Publications by authors named "Arjun Datt Law"

31 Publications

Association of Factors influencing selection of upfront hematopoietic cell transplantation versus non-transplant therapies in Myelofibrosis: Transplant decisions in MF.

Transplant Cell Ther 2021 Mar 30. Epub 2021 Mar 30.

Medical Oncology and Hematology, Princess Margaret Cancer Centre, University of Toronto, Toronto, Ontario, Canada.

Background: Despite the curative potential of allogeneic hematopoietic cell transplantation (HCT) for myelofibrosis (MF), a significant number of patients do not undergo HCT. Factors influencing treatment preferences are not well studied in MF.

Objective(s): This study's objective was to identify patient, disease, and donor-related factors influencing HCT decision in MF. A secondary objective was to compare survival in patients who elected upfront HCT or non-transplant therapy.

Study Design: We conducted a retrospective chart review amongst patients meeting criteria for transplant indication, evaluating clinical characteristics, treatment preferences, and outcomes.

Results: Of the 183 study eligible patients <70 years, 129 (70%) developed an HCT indication. Age >60 years was significantly associated with higher rates of HLA-typing refusal (13/72 vs. 1/44, p = 0.02). Caucasian ethnicity was significantly associated with an increased rate of identifying well matched donors compared to non-Caucasian (75% vs. 48%, p = 0.02). Of the 69 patients with well-matched donors, 34 (49%) preferred not to pursue upfront HCT despite a transplant indication. Patient preferences for non-transplant therapies was the most common reason for declining HCT. We did not find any difference in survival between patients pursuing upfront HCT versus non-transplant therapies, although more patients were in remission in the HCT arm at the last follow-up.

Conclusion(s): Caucasian ethnicity patients were significantly more likely to identify a well-matched donor compared to non-Caucasian patients. Despite availability of a well-matched donor, a significant proportion of MF patients with transplant indication do not pursue HCT. Patient age, donor type and patient preferences play a major part in selection of upfront HCT. While a survival difference was not observed between upfront HCT versus non-transplant therapy, more patients in the HCT arm were in remission at the last follow up.
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http://dx.doi.org/10.1016/j.jtct.2021.03.027DOI Listing
March 2021

Predictors of outcomes of therapy-related acute myeloid leukemia after allogeneic hematopoietic stem cell transplantation.

Hematol Oncol Stem Cell Ther 2021 Mar 19. Epub 2021 Mar 19.

Hans Messner Allogeneic Blood and Marrow Transplantation Program, Princess Margaret Cancer Center, University of Toronto, Toronto, ON, Canada. Electronic address:

Background/objective: Existing literature on allogeneic hematopoietic stem cell transplantation (allo-HSCT) in therapy-related acute myeloid leukemia (t-AML) is confounded by the inclusion of patients with secondary AML and t-MDS. We aim to report our 20-year experience of HSCT in t-AML.

Methods: We retrospectively reviewed patients with t-AML who underwent HSCT. Patients were analyzed for prior malignancy, therapy, time to diagnosis of t-AML, transplant details, relapse-free survival (RFS), overall survival (OS), and predictors of outcomes.

Results: In total, 68 patients (59.9% female; median age, 56.5 years) underwent HSCT. Acute and chronic graft-versus-host disease (GVHD) occurred in 39 (57.4%) and 23 (33.8%) patients, respectively. Cumulative incidence of relapse, nonrelapse mortality, RFS, and OS at 2 years were 17.9%, 34.5%, 47.6%, and 49.3%, respectively. Significant predictors of reduced OS were presence of 11q23 rearrangement (hazard ratio [HR], 3.24), using induction regimens other than FLAG-Ida or 7 + 3 (HR, 3.65), haploidentical donors (HR, 3.48), Eastern Cooperative Oncology Group performance status 2 or higher (HR, 5.83), and using cyclosporine A-methotrexate as GVHD prophylaxis (HR, 2.41). A significant decrement in survival was seen with an increasing number of any of these prognostic factors.

Conclusion: Outcomes of t-AML are satisfactory after allo-HSCT. Patients with t-AML with good-risk karyotypes, good performance status, having HLA-matched donors, and receiving intensive induction regimens have better outcomes after HSCT.
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http://dx.doi.org/10.1016/j.hemonc.2021.03.003DOI Listing
March 2021

Moderate-severe grade of chronic graft versus host disease and younger age (less than 45 years old) are risk factors for avascular necrosis in adult patients undergoing allogeneic hematopoietic cell transplantation.

Ann Hematol 2021 May 12;100(5):1311-1319. Epub 2021 Mar 12.

Hans Messner Allogeneic Blood and Marrow Transplant Program, Division of Medical Oncology and Hematology, Princess Margaret Cancer Centre, University Health Network, 700 University Ave., Toronto, Ontario, M5G 1Z5, Canada.

Avascular necrosis (AVN) is a debilitating complication of allogeneic hematopoietic cell transplantation (HCT). A retrospective review of 845 patients who underwent HCT was conducted. Cumulative incidence of AVN was 6.3% at 4 years. The following risk factors were significantly associated with AVN risk on univariate analysis: age < 45 (p=0.004), moderate to severe chronic GvHD (p<0.001), reduced intensity conditioning (p=0.02), and a diagnosis of acute leukemia (p=0.045). Multivariate analysis confirmed two risk factors: younger age (<45 years), 9.0% vs 4.4% (p=0.011, hazard ratio (HR) 2.134), and moderate-severe chronic GvHD, 15.4% vs 2.1% (p<0.001, HR 4.950). A risk score model was generated assigning a score to each risk factor. A score of 1 was assigned to moderate-severe GvHD or those with age <45. Total score was calculated, thus dividing patient into three groups: low (score 0, n=349, 41.3%), intermediate (score 1, n=379, 44.9%), and high risk (score 2; n=116, 13.7%). This risk score could stratify the patients according to AVN risk (p<0.001). The risk of AVN was 1.5% in the low risk, 6.2% in the intermediate risk, and 20.8% in the high risk groups. Moderate-severe chronic GvHD and younger age (<45 years) are key risk factors for AVN following allogeneic HCT.
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http://dx.doi.org/10.1007/s00277-021-04480-5DOI Listing
May 2021

Outcomes of adult patients with acute myeloid leukemia and unsuccessful cytogenetic analysis undergoing allogeneic hematopoietic stem cell transplantation.

