Publications by authors named "Amandeep Salhotra"

49 Publications

Belumosudil for Chronic Graft-versus-Host Disease (cGVHD) After 2 or More Prior Lines of Therapy: The ROCKstar Study.

Blood 2021 Jul 15. Epub 2021 Jul 15.

Kadmon Corporation, West Chicago, Illinois, United States.

Belumosudil, an investigational oral selective inhibitor of rho-associated coiled-coil-containing protein kinase-2 (ROCK2), reduces type 17 and follicular helper T cells via downregulation of signal transducer and activator of transcription 3 (STAT3) and enhances regulatory T cells via upregulation of signal transducer and activator of transcription 5 (STAT5). Belumosudil may effectively treat patients with cGVHD, a major cause of morbidity and late nonrelapse mortality after an allogeneic hematopoietic cell transplant. This phase 2, randomized, multicenter registration study evaluated belumosudil 200 mg QD (n=66) and 200 mg BID (n=66) in subjects with cGVHD who had received 2 to 5 prior lines of therapy. The primary end point was best overall response rate (ORR). Duration of response (DOR), changes in Lee Symptom Scale score, failure-free survival, corticosteroid dose reductions and overall survival were also evaluated. Overall median follow-up was 14 months. The best ORR (95% CI) of belumosudil 200 mg QD and 200 mg BID was 74% (62%-84%) and 77% (65%-87%), respectively, with high response rates observed in all subgroups. All affected organs demonstrated complete responses. The median DOR was 54 weeks; 44% of subjects have remained on therapy for ≥1 year. Symptom reduction with belumosudil 200 mg QD and 200 mg BID was reported in 59% and 62% of subjects, respectively. Adverse events (AEs) were consistent with those expected in patients with cGVHD receiving corticosteroids and other immunosuppressants. Sixteen subjects (12%) discontinued belumosudil due to possible drug-related AEs. Belumosudil, a promising therapy for cGVHD, was well tolerated with clinically meaningful responses. (Funded by Kadmon Corporation, LLC; ClinicalTrials.gov number, NCT03640481.).
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http://dx.doi.org/10.1182/blood.2021012021DOI Listing
July 2021

Posttransplant cyclophosphamide as GVHD prophylaxis for peripheral blood stem cell HLA-mismatched unrelated donor transplant.

Blood Adv 2021 06;5(12):2650-2659

Department of Hematology and HCT.

Efficacy of PTCy after mismatched unrelated donor (MMUD) HCT is unknown. In this pilot clinical trial, we enrolled 38 patients with hematologic malignancies scheduled to undergo MMUD-HCT (≥6/8 HLA-matched donors) onto 1 of 2 conditioning strata: myeloablative using fludarabine and fractionated total body irradiation (n = 19) or reduced intensity with fludarabine/melphalan (n = 19). Graft source was peripheral blood stem cells (PBSCs), and GVHD prophylaxis was PTCy, tacrolimus, and mycophenolate mofetil. Patients' median age was 53 years (range, 21-72 years). Median number of HLA mismatches was 2 (range, 1-4) of 12 loci. Twenty-three patients (61%) were considered racial (n = 12) or ethnic (n = 11) minorities. Median time to neutrophil engraftment was 16 days (range, 13-35 days). With a median follow-up of 18.3 months (range, 4.3-25.0 months) for surviving patients, 1-year overall survival (OS) and GVHD-free/relapse-free survival (GRFS) were 87% (95% confidence interval [CI]: 71-94) and 68% (95% CI: 51-81), respectively. Cumulative incidence of nonrelapse mortality at 100 days and 1 year were 0% and 11% (95% CI: 4-27), respectively, whereas relapse/progression was 11% (95% CI: 4-27). Cumulative incidence of 100-day acute GVHD grades 2-4 and 3-4 and 1-year chronic GVHD were 50% (95% CI: 36-69), 18% (95% CI: 9-36), and 48% (95% CI: 34-68), respectively. The rate of moderate/severe chronic GVHD was 3% in the entire cohort. We showed highly promising OS/GRFS rates with an acceptable risk profile after PBSC-MMUD-HCT with PTCy. This trial was registered at www.clinicaltrials.gov as #NCT03128359.
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http://dx.doi.org/10.1182/bloodadvances.2021004192DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8270662PMC
June 2021

First Multimodal, Three-Dimensional, Image-Guided Total Marrow Irradiation Model for Preclinical Bone Marrow Transplantation Studies.

Int J Radiat Oncol Biol Phys 2021 Jun 11. Epub 2021 Jun 11.

Department of Radiation Oncology, City of Hope Medical Center, Duarte, California; Beckman Research Institute of City of Hope, Duarte, California; Department of Radiation Oncology, University of Minnesota, Minneapolis, Minnesota. Electronic address:

Purpose: Total marrow irradiation (TMI) has significantly advanced radiation conditioning for hematopoietic cell transplantation in hematologic malignancies by reducing conditioning-induced toxicities and improving survival outcomes in relapsed/refractory patients. However, the relapse rate remains high, and the lack of a preclinical TMI model has hindered scientific advancements. To accelerate TMI translation to the clinic, we developed a TMI delivery system in preclinical models.

