortical involvement on MRI is associated with seizure, blurred vision, and dysarthria versus ATL and OLE, which involve deep white matter and cause mainly cognitive dysfunction. The different syndromes also carry different prognoses. All patients with Flu-associated encephalopathy had a median overall survival of only 169 days. Those with ATL had shorter overall survival (median 66 days) than patients with PRES (median 208 days). Potential risk factors for Flu-associated encephalopathy were older age, poor renal function, Flu dose, previously treated central nervous system (CNS) disease, or previous Flu-based transplant conditioning. Additional risk factors for PRES CNS toxicity are CsA use and acute hypertension. Flu pharmacokinetic studies may be useful to reduce life-threatening Flu-associated risks of neurotoxicity
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Busulfan Pharmacokinetics Using 25% Adjusted Body Weight in Obese Stem Cell Transplant Patients
The use of adjusted body weight for dosing of conditioning chemotherapy is recommended in obese stem cell transplant (SCT) patients. Busulfan (Bu), specifically, has several acceptable dosing regimens per evidence based guidelines. We evaluated whether a 25% correction in dosing weight may underestimate the targeted area under the curve (AUC) for this narrow therapeutic agent.
The primary objective was the number of patients requiring a clinically relevant PK-guided dose adjustment (change in dose of 10% or more). Secondary objectives include any increase or decrease in dosing, as well as the magnitude of dose adjustments.
Single center retrospective chart review of adult obese SCT patients receiving Bu as a part of their conditioning regimen. Bu was administered intravenously once daily at a dose of 130 mg/m2 for 4 planned doses in the allogeneic (allo) and 3 planned in the autologous (auto) population with an AUC goal of 5000 µmol*min/dose. The dose was calculated using the 25% adjusted body weight equation (AdjBW25) and pharmacokinetic (PK) samples were sent from the first day of Bu.
Fifty-five obese SCT patients (51 allo and 4 auto) were identified between 2017 to 2019 who underwent PK levels with Bu. Majority of allo patients were transplanted for acute myeloid leukemia (61%); received matched unrelated (43%) or matched related donor transplants (33%), and received fludarabine/Bu (95%) based conditioning. All the auto patients received thiotepa, Bu, and cyclophosphamide (TBC) regimen. Forty-four (80%) patients required a clinically relevant dose adjustment. In the allo SCT group, 45/51 (88%) patients required a dose change with 36 (71%) requiring a median increase in dose by 37% (range 3 -126%) and 9 (18%) requiring a median decrease in dose by 12% (range 7-29%). Following the first dose, the median AUC was 4318 µmol*min (range 2994 - 5854 µmol*min) and after PK-guided adjustment the median AUC of all doses was 4934 µmol*min (range 4215 - 5061 µmol*min). In the auto SCT group, 4/4 (100%) patients required a dose change with 1 (25%) requiring an increase in dose by 28%, and 3 (75%) requiring a median decrease in dose by 100% (range 13 – 100%). Following the first dose, the median AUC was 6285 µmol*min (range 4213 - 8995 µmol*min) and after PK-guided adjustment the median AUC of all doses was 4948 µmol*min (range 4609 - 5997 µmol*min).
Overall, the majority of our allo SCT patients required a clinically significant increase in Bu dose. However, in our auto SCT patients, the majority required a significant decrease in dose that translated into omitting the last dose in two patients. Using PK-guided dose adjustments were critical in achieving our desired AUC goal and, based on our findings, using AdjBW25 may not be adequate. Further studies are warranted to identify the most appropriate dosing weight for obese patients, as well as allo versus auto recipients
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Novel Therapy for Aggressive Cutaneous T-Cell Lymphoma Leading to Complete Clinical Remission before Allogenic Stem Cell Transplantation
Abstract Cutaneous T-cell lymphomas (CTCL) represent up to 80% of extranodal non-Hodgkin Lymphomas, the most common being Mycosis Fungoides (MF) with or without its leukemic stage Sezary Syndrome and Primary cutaneous CD30+ T-cell lymphoproliferative disorders. Prognosis for advanced stages is poor, with 5-year survival 40-70% for patients with advanced skin stages, and 15-40% for those with extracutaneous involvement and CD30+ transformed CTCL. The disease is considered incurable, and most patients will undergo at least two different lines of therapy, and up to 36% undergo at least four different lines due to a short duration of remissions. Local and systemic therapies are provided stepwise based on extension and aggressive histologic features. Systemic options for advanced-stages include bexarotene, methotrexate, interferon, histone deacetylates inhibitors, extracorporeal photopheresis (ECP), antibody drug conjugates, and systemic single or multiple agent chemotherapies. The longest response durations were reported after allogeneic stem cell transplantation in contrast to autologous transplantation and conventional chemotherapy. Disease status prior to transplant is a major predictive of better outcome, but it is typically difficult