Hematol Oncol Stem Cell Ther 2020 Oct 8. Epub 2020 Oct 8.

Hans Messner Allogeneic Blood and Marrow Transplant Program, Princess Margaret Cancer Center, University of Toronto, Toronto, Ontario, Canada. Electronic address:

Objective/background: Unsuccessful cytogenetic (US) analysis at baseline has been reported to be a poor prognostic feature in patients with acute myeloid leukemia (AML). We conducted this study to examine the prognostic impact of UC/inconclusive cytogenetic analysis on outcomes in patients with AML undergoing allogeneic hematopoietic stem cell transplantation (Allo HSCT).

Methods: We retrospectively analyzed all adults undergoing Allo HSCT for AML from January 2011 to August 2019. Patients with any documented cytogenetic abnormalities were excluded. Baseline characteristics and transplant outcomes were compared between patients with normal cytogenetics and those with UC.

Results: Overall, 243 AML patients (median age, 55 years; 55.1% female) were included. UC were reported in 79 patients, whereas 164 patients had a normal karyotype. The two groups were similar to each other in terms of baseline demographics, treatment received, and transplant related variables. There was no difference between patients with UC and normal cytogenetics in terms of relapse-free survival (66 months vs. 42 months, p = .53) or overall survival (OS; 77 months vs. 76 months, p = .72). Survival parameters remained similar even in subgroup analysis based on NPM1 and FLT3 mutation status. Significant predictors of OS after Allo HSCT in AML patients with UC were increased age at time of Allo HSCT (hazard ratio [HR] = -1.049; 95% confidence interval [CI], 1.005-1.095), favorable (NPM1/FLT3) mutation profile (HR = 0.11; 95% CI, 0.01-0.84), neutrophil engraftment < 17 days, and absence of chronic graft-versus-host disease (HR = 3.27; 95% CI, 1.20-8.60).

Conclusion: Outcomes after Allo HSCT are comparable between AML patients with UC analysis and patients with normal cytogenetics even after stratification based on molecular risk factors. Allogeneic Allo HSCT may mitigate the poor prognosis of UC analysis in patients with AML.
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http://dx.doi.org/10.1016/j.hemonc.2020.09.001DOI Listing
October 2020

Prolactin, a potential biomarker for chronic GVHD activity.

Eur J Haematol 2021 Feb 26;106(2):158-164. Epub 2020 Oct 26.

Section of Medical Oncology and Hematology, Department of Medicine, University of Toronto, Toronto, Ontario, Canada.

Introduction: The polypeptide prolactin (PRL) is a peptide hormone and a cytokine mostly secreted from the anterior pituitary gland. PRL is also synthesized in extra pituitary tissues including thymocytes and T lymphocytes. Considering the need for chronic GVHD (cGVHD) biomarkers, we explored the relationship between hyperprolactinemia and active cGVHD in a cohort of long-term post-alloHCT survivors.

Methods: Three-hundred sixteen adults underwent alloHCT between 2010 and 2016, survived more than 1 year and were included. All patients underwent a regular annual assessment that includes a hormone profile with serum PRL levels.

Results: Overall, 236 (74.7%) patients had cGVHD, and in 199 (63%), the grade was moderate or severe. Sixty-five (21%) recipients had active cGVHD at the time of the annual evaluation, and hyperprolactinemia was documented in 63 (19.9%) patients. Hyperprolactinemia correlated with cGVHD activity (Odds Ratio 6.9 (95% CI; 3.6-13.1); P < .001) in the multivariate analysis. In conclusion, patients with hyperprolactinemia were 6.4 times more likely to have active cGVHD in comparison with those patients with normal levels of PRL (P < .001).

Conclusion: Prolactin may serve as a biomarker for cGVHD activity. Further studies are required to confirm these findings, and to explore if hyperprolactinemia has an impact on cGVHD severity and prognosis.
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http://dx.doi.org/10.1111/ejh.13531DOI Listing
February 2021

High incidence but low mortality of EBV-reactivation and PTLD after alloHCT using ATG and PTCy for GVHD prophylaxis.

Leuk Lymphoma 2020 12 25;61(13):3198-3208. Epub 2020 Jul 25.

Department of Medicine, Division of Medical Oncology and Hematology, University of Toronto, Toronto, ON, Canada.

We explore risk factors and impacts of post-transplant EBV-Reactivation (EBV-R) and PTLD in 270 patients that underwent RIC alloHCT using ATG-PTCy and cyclosporine for GVHD prophylaxis. Twenty-five (12%) patients had probable ( = 7) or proven ( = 18) PTLD. Patients were managed with reduction of immunosuppression and 22 with weekly rituximab (375 mg/m IV). ORR was 84%; 8 (32%) recipients died, and one-year OS and NRM of patients with PTLD was 59.7% and 37%, respectively. One hundred seventy-two (63.7%) recipients had EBV-R. One-year OS and RFS of patients with EBV-R were 68.2% and 60.6%, and of EBV-Negative patients were 62.1% and 50.1%, respectively. High incidence but low mortality of EBV-R and PTLD was documented. EBV-R induced a protective effect on RFS in multivariable analysis (HR 0.91,  = .011). Therefore, EBV-R may have a protective effect on RFS in this setting. Further research is necessary to evaluate the interplay of EBV-R, immune reconstitution, and post-transplant outcomes.
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http://dx.doi.org/10.1080/10428194.2020.1797010DOI Listing
December 2020

Pilot prospective study of Frailty and Functionality in routine clinical assessment in allogeneic hematopoietic cell transplantation.

Bone Marrow Transplant 2021 Jan 30;56(1):60-69. Epub 2020 Jun 30.

Department of Medicine, Section of Medical Oncology and Hematology, University of Toronto, Toronto, ON, Canada.