Methods And Materials: A Precision X-RAD SmART irradiator was used for TMI model development. Images acquired with whole-body contrast-enhanced computed tomography (CT) were used to reconstruct and delineate targets and vital organs for each mouse. Multiple beam and CT-guided Monte Carlo-based plans were performed to optimize doses to the targets and to vary doses to the vital organs. Long-term engraftment and reconstitution potential were evaluated by a congenic bone marrow transplantation (BMT) model and serial secondary BMT, respectively. Donor cell engraftment was measured using noninvasive bioluminescence imaging and flow cytometry.

Results: Multimodal imaging enabled identification of targets (skeleton and spleen) and vital organs (eg, lungs, gut, liver). In contrast to total body irradiation (TBI), TMI treatment allowed variation of radiation dose exposure to organs relative to the target dose. Dose reduction mirrored that in clinical TMI studies. Similar to TBI, mice treated with different TMI regimens showed full long-term donor engraftment in primary BMT and second serial BMT. The TBI-treated mice showed acute gut damage, which was minimized in mice treated with TMI.

Conclusions: A novel multimodal image guided preclinical TMI model is reported here. TMI conditioning maintained long-term engraftment with reconstitution potential and reduced organ damage. Therefore, this TMI model provides a unique opportunity to study the therapeutic benefit of reduced organ damage and BM dose escalation to optimize treatment regimens in BMT and hematologic malignancies.
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http://dx.doi.org/10.1016/j.ijrobp.2021.06.001DOI Listing
June 2021

Use of high-dose mesna and hyperhydration leads to lower incidence of hemorrhagic cystitis after posttransplant cyclophosphamide-based allogeneic transplantation.

Bone Marrow Transplant 2021 Jun 9. Epub 2021 Jun 9.

Department of Hematology and Hematopoietic Cell Transplantation, City of Hope, Duarte, CA, USA.

Currently, there is no consensus on best practices to prevent hemorrhagic cystitis (HC) in patients receiving posttransplant cyclophosphamide (PTCy). We retrospectively reviewed 194 patients undergoing their first hematopoietic cell transplant (HCT) who received PTCy from 2014 to 2018 to describe the incidence and severity of HC, identify potential risk factors, and impact of HC on HCT outcomes. Standard HC prophylaxis was hyperhydration with forced diuresis and mesna at 320% the daily dose of PTCy. Incidence of HC was 31.4% at day +100 of HCT. Median onset of HC was 12 days with 11.5% grade 3 HC and no Grade 4 HC. Patients with chemical HC experienced earlier onset (7 days vs. 34 days, p < 0.001) with a shorter median resolution time (5 days vs. 14 days, p = 0.001) when compared to BK-associated HC. In multivariate analysis, age above 60 years (HR 4.16, p = 0.006) and myeloablative conditioning (HR 2.44, p = 0.054) were associated with higher risk for HC, but overall, HC did not affect nonrelapse mortality or overall survival. In conclusion, hyperhydration with forced diuresis combined with aggressive mesna dosing is an effective strategy in preventing severe PTCy-associated HC, subsequently preventing any negative impact on transplant outcome.
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http://dx.doi.org/10.1038/s41409-021-01364-0DOI Listing
June 2021

Secondary cytogenetic abnormalities in core-binding factor AML harboring inv(16) vs t(8;21).

Blood Adv 2021 05;5(10):2481-2489

Adult Bone Marrow Transplant Service, Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, NY.

Patients with core-binding factor (CBF) acute myeloid leukemia (AML), caused by either t(8;21)(q22;q22) or inv(16)(p13q22)/t(16;16)(p13;q22), have higher complete remission rates and longer survival than patients with other subtypes of AML. However, ∼40% of patients relapse, and the literature suggests that patients with inv(16) fare differently from those with t(8;21). We retrospectively analyzed 537 patients with CBF-AML, focusing on additional cytogenetic aberrations to examine their impact on clinical outcomes. Trisomies of chromosomes 8, 21, or 22 were significantly more common in patients with inv(16)/t(16;16): 16% vs 7%, 6% vs 0%, and 17% vs 0%, respectively. In contrast, del(9q) and loss of a sex chromosome were more frequent in patients with t(8;21): 15% vs 0.4% for del(9q), 37% vs 0% for loss of X in females, and 44% vs 5% for loss of Y in males. Hyperdiploidy was more frequent in patients with inv(16) (25% vs 9%, whereas hypodiploidy was more frequent in patients with t(8;21) (37% vs 3%. In multivariable analyses (adjusted for age, white blood counts at diagnosis, and KIT mutation status), trisomy 8 was associated with improved overall survival (OS) in inv(16), whereas the presence of other chromosomal abnormalities (not trisomy 8) was associated with decreased OS. In patients with t(8;21), hypodiploidy was associated with improved disease-free survival; hyperdiploidy and del(9q) were associated with improved OS. KIT mutation (either positive or not tested, compared with negative) conferred poor prognoses in univariate analysis only in patients with t(8;21).
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http://dx.doi.org/10.1182/bloodadvances.2020003605DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8152510PMC
May 2021

ROCK2 Inhibition With Belumosudil (KD025) for the Treatment of Chronic Graft-Versus-Host Disease.

J Clin Oncol 2021 Jun 20;39(17):1888-1898. Epub 2021 Apr 20.

Fred Hutchinson Cancer Research Center, Seattle, WA.

Purpose: The rho-associated coiled-coil-containing protein kinase-2 (ROCK2) signaling pathway regulates the Th17/regulatory T cells balance and controls profibrotic pathways. Selective ROCK2 inhibition with belumosudil (KD025) may offer a novel approach to the management of chronic graft-versus-host disease (cGVHD).