to achieve strong pretransplant remissions. Some suggested utilizing total electron beam radiation but this can predispose the patient to more infection due to skin injury. We had the case of a patient with refractory CD30+ transformed CTCL who successfully achieved clinical remission in anticipation for transplant with a novel outpatient regimen including high-dose methotrexate with limited toxicity. Table 1 shows the regimen that was employed to achieve a complete cutaneous remission, allowing progression to haploidentical allogeneic stem cell transplantation. We designed this for a 58-year-old male, previously treated over a period of 12 years for skin rashes that ultimately were diagnosed as CTCL/MF: C6D4+, CD8+ and CD25-, CD30- and positive T-cell receptor gene rearrangement. Sezary cell count was 2%, and there was no evidence of systemic involvement. Sequential therapies were employed by dermatology, including topical clobetasol, weekly oral (PO) methotrexate (MTX), ECP and bexarotene up to 150mg/m2 PO twice a day, but disease progressed to skin tumor stage, biopsy confirmed. Multiple additional therapies followed including phototherapy and interferon, but the disease began progressing aggressively by fall 2017 when hematology became involved. Again there was no evidence of systemic disease, and the Sezary count was 0%, but skin disease progressed, with ~80% skin involvement, some biopsy proved to be CD30+ with large cell transformation. The patient was started on Brentuximab Vedotin (BV) 1.8mg/Kg intravenous (IV) every 21 days (Q21D) and after 5 cycles developed major resolution of most tumor lesions, but developed progression of residual lesions that were biopsy proven to be MF, CD30- with no large cell transformation. Bendamustine 90mg/m2 IV on day 1 and day 2 Q21D was added to BV regimen for 2 cycles with further progression so was discontinued. The patient was referred for allogeneic transplant, but a strong remission was desired prior to proceeding, and we therefore designed the regimen in Table 1 as a novel approach to allow transplant. The patient achieved a complete cutaneous clinical response after cycle 2 and went on to receive a third cycle, after which he proceeded in July 2018 to haploidentical allogenic transplantation conditioned with Fludarabine, total body irradiation and post-transplant cyclophosphamide. Etoposide IV and MTX PO are both approved as systemic therapies of disease as per National Comprehensive Cancer Network Guidelines, although no reports of use of IV MTX or in combination with Etoposide have been found on literature. High-dose IV MTX is given as inpatient as requires close toxicity surveillance, hydration, urine alkalization and MTX serum level monitoring in parallel to folinic acid rescue by protocol. Side effect profile was limited to mild nausea controlled on ondansetron PO and no evidence of renal or liver toxicity was found. Surveillance and supportive care were successfully provided as an outpatient as per Table 1. This exemplifies an effective outpatient regimen with low toxicity and significant cost reduction that successfully achieved remission in anticipation for transplantation. Disclosures No relevant conflicts of interest to declare
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Catheter Complications in Patients Undergoing Extracorporeal Photopheresis for Management of Graft-Versus-Host Disease
Complications associated with central vascular access (VA) in patients (pts) undergoing extracorporeal photopheresis (ECP) may limit therapy. VA options often include dual lumen vortex (DLV) implantable and tunneled trifusion/other (TF) catheters. There is limited data about VA associated complications such as infection, thrombosis, and equipment failure in those undergoing ECP.
Our primary aim was to describe VA associated complications during ECP.
We retrospectively reviewed pts who received ECP at our institution from January 2011 to October 2019. We examined episodes of cellulitis, catheter associated bacterial infection (CLABSI), catheter removal/exchange (CRE), and discontinuation of ECP.
Fifty-two pts had at least 4 ECP sessions using VA. 12 were treated for acute and 40 for chronic/overlap GvHD (cGvHD). Overall, median # ECP sessions (ES) was 35 (range 4-311), median # ECP months (EM) was 7 (range 0.5 to 86). Total number of VA events = 21.
In cGvHD (n=40), Median ES was 50 (range 14-311). With DLV catheters (16/40 pts), total VA events = 8 (1 event every 133 ES). 5 events required CRE, and 3 pts resumed ECP after event. With TF catheters (24/40 pts), total VA events = 8 (1 event every 142 ES). 2 events required CRE, and 4 pts restarted ECP after event.
In acute GVHD (n=12), median ES was 15 (range 4-83). 11/12 used a TF catheter. CLABSI was diagnosed in 5/12 pts, all of whom were already hospitalized for GvHD therapy. 3/5 required CRE. ECP was discontinued in all events due to progressive GvHD or infection.
During ECP for cGvHD treatment, DLV and TF catheters have similar number of complications (p=0.81) when adjusted for total ES and EM. VA events are a major cause of ECP discontinuation. In aGvHD, the high incidence of CLABSI is attributed to severe immunosuppression from therapy rather than specific catheter related events
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