A Frailty and Functionality evaluation for alloHCT was implemented using existing resources. We describe the implementation of this evaluation across all ages and at first consultation, and correlate results with posttransplant outcomes in 168 patients. The evaluation consists of: Clinical Frailty Scale (CFS), Instrumental Activities of Daily Living (IADL), grip strength (GS), timed up and go test (TUGT), self-rated health question (SRH), Single question of Falls, albumin and C-Reactive Protein (CRP) levels. Median time to perform the evaluation was 5-6 min. Median age was 58 years (range: 19-77) and median follow-up was 5.3 months. TUGT > 10 s (HR 2.92; p = 0.003), raised CRP (HR 4.40; p < 0.001), and hypoalbuminemia (HR 2.10; p = 0.043) were significant risk factors for worse overal survival (OS). CFS ≥ 3 (HR 3.11; p = 0.009), TUGT > 10 s (HR 3.47; p = 0.003), GS (HR 2.56; p = 0.029), SRH ( 10 s and raised CRP were significant predictors for worse OS and NRM. SRH (
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http://dx.doi.org/10.1038/s41409-020-0979-1DOI Listing
January 2021

Less Is More: Superior Graft-versus-Host Disease-Free/Relapse-Free Survival with Reduced-Intensity Conditioning and Dual T Cell Depletion in Acute Myelogenous Leukemia.

Biol Blood Marrow Transplant 2020 08 16;26(8):1511-1519. Epub 2020 May 16.

Hans Messner Allogeneic Blood and Marrow Transplantation Program, Division of Medical Oncology and Hematology, Princess Margaret Cancer Centre, University Health Network, Toronto, Ontario, Canada; Hematology Department, Institut Català d'Oncologia-Hospitalet, IDIBELL, Barcelona, Spain.

In this study, we compared the outcomes of patients with acute myelogenous leukemia (AML) in complete remission treated with myeloablative conditioning (MAC) and those treated with reduced-intensity conditioning (RIC) before allogeneic hematopoietic stem cell transplantation (allo-HCT). In addition, we explored the efficacy of dual T cell depletion using anti-thymocyte globulin (ATG) and post-transplantation cyclophosphamide (PTCy) for the prevention of graft-versus-host disease (GVHD) in patients undergoing RIC allo-HCT. Our study cohort comprised 356 adults with AML in complete remission who underwent allo-HCT between 2013 and 2018. One hundred eleven patients (31.2%) received a MAC regimen, and 245 (68.8%) received an RIC regimen. One hundred seventy-one of the patients who received an RIC regimen (68.4%) received ATG, PTCy, and cyclosporine (ATG-PTCY-CsA) for GVHD prophylaxis in accordance with our institutional protocol. Data were collected retrospectively and updated in July 2019. With a median follow-up of 14.5 months (range, 0 to 76 months), 161 patients (45.2%) died, and 66 (18.5%) relapsed. Two-year overall survival (OS), relapse-free survival (RFS), and GVHD-free/RFS (GRFS) were 55%, 52.6%, and 35%, respectively. The intensity of the conditioning regimen, with or without ATG-PTCY-CsA, did not have a significant impact on OS and RFS. However, RIC in combination with ATG-PTCY-CsA was associated with a significantly lower cumulative incidence of acute GVHD and chronic GVHD. The use of RIC with ATG-PTCy-CsA was a significant predictor for higher GRFS secondary to the reduction of clinically relevant GVHD (P= .0001). In patients with AML, RIC allografts and dual T cell modulation with ATG and PTCy led to superior GRFS. The use of this GVHD prophylaxis strategy, along with mitigation of conditioning toxicity using RIC, may result in better long-term quality of life for allo-HCT recipients.
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http://dx.doi.org/10.1016/j.bbmt.2020.04.021DOI Listing
August 2020

Outcomes of therapy-related acute lymphoblastic leukemia in adults after allogeneic stem cell transplantation.

Eur J Haematol 2020 Jul 18;105(1):24-29. Epub 2020 Mar 18.

Hans Messner Allogeneic Blood and Marrow Transplantation Program, Princess Margaret Cancer Center, University of Toronto, Toronto, ON, Canada.

Introduction: Therapy-related acute lymphoblastic leukemia (t-ALL) is an increasingly recognized subset of therapy-related acute leukemia. There are limited data on the role of allogeneic hematopoietic stem cell transplantation (HSCT) in t-ALL. Recent reports suggest comparable outcomes of t-ALL with de novo ALL after HSCT.

Patients And Methods: We retrospectively reviewed all patients of t-ALL who underwent HSCT at our center. Patients were analyzed for prior malignancy, therapy, time to diagnosis of t-ALL, clinical, laboratory characteristics, transplant details, relapse-free survival (RFS), and overall survival (OS).

Results: Eighteen patients (M:F ratio 1:1; Median age 44 years) underwent HSCT for t-ALL. Median latent period from primary malignancy to t-ALL was 44.8 months. 11q23 rearrangement and t(9;22) were present in 33.3% and 22.2% patients, respectively. Stem cell donors were matched related, matched unrelated, and haploidentical in 27.8% (n = 5), 55.6% (n = 10), and 16.7% (n = 3) patients, respectively. Five patients died before D+ 100 (27.8%). Estimated 2-year RFS and OS were 47.1% and 51.8%, respectively. We did not find any pretransplant and post-transplant risk factors that were predictive of improved OS or RFS after multivariate analysis.

Conclusions: Allogeneic HSCT outcomes in t-ALL were comparable to HSCT outcomes in de novo ALL. Multicenter studies with more patients and longer follow-up may provide factors affecting outcome and survival.
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http://dx.doi.org/10.1111/ejh.13403DOI Listing
July 2020

Dual T-cell depletion with ATG and PTCy for peripheral blood reduced intensity conditioning allo-HSCT results in very low rates of GVHD.

Bone Marrow Transplant 2020 09 5;55(9):1773-1783. Epub 2020 Feb 5.

Messner Allogeneic Blood and Marrow Transplantation Program, Division of Medical Oncology and Hematology. Princes Margaret Cancer Centre, University Health Network, Toronto, ON, Canada.