Patients And Methods: A phase IIa, open-label, dose-finding study of belumosudil enrolled 54 patients with cGVHD who had received one to three prior lines of therapy (LOTs). The primary end point was overall response rate (ORR).

Results: The median time from cGVHD diagnosis to enrollment was 20 months. Seventy-eight percent of patients had severe cGVHD, 50% had ≥ 4 organs involved, 73% had cGVHD refractory to their last LOT, and 50% had received ≥ 3 prior LOTs. With an overall median follow-up of 29 months, the ORR (95% CI) with belumosudil 200 mg once daily, 200 mg twice daily, and 400 mg once daily was 65% (38% to 86%), 69% (41% to 89%), and 62% (38% to 82%), respectively. Responses were clinically meaningful, with a median duration of response of 35 weeks, and were associated with quality-of-life improvements and corticosteroid (CS) dose reductions. CS treatment was discontinued in 19% of patients. The failure-free survival rate was 76% (62% to 85%) and 47% (33% to 60%) at 6 and 12 months, respectively. The 2-year overall survival rate was 82% (69% to 90%). Belumosudil was well-tolerated, with low rates of cytopenia. There were no unexpected adverse events and no apparent increased risk of infection, including cytomegalovirus infection and reactivation.

Conclusion: Belumosudil treatment resulted in a high ORR and overall survival rate and demonstrated quality-of-life improvements, CS dose reductions, and limited toxicity. Data from the study indicated that belumosudil may prove to be an effective therapy for patients with treatment-refractory cGVHD.
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http://dx.doi.org/10.1200/JCO.20.02754DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8189612PMC
June 2021

Efficacy of blinatumomab for MRD relapse in ALL post allogenic HCT.

Leuk Res 2021 05 30;104:106579. Epub 2021 Mar 30.

Gehr Family Center for Leukemia Research, Department of Hematology and Hematopoietic Cell Transplantation, City of Hope National Medical Center, Duarte, CA, United States. Electronic address:

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http://dx.doi.org/10.1016/j.leukres.2021.106579DOI Listing
May 2021

Allogeneic Hematopoietic Cell Transplantation for Relapsed and Refractory Philadelphia Negative B Cell ALL in the Era of Novel Salvage Therapies.

Transplant Cell Ther 2021 03 22;27(3):255.e1-255.e9. Epub 2020 Dec 22.

Gehr Family Center for Leukemia Research, Department of Hematology and Hematopoietic Cell Transplantation, City of Hope National Medical Center, Duarte, California.

Introduction of novel salvage therapies and expansion of the donor pool within the past decade have allowed more patients with relapsed/refractory (r/r) B cell acute lymphoblastic leukemia (B-ALL) to receive allogeneic hematopoietic cell transplantation (alloHCT). The impact of each salvage therapy on transplant outcomes have not been compared. Our primary objective was to determine post-HCT relapse-free survival (RFS) in adult patients with r/r Philadelphia-chromosome negative (Ph) B-ALL. We retrospectively studied alloHCT outcomes in 108 adult patients with r/r Ph B-ALL transplanted in morphological remission achieved by salvage therapy. Salvage therapies were chemotherapy-based combination (n = 45, 42%), blinatumomab (n=43, 40%), inotuzumab (n = 14, 13%), or CAR T cells (n = 6, 6%). The 2-year RFS and overall survival (OS) were 44% and 50%, respectively. In multivariable analysis, conditioning with reduced-intensity or non-myeloablative regimens (hazard ratio [HR] = 2.23, 95% confidence interval [CI], 1.31-3.80; P = .003), having received ≥3 lines of therapies prior to transplant (HR = 2.66, 95% CI, 1.56-4.54; P < .001), and inotuzumab (HR = 2.42, 95% CI, 1.14-5.12; Wald P value = .021) were independently associated with lower RFS. Blinatumomab (HR = 1.10, 95% CI, 0.62-1.96) had comparable RFS to chemotherapy. Incidence of hepatic sinusoidal syndrome was highest with inotuzumab (P < .001); however, 30-day mortality and intensive care unit admissions were not different per salvage therapy. The alloHCT in r/r Ph B-ALL after remission induction with blinatumomab or chemotherapy led to encouraging outcomes if morphologic CR was achieved. In contrast, pretransplantation inotuzumab therapy was associated with inferior RFS. Larger studies are warranted to confirm our observations. Early transplantation after relapse and the utilization of myeloablative conditioning, when feasible, were key factors associated with improved outcomes after alloHCT in these patients.
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http://dx.doi.org/10.1016/j.jtct.2020.12.020DOI Listing
March 2021

Outcome of Allogeneic Hematopoietic Cell Transplantation after Venetoclax and Hypomethylating Agent Therapy for Acute Myelogenous Leukemia.

Biol Blood Marrow Transplant 2020 12 29;26(12):e322-e327. Epub 2020 Aug 29.

Department of Hematology and Hematopoietic Cell Transplantation, Gehr Family Center for Leukemia Research, City of Hope Medical Center, Duarte, California. Electronic address:

The combination of hypomethylating agents with the selective Bcl-2 inhibitor venetoclax (HMA-VEN) has emerged as a highly active regimen in patients with acute myelogenous leukemia (AML) in both the upfront and relapsed/refractory (r/r) settings. We report our early experience with a cohort of patients who were able to proceed to allogeneic hematopoietic cell transplantation (alloHCT) after HMA-VEN therapy. Thirty-two patients with AML (19 r/r and 13 de novo) with a median age of 62 years underwent alloHCT after HMA-VEN therapy. Twenty-two (68.8%) were in complete remission (CR)/CR with incomplete count recovery at time of HCT. With a median follow up of 14.4 months, the 1-year overall survival (OS) was 62.5%, and disease-free survival was 43.8%. The 1-year nonrelapse mortality rate was 18.8%, and the cumulative incidence of relapse was 37.5%. Among patients who underwent alloHCT in CR, the 1-year OS was 77.3%, and the cumulative incidence of nonrelapse mortality was 9.1%. The cumulative incidence of grade II-IV acute graft-versus-host disease was 43.8%. We conclude that alloHCT after HMA-VEN is therapy associated with favorable allogeneic HCT outcomes in newly diagnosed older patients with AML, as well as those with r/r AML.
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http://dx.doi.org/10.1016/j.bbmt.2020.08.027DOI Listing
December 2020

Levocarnitine for pegasparaginase-induced hepatotoxicity in acute lymphoblastic leukemia.

Leuk Lymphoma 2020 12 13;61(13):3161-3164. Epub 2020 Aug 13.

Department of Hematology and Hematopoietic Cell Transplantation, City of Hope National Medical Center, Duarte, CA, USA.

Pegasparaginase (PEG-Asp), commonly used in acute lymphoblastic leukemia (ALL), is associated with hyperbilirubinemia and elevated transaminases. Treatment of acute hepatotoxicity is limited to case studies reporting success with levocarnitine (LC). In a retrospective analysis, 25 ALL patients experienced Grade ≥3 hyperbilirubinemia and/or elevated transaminases following a single dose of PEG-Asp where 12 patients received LC compared to 13 patients with no intervention. Median LC dose was 50 mg/kg/day for a median of 11 days. Median values were greater in the LC group: total bilirubin 5.2 mg/dL vs 4.5 mg/dL ( = 0.19), AST 75.5 units/L vs. 30 units/L ( = 0.05), and ALT 263.5 units/L vs 47 units/L ( = 0.003). Time to resolution (TTR) did not significantly differ between LC and control ( = 0.08), however, patients on LC did resume therapy sooner ( = 0.17). Although significant limitations exist in the study, LC did not result in a clinically significant impact when used to treat PEG-Asp-induced hepatotoxicity.
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http://dx.doi.org/10.1080/10428194.2020.1805108DOI Listing
December 2020

Venetoclax and hypomethylating agents in FLT3-mutated acute myeloid leukemia.

Am J Hematol 2020 Jul 6. Epub 2020 Jul 6.

Department of Hematology and Hematopoietic Cell Transplantation, City of Hope Medical Center, Gehr Family Center for Leukemia Research, Duarte, California, USA.

FMS-like tyrosine kinase 3 (FLT3) mutations are prevalent in acute myeloid leukemia (AML), and their presence confers adverse risk. FLT3-mutated (FLT3m) AML is a challenging leukemia to manage, particularly in older and unfit patients as well as patients with relapsed/refractory (r/r) disease. We retrospectively analyzed the outcomes of 50 FLT3m AML patients (17 treatment-naïve, 33 r/r) treated with venetoclax (VEN) and hypomethylating agents (HMA). The overall CR/CRi rate with VEN-HMA was 60% (94% in treatment-naïve AML and 42% in r/r AML). Early (60-days) treatment related mortality was 2%. The r/r AML setting was an independent predictor of lower complete response (OR: 0.08; 95%CI: 0.00-0.60, P = .03). Cytogenetics-molecular risk, concurrent mutations, the type of FLT3 mutation (ITD vs TKD), the ITD allelic ratio, the type of HMA, age, prior exposure to HMA and receipt of prior allogeneic transplant did not independently impact response or leukemia-free survival (LFS). Concurrent IDH mutations were associated with lower CR/CRi (P = .01), while ASXL1 or TET2 mutations showed a non-significant association toward higher CR/CRi (P = .07, for both). However, none of the concurrent mutations were an independent predictor for response when adjusted to AML setting. In conclusion, VEN-HMA is associated with encouraging efficacy in FLT3m AML among both newly diagnosed unfit and r/r patients.
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http://dx.doi.org/10.1002/ajh.25929DOI Listing
July 2020

Long-Term Outcomes of Allogeneic Hematopoietic Cell Transplant with Fludarabine and Melphalan Conditioning and Tacrolimus/Sirolimus as Graft-versus-Host Disease Prophylaxis in Patients with Acute Lymphoblastic Leukemia.

Biol Blood Marrow Transplant 2020 08 19;26(8):1425-1432. Epub 2020 May 19.