The efficacy of posttransplant cyclophosphamide (PTCy) and antithymocyte globulin (ATG) in controlling GVHD has been previously reported. We aim to study the safety and efficacy of the use of dual T-cell depletion with ATG and PTCy for peripheral blood reduced intensity conditioning regimen allo-HSCT in 270 patients with hematological malignancies. Median follow-up was 12.7 months. Nineteen percent of patients received grafts from a matched related donor, 46% from 10/10 matched unrelated donors (MUD), 16% from 9/10 MUD and 19% from haploidentical donors. Graft failure rate was 9%. CMV and EBV reactivation rates were 58 and 64%. The cumulative incidence of grade II-IV and III-IV acute GVHD at day + 100 was 20.1% and 4.6%, respectively. The CI of moderate/severe chronic GVHD at 1 year was 12.4%. There were no differences in the incidence of GVHD according to donor type. One-year OS, RFS, NRM, CIR, and GVHD-free/RFS respectively were 65.2%, 56.9%, 22.7%, 20.3%, and 47.6%. Higher disease-risk index and worse Karnofsky performance status were significant factors for poor outcomes. In conclusion, the use of T-cell dual depletion with ATG and PTCy results in very low rates of acute and chronic GVHD and acceptable relapse rates and NRM.
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http://dx.doi.org/10.1038/s41409-020-0813-9DOI Listing
September 2020

Impact of CD34+ cell dose on reduced intensity conditioning regimen haploidentical hematopoietic stem cell transplantation.

Eur J Haematol 2020 Jan 6;104(1):36-45. Epub 2019 Oct 6.

Section of Medical Oncology and Hematology, Department of Internal Medicine, University of Toronto, ON, Canada.

Objectives: Haploidentical hematopoietic stem cell transplant (haplo-SCT) has been associated with higher rates of graft rejection, and a higher dose of CD34+ cell dose is frequently requested. We aim to explore the impact of CD34+ cell dose in peripheral blood stem cell (PBSC) grafts using reduced intensity conditioning (RIC) in haplo-SCT.

Methods: Sixty-eight consecutive haplo-SCT in adult patients were included. Graft-vs-host disease (GVHD) prophylaxis consisted on ATG, PTCy, and CsA. The cohort was divided in two groups using CD34+ dose of ≥ 9 × 10 CD34+/Kg as cutoff point. Median follow-up was 8.9 months.

Results: Median cell dose infused was 9.32 × 10 CD34+/Kg. Forty (58.8%) recipients received grafts with CD34+ cells ≥9 × 10 /kg. The infusion ≥ 9 × 10 CD34+/Kg cell dose had a negative impact in overall survival (P = .03) after adjusting for age at transplant. The cumulative incidence of acute GVHD and graft failure were not significantly influenced per CD34+ cell dose. Only four recipients had grade III aGVHD, and all of them received grafts with a CD34+ cell dose ≥ 9 × 10 .

Conclusion: In RIC haplo-SCT, recipients may not benefit from PBSC grafts with a CD34+/kg cell dose higher than 9 × 10 cells/kg, as it can have an adverse impact in post-transplant outcome.
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http://dx.doi.org/10.1111/ejh.13332DOI Listing
January 2020

Reduced-intensity conditioning allogeneic transplant with dual T-cell depletion in myelofibrosis.

Eur J Haematol 2019 Dec 30;103(6):597-606. Epub 2019 Sep 30.

Messner Allogeneic Blood and Marrow Transplantation Program, Division of Medical Oncology and Hematology, Princess Margaret Cancer Centre, University Health Network, Toronto, ON, Canada.

Background: There remains a significant mortality in recipients with MF who undergo allogeneic stem cell transplant (allo-HSCT). The combination of antithymocyte globulin (ATG) and post-transplant cyclophosphamide (PTCy) provides good control of graft-versus-host disease (GVHD) when peripheral blood stem cell grafts are used.

Methods: We report the outcome of 37 recipients with myelofibrosis who underwent reduced-intensity conditioning (RIC) allo-HSCT with ATG and PTCy. Median follow-up was 16.4 months.

Results: Nine (24.3%) recipients received 10/10 MRD grafts, 17 (45.9%) 10/10 MUD grafts, 4 (10.8%) 9/10 MUD grafts, and 7 (18.9%) haploidentical donor grafts. Six (16.3%) patients had graft failure. The cumulative incidence of grade II-IV and grade III-IV aGVHD at day +100 and moderate/severe chronic GVHD at 1 year was as follows: 13.5%, 5.4%, and 17%. There were no deaths secondary to GVHD. One-year overall survival (OS), relapse-free survival (RFS), non-relapse mortality (NRM), and GVHD-free/RFS (GRFS) were respectively 74.4%, 71.3%, 23%, and 43.3%. Those recipients who had worse KPS ≤ 80% had worse OS and RFS.

Conclusion: RIC allo-HSCT with ATG and PTCy results in high OS and RFS in patients with myelofibrosis and absence of mortality secondary to GVHD. Further investigations are required to reduce NRM and graft failure rates.
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http://dx.doi.org/10.1111/ejh.13327DOI Listing
December 2019

Reduced intensity allogeneic stem cell transplant with anti-thymocyte globulin and post-transplant cyclophosphamide in acute myeloid leukemia.

Eur J Haematol 2019 Nov 9;103(5):510-518. Epub 2019 Sep 9.

Messner Allogeneic Blood and Marrow Transplantation Program, Division of Medical Oncology and Hematology, Princess Margaret Cancer Centre, University Health Network, Toronto, ON, Canada.

Objectives: We aimed to study the efficacy of reduced intensity conditioning (RIC) allo-HSCT combined with anti-thymocyte globulin (ATG) and post-transplant cyclophosphamide (PTCy) for graft-versus-host disease (GVHD) prophylaxis in AML.

Methods: One hundred forty-seven patients were included. All patients underwent unmanipulated peripheral blood stem cell RIC allo-HSCT. Median follow-up was 12.8 months (range 0.5-39).

Results: Median age was 58 years. Twenty-nine (20%) recipients received 10/10 MRD grafts, 69 (47%) 10/10 MUD grafts, 20 (13.6%) 9/10 MMUD, and 29 (20%) haploidentical grafts. The cumulative incidence of grade II-IV and III-IV acute GVHD at day +100, and moderate/severe chronic GVHD at 1-year were as follow: 14.3%, 1.4%, and 8.3%. There were no significant differences according to donor type (P = .46) and cumulative incidence of GVHD. One-year overall survival (OS), relapse-free survival (RFS), non-relapse mortality, and GVHD-free/Relapse-free survival were as follows: 66.9% (95% CI 58.4-74), 59.9%, and 18.7% and 53.7%. KPS ≤ 80 was predictive of worst OS (P = .04). Those recipients who received MUD transplants had better RFS (P = .01).

Conclusions: RIC allo-HSCT combined with ATG and PTCy is safe and a potentially curative strategy and it is associated with impressive GRFS in AML.
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http://dx.doi.org/10.1111/ejh.13321DOI Listing
November 2019

Combination of the Centre for International Blood and Marrow Transplant Registry Risk Score and the Global Severity Score Enhances Prognostic Risk Stratification in Patients Receiving Frontline Therapy for Chronic Graft-versus-Host Disease.

Biol Blood Marrow Transplant 2019 09 4;25(9):1761-1769. Epub 2019 Jun 4.

Allogeneic Blood and Marrow Transplant Program, Princess Margaret Cancer Centre, University of Toronto, Toronto, Ontario, Canada. Electronic address:

The Centre for International Blood and Marrow Transplant Registry (CIBMTR) score has been shown to be prognostic for overall survival (OS) and nonrelapse mortality (NRM) but has been shown in several single-center studies to classify a large proportion of patients with chronic graft-versus-host disease (cGVHD) in the lower risk groups (RG1 to RG2), thereby limiting its prognostic utility for those patients. We evaluate the CIBMTR score, the Global Severity Score (GSS), and a novel risk score developed to improve on the limitations of the CIBMTR with respect to clinically relevant outcomes, including failure-free survival (FFS), in patients receiving frontline systemic treatment for cGVHD. We identified 277 patients between 2002 and 2012 at the Princess Margaret Cancer Centre in Toronto, Canada, who developed cGVHD and were treated with at least 1 line of systemic therapy. cGVHD was graded by GSS, and patients were stratified by CIBMTR. We evaluated OS, NRM, relapse, and FFS within GSS grade groups, as well as CIBMTR RGs, and used a novel prognostic risk score. The median FFS duration was 164 days in the severe GSS group versus 238 days in the moderate-grade group and 304 days in mild-grade group (P= .001). The median FFS duration was 501 days in CIBMTR RG1 versus 291 days in RG2 and 166 days in RG3 to RG6 (P = .003). A novel risk score combining the GSS and CIBMTR scores was prognostic of OS, NRM, and FFS and was able to subdivide patients with cGVHD in CIBMTR RG1 to RG2 into distinct prognostic risk categories. The CIBMTR risk score and the GSS are well correlated with FFS, OS, and NRM following frontline systemic treatment for cGVHD. A new risk score model combining the CIBMTR risk score and the GSS could enhance risk stratification in the lower CIBMTR risk groups.
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http://dx.doi.org/10.1016/j.bbmt.2019.05.029DOI Listing
September 2019

Vitamin D deficiency in adult patients with ulcerative colitis: Prevalence and relationship with disease severity, extent, and duration.

Indian J Gastroenterol 2019 Feb 13;38(1):6-14. Epub 2019 Mar 13.

Department of Gastroenterology, Postgraduate Institute of Medical Education and Research, Chandigarh, 160 012, India.

Background: Vitamin D plays a key role in gut immunity and maintenance of the mucosal barrier. Vitamin D deficiency (VDD) worsens ulcerative colitis (UC) and its supplementation ameliorates the disease in mouse models. The prevalence and predictors of VDD in UC are not known.

Methods: Consecutive patients with UC (n = 80) underwent clinical, endoscopic, and histological evaluation to assess the extent, severity using UC disease activity index (UCDAI) score, and duration of illness. An equal number of age and gender-matched healthy adults without any features of inflammatory bowel disease (IBD) living in the same latitude were identified as controls. The serum 25-hydroxy vitamin D level was estimated. The subjects were classified as deficient (< 20 ng/mL), insufficient (20-32 ng/mL), sufficient (32-80 ng/mL), and optimal (> 80 ng/mL) based on vitamin D levels. Chi-square test and Mann-Whitney U test were done to identify factors associated with vitamin D deficiency.

Results: The patients and controls were similar in age and gender (40 ± 11.4 years, 51% male vs. 40 ± 12 years, 51% male; p = 1.000). Median vitamin D levels among patients were lower than the controls (18.1 ng/mL [IQR 14] vs. 32.5 ng/mL [IQR 36]; p < 0.001). Patients were more often VDD (56% vs. 40%) or insufficient (34% vs. 9%) and less often sufficient (9% vs. 40%) or optimal (1% vs. 11%), in contrast to controls (p < 0.001). Median vitamin D levels were lower in those with UCDAI > 6 (15 vs. 21 ng/mL; p = 0.01), having pancolitis (13 vs. 21 ng/mL, p = 0.01), and longer duration of illness > 2 years (13.8 vs. 20.8; p = 0.025). Vitamin D levels showed a negative correlation with frequency of stools (rho = - 0.244, p = 0.05), disease duration (rho = - 0.244, p = 0.007) and UCDAI score (r = - 0.348, p = 0.002).

Conclusion: VDD is highly prevalent among patients with UC. Patients with longer disease duration, more severe symptoms, and pancolitis are likely to have lower vitamin D levels.
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http://dx.doi.org/10.1007/s12664-019-00932-zDOI Listing
February 2019

Sequential liver and haematopoietic stem cell transplantation in a case of fulminant hepatitis associated liver failure and aplastic anaemia.

Eur J Haematol 2019 Apr 15;102(4):375-377. Epub 2019 Feb 15.

Hans Messner Allogeneic Blood and Marrow Transplant Program, Princess Margaret Cancer Centre, Toronto, Ontario, Canada.