Department of Hematology and HCT, City of Hope, Duarte, California; Department of Computational Quantitative Medicine/BRI, City of Hope, Duarte, California. Electronic address:

Acute lymphoblastic leukemia (ALL) is associated with poor survival in older adults, and allogeneic hematopoietic cell transplant (HCT) with reduced-intensity conditioning (RIC) has been an increasingly used strategy in this population. At City of Hope we conducted a retrospective analysis of 72 patients who underwent allogeneic HCT with fludarabine and melphalan (FluMel) as the conditioning regimen between 2005 and 2018, from either a matched sibling or fully matched unrelated donor while in complete remission. Tacrolimus and sirolimus (T/S) were used as graft-versus-host disease (GVHD) prophylaxis. Overall survival and progression-free survival at 4 years post-HCT were 58% and 44%, respectively. The cumulative incidences of relapse/progression and nonrelapse mortality at 4 years were 34% and 22%, respectively. Patients with Philadelphia chromosome-positive (Ph+) ALL had a significantly lower cumulative incidence of relapse/progression (20% versus 48% for patients with Ph-negative status, P = .007). In conclusion, RIC HCT with FluMel conditioning and T/S GVHD prophylaxis was associated with favorable outcomes in patients with Ph+ ALL and should be considered as a viable consolidative therapy for adult patients with ALL.
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http://dx.doi.org/10.1016/j.bbmt.2020.04.015DOI Listing
August 2020

Ruxolitinib for the treatment of graft-versus-host disease.

Expert Rev Clin Immunol 2020 04 1;16(4):347-359. Epub 2020 Apr 1.

Department of Hematology/Hematopoietic Cell Transplantation, City of Hope National Medical Center, Duarte, CA, USA.

: Ruxolitinib is an oral selective JAK1/JAK2 inhibitor, initially approved by the FDA for the treatment of intermediate-2 or high-risk myelofibrosis and patients with polycythemia vera who have had an inadequate response or are intolerant to hydroxyurea.: Accumulating evidence supports the role of JAK1/JAK2 pathways in the pathogenesis of graft-versus-host disease (GVHD), and preclinical studies have demonstrated promising efficacy of ruxolitinib in treatment/prevention of GVHD. Early clinical observations that ruxolitinib was effective in treatment of steroid-refractory (SR) acute and chronic GVHD led to the development of prospective clinical trials; Phase II REACH1 (NCT02953678), Phase III REACH2 (NCT02913261), and REACH3 (NCT03112603). Based on the data from the REACH1 trial, ruxolitinib was approved by the FDA in May 2019 for SR acute GVHD in adult and pediatric patients 12 years and older.: Ruxolitinib and other JAK1/JAK2 inhibitors hold promise in other treatment settings such as GVHD prevention and/or first-line therapy.
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http://dx.doi.org/10.1080/1744666X.2020.1740592DOI Listing
April 2020

Outcomes of Allogeneic Hematopoietic Cell Transplantation after Salvage Therapy with Blinatumomab in Patients with Relapsed/Refractory Acute Lymphoblastic Leukemia.

Biol Blood Marrow Transplant 2020 06 5;26(6):1084-1090. Epub 2020 Feb 5.

Department of Hematology and HCT, City of Hope, Duarte, California.

Historically, outcomes of adult patients with relapsed acute lymphoblastic leukemia (ALL) who fail to enter remission with conventional chemotherapy are very poor. Blinatumomab, a bispecific CD3/CD19 antibody, has shown remarkable activity in relapsed/refractory (r/r) ALL. Although allogeneic hematopoietic cell transplant (HCT) is the recommended consolidation therapy for patients with r/r ALL who respond to salvage therapy, HCT and toxicity outcomes for those who received blinatumomab salvage and HCT remain largely unknown. We treated 89 patients with r/r ALL with blinatumomab, of whom 43 patients (48%) achieved remission. Here we describe our single-center experience in the subset of patients who responded to blinatumomab salvage therapy for eradication of either gross (n = 24) or minimal residual disease (n = 11) before HCT. Overall survival at 1 and 2 years after allogeneic HCT was 77% and 52%, respectively. Leukemia-free survival at 1 and 2 years were 65% and 40%, respectively. Additionally, with blinatumomab administration pre-HCT, no unusual toxicities such as delayed neutrophil/platelet engraftment or graft failure were observed. Acute grades II to IV graft-versus-host disease (GVHD) at day +100 post-HCT was at 43% and 2-year chronic GVHD was 36%, both comparable with historic control subjects. Finally, results of our subset analysis based on pre-HCT minimal residual disease (MRD) status indicated no significant difference in survival outcomes among patients undergoing transplant in MRD-negative status and the entire cohort. In conclusion, based on results of this study, blinatumomab may be considered as a safe and effective agent for r/r ALL patients before HCT.
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http://dx.doi.org/10.1016/j.bbmt.2020.01.029DOI Listing
June 2020

Invasive fungal infections in acute myeloid leukemia treated with venetoclax and hypomethylating agents.

Blood Adv 2019 12;3(23):4043-4049

Gehr Family Center for Leukemia Research, Department of Hematology and Hematopoietic Cell Transplantation.

The combination of venetoclax with hypomethylating agents (VEN-HMAs) showed promising activity in newly diagnosed and relapsed/refractory (r/r) acute myeloid leukemia (AML). Treatment with VEN-HMAs results in prolonged cytopenia, thereby exposing patients to invasive fungal infections (IFIs). Here, we retrospectively studied a cohort of 119 AML patients treated with VEN-HMAs and analyzed the occurrence of IFIs, as well as our practice of antifungal prophylaxis, with the aim to identify the nature and risk factors for IFIs and their association with the type of antifungal prophylaxis used. The intended antifungal prophylaxis was micafungin in 38% of patients, azoles in 41% of patients, and none in 21% of patients. Older age was associated with no antifungal prophylaxis or micafungin use and lesser use of azoles (P = .043). We recorded 15 (12.6%) patients who developed probable or proven IFIs, with a median onset of 72 days (range, 35-281) after starting therapy. IFIs were more common among nonresponders compared with responders to VEN-HMA therapy (22% vs 6%, P = .0132) and in r/r compared with newly diagnosed AML (19% vs 5%, P = .0498); however, the antifungal prophylaxis used, patient age, hypomethylating agent schedule, history of prior allogeneic transplant, and initial neutropenia duration did not influence the development of IFIs during therapy. We conclude that the overall risk of IFIs during VEN-HMA therapy is low. The risk of IFIs is higher in nonresponders and in those who were treated in the r/r setting; these patients need reevaluation of their antifungal prophylaxis to minimize the risk of IFIs during therapy.
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http://dx.doi.org/10.1182/bloodadvances.2019000930DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6963254PMC
December 2019

Pulmonary hypertension is associated with increased nonrelapse mortality after allogeneic hematopoietic cell transplantation for myelofibrosis.

Bone Marrow Transplant 2020 05 6;55(5):877-883. Epub 2019 Nov 6.

Department of Hematology and Hematopoietic Cell Transplantation, City of Hope Medical Center, Duarte, CA, USA.

Allogeneic hematopoietic cell transplantation (alloHCT) is the only curative therapy for primary myelofibrosis (MF) as well as myelofibrosis secondary to other myeloproliferative neoplasms (MPN). Pulmonary hypertension (PH) is a known complication of MF and may occur in up to 50% of such patients. PH (defined as a mean pulmonary artery pressure ≥25 mmHg at rest) can eventually lead to right heart failure and may be associated with complications after alloHCT. We examined the association of PH with alloHCT outcome in patients with MF associated with MPN. Pre- and post-HCT echocardiograms were reviewed to estimate the peak pulmonary artery systolic pressure (PASP). Median PASP was 37.0 mmHg (range: 16.0-57.9) prior to HCT with 37 of 65 patients (57%) studied. With median follow-up of 35.0 months (range: 3.3-119.4) PH was significantly associated with inferior OS (58.9% vs. 88.8%, P = 0.025), primarily due to increased NRM (21.6% vs. 7.1%, P = 0.007). The majority of the deaths (8 of 14) in patients with PH occurred within 100 days after HCT. In patients with an available post-HCT echocardiogram (n = 33), the median PASP was 30 mmHg (range: 5.0-56.2); eight patients (24%) had persistent PH. Compared with pre-HCT values, PASP was significantly reduced after HCT (p < 0.001). We conclude that PH is associated with inferior survival due to the increased NRM in patients with MF undergoing alloHCT. PH appears at least partially reversible after successful alloHCT. PH should be considered a risk factor for early mortality after alloHCT and surveillance of pulmonary artery pressure in MF patients being considered for alloHCT may be useful.
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http://dx.doi.org/10.1038/s41409-019-0741-8DOI Listing
May 2020

Long-Term Outcomes of Patients with Acute Myelogenous Leukemia Treated with Myeloablative Fractionated Total Body Irradiation TBI-Based Conditioning with a Tacrolimus- and Sirolimus-Based Graft-versus-Host Disease Prophylaxis Regimen: 6-Year Follow-Up from a Single Center.

Biol Blood Marrow Transplant 2020 02 16;26(2):292-299. Epub 2019 Sep 16.

Department of Hematology and HCT, City of Hope, Duarte, California.

Cyclophosphamide (Cy)/etoposide combined with fractionated total body irradiation (FTBI) or i.v. busulfan (Bu) has been the main conditioning regimens for allogeneic hematopoietic cell transplantation (alloHCT) for young patients with acute myelogenous leukemia (AML) eligible for a myeloablative conditioning (MAC) regimen. Recent data has suggested that i.v. Bu could be the preferred myeloablative regimen in patients with myeloid malignancies. However, Bu-based regimens are associated with higher rates of sinusoidal obstruction syndrome. Here we report long-term survival outcomes of patients with AML receiving FTBI combined with Cy or etoposide before undergoing alloHCT at City of Hope (COH). We obtained a retrospective review of a prospectively maintained institutional registry of clinical outcomes in 167 patients (median age, 41 years; range, 18 to 57 years) with AML in first or second complete remission who underwent alloHCT at COH between 2005 and 2015. Eligible patients received a MAC regimen with FTBI (1320 cGy) and Cy (120 mg/kg) for unrelated donor transplantation or etoposide (60 mg/kg) for related donor transplantation. Graft-versus-host disease (GVHD) prophylaxis was provided with tacrolimus and sirolimus. In this retrospective study, 6-year overall survival was 60% and nonrelapse mortality was 15%. The GRFS rate was 45% at 1 year and 39% at 2 years. We also describe late metabolic effects and report the cumulative incidence of secondary malignancies (9.5%). Overall, in this young adult patient population, our results compare favorably to chemotherapy-based (i.v. Bu) conditioning regimens without significant long-term toxicity arising from TBI-based regimens.
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http://dx.doi.org/10.1016/j.bbmt.2019.09.017DOI Listing
February 2020

The feasibility of venetoclax and decitabine in therapy-related acute myeloid leukemia with concurrent advanced non-hematological malignancies.

Leuk Res 2019 09 30;84:106196. Epub 2019 Jul 30.