The management of severe aplastic anaemia is particularly challenging when it occurs in the context of recent liver transplantation. Rapid identification of a suitable donor followed by allogeneic haematopoietic stem cell transplantation is the only curative option. This scenario is often complicated by potentially life-threatening infections that develop as a consequence of immunosuppression. Alternative donor transplantation using suitably matched unrelated donors can be potentially life-saving when suitably matched sibling donors are unavailable. Above all, a dedicated interdisciplinary approach with seamless communication between hepatology, transplant surgery, haematology, and stem cell transplant services is essential to achieving optimal outcomes. Herein, we describe a case of severe hepatitis leading to hepatic failure who was treated with liver transplantation from a deceased donor, and later received an allogeneic haematopoietic stem cell transplantation from a matched unrelated donor for hepatitis-associated aplastic anaemia.
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http://dx.doi.org/10.1111/ejh.13213DOI Listing
April 2019

Reduced-Intensity Conditioning and Dual T Lymphocyte Suppression with Antithymocyte Globulin and Post-Transplant Cyclophosphamide as Graft-versus-Host Disease Prophylaxis in Haploidentical Hematopoietic Stem Cell Transplants for Hematological Malignancies.

Biol Blood Marrow Transplant 2018 11 7;24(11):2259-2264. Epub 2018 Aug 7.

Allogeneic Blood and Marrow Transplantation Program, Division of Medical Oncology and Hematology, Princess Margaret Cancer Centre, Toronto, Canada. Electronic address:

Haploidentical hematopoietic stem cell transplantation (haploHSCT) with conditioning regimens using post-transplant cyclophosphamide (PTCy) for peripheral blood stem cell (PBSC) grafts is limited by comparably higher rates of acute and chronic graft-versus-host disease (GVHD). Antithymocyte globulin (ATG) may mitigate this risk. We evaluated haploHSCT after reduced-intensity conditioning (RIC) with ATG, PTCy, and cyclosporine to prevent rejection and GVHD. Fifty adults underwent haploHSCT from August 2016 to February 2018. RIC included fludarabine (30 mg/m/day on days -5 to -2), busulfan (3.2 mg/m/day on days -3 and -2), and total body irradiation (200 cGy) on day -1. Unmanipulated PBSCs were infused on day 0. GVHD prophylaxis included ATG (4.5 mg/kg over days -3 to -1), PTCy (50 mg/kg/day on days +3 and +4), and cyclosporine from day +5. Median age was 56 years (range, 22 to 70 years); 25 (73.5%) patients were in first complete remission (CR1), 5 (14.7%) were in second complete remission (CR2), and 8 (23.5%) had active disease. Median time to neutrophil engraftment was 16 days (range, 8 to 43 days). At day +100, the cumulative incidence of acute GVHD of any grade, and grades III to IV was 38.3% and 5.2%, respectively. Mild chronic GVHD was seen in 15.5%. Cytomegalovirus (CMV) reactivation occurred in 37 (74%) cases and CMV disease occurred in 4 (11.5%) cases. Epstein-Barr virus (EBV) reactivation occurred in 21 (61.8%) patients. The incidence of histologically confirmed post-transplantation lymphoproliferative disorder (PTLD) was 5.8%. Four patients received rituximab. There were no CMV, EBV, or PTLD-related deaths. Six-month and 1-year overall survival (OS), cumulative incidence of relapse (CIR), and nonrelapse mortality (NRM) were 73.9%, 10.2%, and 19.4%, respectively, and 48.1%, 16% and 38.2%, respectively. Infection was the most common cause of death (18%). Unmanipulated haploidentical PBSC transplantation following RIC with ATG, PTCy, and cyclosporine as a GVHD prevention strategy results in low rates of acute and chronic GVHD.
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http://dx.doi.org/10.1016/j.bbmt.2018.07.008DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7110605PMC
November 2018

A phase I trial of NK-92 cells for refractory hematological malignancies relapsing after autologous hematopoietic cell transplantation shows safety and evidence of efficacy.

Oncotarget 2017 Oct 12;8(51):89256-89268. Epub 2017 Jul 12.

Cell Therapy Program, Princess Margaret Cancer Centre, Toronto, ON, Canada.

Background: Autologous NK cell therapy can treat a variety of malignancies, but is limited by patient-specific variations in potency and cell number expansion. In contrast, allogeneic NK cell lines can overcome many of these limitations. Cells from the permanent NK-92 line are constitutively activated, lack inhibitory receptors and appear to be safe based on two prior phase I trials.

Materials And Methods: We conducted a single-center, non-randomized, non-blinded, open-label, Phase I dose-escalation trial of irradiated NK-92 cells in adults with refractory hematological malignancies who relapsed after autologous hematopoietic cell transplantation (AHCT). The objectives were to determine safety, feasibility and evidence of activity. Patients were treated at one of three dose levels (1 × 10 cells/m, 3 × 10 cells/m and 5 × 10 cells/m), given on day 1, 3 and 5 for a planned total of six monthly cycles.

Results: Twelve patients with lymphoma or multiple myeloma who relapsed after AHCT for relapsed/refractory disease were enrolled in this trial. The treatment was well tolerated, with minor toxicities restricted to acute infusional events, including fever, chills, nausea and fatigue. Two patients achieved a complete response (Hodgkin lymphoma and multiple myeloma), two patients had minor responses and one had clinical improvement on the trial.

Conclusions: Irradiated NK-92 cells can be administered at very high doses with minimal toxicity in patients with refractory blood cancers, who had relapsed after AHCT. We conclude that high dose NK-92 therapy is safe, shows some evidence of efficacy in patients with refractory blood cancers and warrants further clinical investigation.
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http://dx.doi.org/10.18632/oncotarget.19204DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5687687PMC
October 2017

L-PROBe: A Novel Non-anthracycline Combination Chemotherapy Regimen for Aggressive B Cell Non-Hodgkin Lymphoma in Elderly Patients.

Indian J Hematol Blood Transfus 2017 Mar 6;33(1):61-68. Epub 2016 Feb 6.

Department of Internal Medicine, Postgraduate Institute of Medical Education and Research, Chandigarh, India.