Department of Hematology and Hematopoietic Cell Transplantation, Gehr Family Center for Leukemia Research, City of Hope, Duarte, CA, United States. Electronic address:

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http://dx.doi.org/10.1016/j.leukres.2019.106196DOI Listing
September 2019

Allogeneic Hematopoietic Cell Transplantation Outcomes in Patients Carrying Isocitrate Dehydrogenase Mutations.

Clin Lymphoma Myeloma Leuk 2019 07 26;19(7):e400-e405. Epub 2019 Apr 26.

Department of Hematology and HCT, City of Hope National Medical Center, Duarte, CA.

Background: Mutations in isocitrate dehydrogenase (IDH)1/2 genes result in nicotinamide adenine dinucleotide phosphate-dependent reduction of α-ketoglutarate and formation of 2-hydroxyglutarate, which blocks normal cellular differentiation and promotes leukemogenesis. Nearly 20% of acute myeloid leukemia (AML) patients carry IDH1/2 mutations. Although multiple investigators have described the prognostic implications of IDH mutations in AML patients receiving chemotherapy, the effect of these mutations on outcomes after allogeneic (allo) hematopoietic cell transplantation (HCT) is unknown.

Patients And Methods: We report on the clinical outcome of a cohort of AML patients, who were tested for IDH mutations and underwent alloHCT at City of Hope (2015-2017). Of a total of 317 screened patients, 99 (31%) underwent alloHCT, of whom 23 carried and 76 did not carry IDH mutations (control).

Results: No statistical significance was detected in patient's overall survival (P = .84). With a median follow-up of 7.8 months, 1-year relapse rate of 29% and 13% was seen in the IDH-mutated and control group, respectively (P = .033). IDH1/2 mutation status remained significantly associated with relapse (hazard ratio, 2.8; P = .046) after inclusion of pre-HCT disease status in a multivariable model.

Conclusion: Our results, despite low patient numbers, indicate that IDH mutations are associated with higher relapse rate after alloHCT. Further prospective studies on post transplantation IDH inhibition is required to improve outcomes in AML patients who carry IDH mutations.
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http://dx.doi.org/10.1016/j.clml.2019.04.007DOI Listing
July 2019

Favorable outcomes for allogeneic hematopoietic cell transplantation in elderly patients with NPM1-mutated and FLT3-ITD-negative acute myeloid leukemia.

Bone Marrow Transplant 2020 02 14;55(2):473-475. Epub 2019 May 14.

Department of Hematology and Hematopoietic Cell Transplantation, Gehr Family Center for Leukemia Research, City of Hope, Duarte, CA, USA.

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http://dx.doi.org/10.1038/s41409-019-0553-xDOI Listing
February 2020

MIPSS70+ v2.0 predicts long-term survival in myelofibrosis after allogeneic HCT with the Flu/Mel conditioning regimen.

Blood Adv 2019 01;3(1):83-95

Department of Hematology and Hematopoietic Cell Transplantation.

Although allogeneic hematopoietic cell transplantation (allo-HCT) is the only curative treatment for myelofibrosis (MF), data are limited on how molecular markers predict transplantation outcomes. We retrospectively evaluated transplantation outcomes of 110 consecutive MF patients who underwent allo-HCT with a fludarabine/melphalan (Flu/Mel) conditioning regimen at our center and assessed the impact of molecular markers on outcomes based on a 72-gene next-generation sequencing panel and Mutation-Enhanced International Prognostic Scoring System 70+ v2.0 (MIPSS70+ v2.0). With a median follow-up of 63.7 months, the 5-year overall survival (OS) rate was 65% and the nonrelapse mortality (NRM) rate was 17%. In mutational analysis, JAK2 V617F and ASXL1 mutations were the most common. By univariable analysis, higher Dynamic International Prognostic Scoring System scores, unrelated donor type, and very-high-risk cytogenetics were significantly associated with lower OS. Only CBL mutations were significantly associated with lower OS (hazard ratio [HR], 2.64; = .032) and increased NRM (HR, 3.68; = .004) after allo-HCT, but CALR, ASXL1, and IDH mutations did not have an impact on transplantation outcomes. Patient classification per MIPSS70 showed worse OS for high-risk (HR, 0.49; = .039) compared with intermediate-risk patients. Classification per MIPSS70+ v2.0 demonstrated better OS when intermediate-risk patients were compared with high-risk patients (HR, 0.291) and much lower OS when very-high-risk patients were compared with high-risk patients (HR, 5.05; ≤ .001). In summary, we present one of the largest single-center experiences of Flu/Mel-based allo-HCT, demonstrating that revised cytogenetic changes and MIPSS70+ v2.0 score predict transplantation outcomes, and thus can better inform physicians and patients in making decisions about allo-HCT.
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http://dx.doi.org/10.1182/bloodadvances.2018026658DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6325305PMC
January 2019

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

Biol Blood Marrow Transplant 2019 02 15;25(2):287-292. Epub 2018 Sep 15.