The management of aggressive B cell lymphomas in elderly patients is associated with poor tolerability of commonly used chemotherapeutic agents. The safety and tolerability of a novel combination chemotherapy regimen utilizing rituximab, lenalidomide, bendamustine, vincristine and prednisolone was assessed in a series of elderly patients with new onset or relapsed/refractory aggressive B cell lymphoma and inability to receive conventional chemotherapy due to poor performance status and/or significant comorbidities. Ten patients (7 male, 3 female) with a median age of 72 years (range 58-79 years) received therapy with lenalidomide (10 mg/day on days 1-14), rituximab (375 mg/m on day 1), bendamustine (90 mg/m on days 1 and 2), vincristine (1.4 mg/m on day 1) and prednisolone (60 mg/m/day on days 1-5) with cycles repeated every 28 days. Grade 3/4 hematological toxicities included neutropenia (30 %), anemia (30 %) and thrombocytopenia (10 %). An overall response rate of 40 % was observed with a median survival of 120 days (range 14-286 days). Three of the patients who responded achieved complete remission at the end of six cycles of therapy. This combination chemotherapy appears to be well tolerated and effective in elderly patients with poor performance status. Larger controlled studies are indicated to clearly demonstrate applicability of this novel regimen.
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http://dx.doi.org/10.1007/s12288-016-0655-1DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5280848PMC
March 2017

Reply to letter to the editor.

Leuk Lymphoma 2017 05 29;58(5):1273-1274. Epub 2016 Sep 29.

a Princess Margaret Cancer Centre, Division of Medical Oncology and Hematology , University Health Network, University of Toronto , Toronto , Ontario , Canada.

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http://dx.doi.org/10.1080/10428194.2016.1233544DOI Listing
May 2017

Hypereosinophilia in a Young Patient: Occam's Razor or Hickam's Dictum?

Indian J Hematol Blood Transfus 2016 Jun 24;32(Suppl 1):340-3. Epub 2014 Dec 24.

Department of Internal Medicine, Postgraduate Institute of Medical Education and Research, Chandigarh, 160012 India.

Hypereosinophilia is an uncommon clinical problem encountered in hematology practice. While most of such cases are secondary or reactive, a significant fraction of cases are due to clonal myeloproliferative disorders. We report a young patient who presented with marked hypereosinophilia and was investigated extensively for its cause. Finally a common tropical infection was responsible for such marked eosinophilia fulfilling the principle of Occam's razor. The case emphasizes the need to search for treatable reactive causes even in presence of marked hypereosinophilia in a tropical country.
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http://dx.doi.org/10.1007/s12288-014-0487-9DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4925477PMC
June 2016

"Unusual Cause Of Tophi With Renal Thrombotic Microangiopathy".

Indian J Hematol Blood Transfus 2016 Jun 16;32(Suppl 1):100-3. Epub 2015 Apr 16.

Department of Internal Medicine, Postgraduate Institute of Medical Education and Research, Chandigarh, 160012 India.

Chronic neutrophilic leukemia (CNL) is a rare entity amongst myeloproliferative neoplasms (MPNs). The classical presentation of CNL is with splenomegaly, mature neutrophilic leucocytosis and hyperuricemia. We herein report a case who presented with symptoms of acute gouty arthritis. Physical examination showed typical red, tender tophi in the right hand, right foot and both pinnae suggesting an acute episode of gout. During evaluation, moderate splenomegaly, mature neutrophilia, hyperuricemia and sub-nephrotic range range proteinuria were noted. Bone marrow examination and kidney biopsy was done. Final diagnosis of CNL with acute gouty arthritis and chronic renal thrombotic microangiopathy (TMA) was made. Although hyperuricemia is a common finding in MPNs but presentation of our case with symptoms of acute tophi and chronic TMA is atypical.
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http://dx.doi.org/10.1007/s12288-015-0539-9DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4925503PMC
June 2016

Fanconi Syndrome: A Rare Initial Presentation of Acute Lymphoblastic Leukemia.

Indian J Hematol Blood Transfus 2016 Jun 27;32(Suppl 1):5-7. Epub 2014 Dec 27.

Department of Internal Medicine, Postgraduate Institute of Medical Education and Research, Chandigarh, 160012 India.

A-14-year old boy, presented with a short history of excessive thirst and increased urine output. Clinical examination showed pallor, generalized lymphadenopathy and hepatosplenomegaly. For evaluation of his polyuric state he underwent routine laboratory investigations, including renal function test, acid-base studies, urine analysis. Blood tests suggested hypokalemia, hypouricemia, hypocalcemia and hyperchloremia with normal liver and kidney function tests. The arterial blood gas analysis was suggestive of normal anion gap metabolic acidosis. Urine analysis was suggestive of hyperuricosuria, hypercalciuria and glycosuria with a positive urine anion gap. His hemogram showed pancytopenia with differential count showing 88% blasts. Bone marrow examination and flowcytometry confirmed the diagnosis of B cell acute lymphoblastic leukemia. Hence this case was atypical and very interesting in the sense that the Fanconi syndrome is very rare to be an initial presenting feature of acute lymphoblastic leukemia. The patient was started on oral as well intravenous supplementation with potassium, bicarbonate, calcium and phosphorus. Simultaneously, as per the modified BFM -90 protocol (four drug based regimen-Prednisolone, vincristine, daunorubicin, cyclophosphamide along with l-asparaginase), he was started on induction protocol. By the end of 3rd week of induction therapy, his urine output started normalizing and finally settled at the end of induction therapy. At present he is in the maintenance phase of chemotherapy.
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http://dx.doi.org/10.1007/s12288-014-0489-7DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4925478PMC
June 2016

Pregnancy: part of life in chronic myelogenous leukemia.

Leuk Lymphoma 2017 02 7;58(2):280-287. Epub 2016 Jul 7.

c Princess Margaret Cancer Centre, Division of Medical Oncology and Hematology , University Health Network, University of Toronto , Toronto , ON , Canada.

Management of pregnant patients with chronic myelogenous leukemia (CML) is challenging. Some of the factors that need to be considered include stage of pregnancy, disease status, and degree of drug exposure. Managing a patient who has been diagnosed while pregnant requires a different approach as compared with a patient who becomes pregnant while on the treatment with a tyrosine kinase inhibitor (TKI). Younger patients may wish to conceive while on treatment and need a more personalized treatment plan based on the degree and duration of their molecular status. Leukapheresis and interferon are useful options in this situation due to teratogenic potential of TKIs. We present a series of clinical vignettes describing our approach to different scenarios and the management options employed in each case. Despite the era of TKIs and their undoubted efficacy and safety, situations such as these require an individualized and multidisciplinary approach to management.
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http://dx.doi.org/10.1080/10428194.2016.1201571DOI Listing
February 2017

Myeloid Sarcoma: An Unusual Case of Mediastinal Mass and Malignant Pleural Effusion with Review of Literature.

Indian J Hematol Blood Transfus 2015 Dec 1;31(4):466-71. Epub 2015 Apr 1.

Department of Internal Medicine, Postgraduate Institute of Medical Education and Research, Chandigarh, 160012 India.

Myeloid sarcoma is an extramedullary tumor seen most commonly in patients with acute myeloid leukemia and less frequently in chronic myeloid leukemia, myelodysplastic syndrome and rarely, in an isolated form without any other underlying malignancy. Malignant pleural effusion in hematological malignancies is rare when compared with solid tumors. We present an unusual case of myeloid sarcoma in which a mediastinal mass with pleural effusion was the initial presentation. A 27 year old gentleman presented with complaints of fever, chest pain and swelling in the anterior chest wall for 6 months. Examination revealed a lump measuring 5 × 5 cm on the left side of the chest wall. Hematological evaluation showed hemoglobin-14.2 g/dL, platelet count-233 × 10(9)/L, TLC-117 × 10(6)/L with normal differential counts. Contrast enhanced computerised tomography (CECT) confirmed the presence of a soft tissue mass in the superior mediastinum abutting against the chest wall. Core biopsy was suggestive of myeloid sarcoma and immunohistochemistry was positive for myeloperoxidase and negative for CD3, CD 20 and CD 23. Pleural fluid analysis showed the presence of malignant cells. Bone marrow examination did not show an excess of blasts. A final diagnosis of extramedullary myeloid sarcoma with malignant pleural effusion was made. The patient was given induction chemotherapy (3 + 7 regimen) with daunorubicin and cytosine arabinoside. Repeat CECT done on day 28 showed complete resolution of pleural effusion and significant reduction in the size of mediastinal mass. The patient has successfully completed three cycles of consolidation therapy following which there has been complete resolution of the mass. He remains asymptomatic on close follow up.
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http://dx.doi.org/10.1007/s12288-015-0536-zDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4542764PMC
December 2015

Management of hypereosinophilia in tropical settings.

Med J Armed Forces India 2015 Jan 25;71(1):60-6. Epub 2014 Dec 25.

Professor & Head, Department of Internal Medicine, Postgraduate Institute of Medical Education and Research, Chandigarh, India.

Hypereosinophilia includes a group of commonly encountered clinical situations with symptoms ranging from mild and clinically innocuous to devastating presentations with high morbidity and mortality. The presentations and complications can be easily missed if the clinician is unaware of the diverse entities responsible for hypereosinophilia. The hypereosinophilic syndromes encompass entities that are associated with varying degrees of organ dysfunction either directly due to eosinophilic infiltration or as a result of substances secreted by the eosinophils. These conditions may be neoplastic or reactive in aetiology and a diligent search for secondary causes is essential. Evaluation and management algorithms in the tropical setting and in developing countries may differ from elsewhere. A review of hypereosinophilia and hypereosinophilic syndromes is presented with a diagnostic and therapeutic decision making algorithm modified for use in the tropical setting.
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http://dx.doi.org/10.1016/j.mjafi.2014.11.008DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4297847PMC
January 2015

Eosinophilic vasculitis: time for recognition of a new entity?

Indian J Hematol Blood Transfus 2014 Sep 16;30(Suppl 1):325-30. Epub 2014 Apr 16.

Department of Internal Medicine, Postgraduate Institute of Medical Education and Research (PGIMER), Chandigarh, 160 012 India.

Hypereosinophilia is part of a group of complex disorders with multisystem involvement. A 23 year old male was admitted to our centre with bilateral popliteal artery and venous thrombosis and impending gangrene of the left forefoot along with deep venous thrombosis of the right lower extremity. Investigations revealed marked peripheral blood eosinophilia (27,669/μL). Bone marrow showed increased eosinophils & eosinophil precursors and no evidence of a clonal disorder. Skin biopsy from the ulcerated lesions showed small vessel vasculitis with intense eosinophilic infiltration. Investigations to look for secondary causes of hypereosinophilia in the form of Antinuclear Antibody, P-Anti Neutrophil Cytoplasmic Antibody (ANCA) and C-ANCA and FIP1L1-PDGFRA, Bcr-Abl and JAK2V617F mutations were negative. The arterial and venous thrombosis and cutaneous vasculitis were linked to the presence of hypereosinophilic syndrome. The patient's illness responded to high dose corticosteroids leading to complete resolution of symptoms. We reviewed the literature on the lesser known entity of eosinophilic vasculitis and its association with thrombosis.
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http://dx.doi.org/10.1007/s12288-014-0384-2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4192264PMC
September 2014

Indian common krait envenomation presenting as coma and hypertension: A case report and literature review.

J Emerg Trauma Shock 2014 Apr;7(2):126-8

Department of Internal Medicine, PGIMER, Chandigarh, India.

Neuroparalytic snake bite is a common emergency situation encountered in India. Common krait (Bungarus caeruleus) and cobra (Naja naja) are important snakes causing neuroparalysis in North India. Despite severe neuroparalysis, patients who receive antivenin and ventilator support in time recover completely. Autonomic disturbances resulting in resting tachycardia, labile hypertension and sweating have been described in common krait envenomation. We present a case of common krait (B. caeruleus) envenomation presenting in the locked-in state and severe hypertension that remained in such a state for over 96 h before a gradual and sustained recovery.
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http://dx.doi.org/10.4103/0974-2700.130887DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4013730PMC
April 2014