Department of Hematology and Hematopoietic Cell Transplantation, City of Hope, Duarte, California; Department of Hematology and Hematopoietic Cell Transplantation, Gehr Family Center for Leukemia Research, City of Hope, Duarte, California. Electronic address:

The current standard of care for patients with Hodgkin lymphoma (HL) and non-Hodgkin lymphoma (NHL) is high-dose conditioning followed by autologous stem cell transplantation (ASCT). For some patients (ie, those with highest-risk disease, insufficient stem cell numbers after mobilization, or bone marrow involvement) allogeneic hematopoietic cell transplantation (alloHCT) offers the potential for cure. However, the majority of patients undergoing alloHCT receive reduced-intensity conditioning as a preparative regimen, and studies assessing outcomes of patients after alloHCT with myeloablative conditioning are limited. In this retrospective study, we reviewed outcomes of 22 patients with recurrent and refractory NHL who underwent alloHCT with myeloablative BEAM conditioning and received tacrolimus/sirolimus as graft-versus-host disease (GVHD) prophylaxis at City of Hope between 2005 and 2018. With a median follow-up of 2.6 years (range, 1.0 to 11.2 years), the probabilities of 2-year overall survival and event-free survival were 58.3% (95% confidence interval [CI], 35.0% to 75.8%) and 45.5% (95% CI, 24.4% to 64.3%), respectively. The cumulative incidence of grade II to IV acute GVHD was 45.5% (95% CI, 23.8% to 64.9%), with only 1 patient developing grade IV acute GVHD. However, chronic GVHD was seen in 55% of the patients (n = 12). Of the 22 eligible patients, 2 had undergone previous ASCT and 2 had undergone previous alloHCT. Both patients with previous ASCT developed severe regimen-related toxicity. Patients who underwent alloHCT with chemorefractory disease had lower survival rates, with 1-year OS and EFS of 44.4% and 33.0%, respectively. In conclusion, alloHCT with a BEAM preparative regimen and tacrolimus/sirolimus-based GVHD should be considered as an alternative option for patients with highest-risk lymphoma whose outcomes are expectedly poor after ASCT.
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http://dx.doi.org/10.1016/j.bbmt.2018.09.009DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6502508PMC
February 2019

Ruxolitinib as Salvage Therapy for Chronic Graft-versus-Host Disease.

Biol Blood Marrow Transplant 2019 02 8;25(2):265-269. Epub 2018 Sep 8.

Department of Hematology and Hematopoietic Cell Transplantation, City of Hope, Duarte, California.

Chronic graft-versus-host disease (cGVHD) continues to be a major complication after allogeneic hematopoietic cell transplantation, significantly affecting patients' quality of life. A regimen of systemic corticosteroids is considered first-line therapy but is often associated with inadequate responses and multiple side effects. In patients with refractory disease, an evidenced-based consensus is lacking as to the single best approach to managing symptoms. Ruxolitinib, a selective JAK1/2 inhibitor, has recently gained favor as a second-line approach in patients with steroid-refractory cGVHD. In this retrospective study, we evaluated the outcomes of 46 patients who received ruxolitinib for cGVHD between March 2016 and December 2017 at our institution, and evaluated ruxolitinib's impact at 6 and 12 months, based on the National Institutes of Health Severity Scale, including organ-specific responses, and mean prednisone dose. Furthermore, we present the first reported probability of ruxolitinib's treatment failure-free survival (FFS) in patients with cGVHD. After 12 months of ruxolitinib therapy, complete response, partial response, and stable disease was observed in 13% (n = 6), 30.4% (n = 14), and 10.9% (n = 5) of patients, respectively. The 1-year probability of FFS was 54.2% (95% confidence interval, .388 to .673), and ruxolitinib use was associated with a reduction in prednisone dose. In conclusion, our data, which represent the largest cohort of patients with cGVHD reported to date, support the use of ruxolitinib for cGVHD refractory to steroids and currently available salvage therapies, discontinued due to lack of response and high cost.
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http://dx.doi.org/10.1016/j.bbmt.2018.09.003DOI Listing
February 2019

Core-binding factor acute myeloid leukemia with t(8;21): Risk factors and a novel scoring system (I-CBFit).

Cancer Med 2018 09 16;7(9):4447-4455. Epub 2018 Aug 16.

Division of Hematology and HCT, City of Hope, Duarte, California.

Background: Although the prognosis of core-binding factor (CBF) acute myeloid leukemia (AML) is better than other subtypes of AML, 30% of patients still relapse and may require allogeneic hematopoietic cell transplantation (alloHCT). However, there is no validated widely accepted scoring system to predict patient subsets with higher risk of relapse.

Methods: Eleven centers in the US and Europe evaluated 247 patients with t(8;21)(q22;q22).

Results: Complete remission (CR) rate was high (92.7%), yet relapse occurred in 27.1% of patients. A total of 24.7% of patients received alloHCT. The median disease-free (DFS) and overall (OS) survival were 20.8 and 31.2 months, respectively. Age, KIT D816V mutated (11.3%) or nontested (36.4%) compared with KIT D816V wild type (52.5%), high white blood cell counts (WBC), and pseudodiploidy compared with hyper- or hypodiploidy were included in a scoring system (named I-CBFit). DFS rate at 2 years was 76% for patients with a low-risk I-CBFit score compared with 36% for those with a high-risk I-CBFit score (P < 0.0001). Low- vs high-risk OS at 2 years was 89% vs 51% (P < 0.0001).

Conclusions: I-CBFit composed of readily available risk factors can be useful to tailor the therapy of patients, especially for whom alloHCT is not need in CR1 (ie, patients with a low-risk I-CBFit score).
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http://dx.doi.org/10.1002/cam4.1733DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6144246PMC
September 2018
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