Santhosh Thyagu

Treatment of Philadelphia chromosome-positive acute lymphoblastic leukaemia with imatinib combined with a paediatric-based protocol.

Although the combination of tyrosine kinase inhibitors with chemotherapy is widely used for young adults with Philadelphia chromosome positive‐acute lymphoblastic leukaemia (Ph+ ALL), the outcome and safety of this combination using intensive paediatric‐based protocols has not been well described. The clinical course of 32 adults age 18–60 years with Ph+ ALL treated with a paediatric‐based protocol plus imatinib was evaluated. The complete response rate was 94%. Grade 3–4 infections, neuropathy, myopathy and liver function abnormalities were common, resulting in major treatment delays and dose reductions, and declines in performance status (physical deconditioning), particularly in patients aged 41–60 years. Median and 3‐year overall survival (OS) was 40·7 months and 53%, respectively, and median and 3‐year even‐free survival (EFS) was 30·1 months and 50%, respectively. OS and EFS were inferior in deconditioned patients. Of 16 patients who underwent haematopoietic stem cell transplantation (HSCT) in first complete remission, six died of non‐relapse complications. There was no significant difference in OS and EFS between transplanted and non‐transplanted patients, based on an intention‐to‐treat and time‐to‐donor identification analysis. The combination of imatinib with a paediatric‐based regimen in adults produced high response rates, but was associated with considerable toxicity and high non‐relapse mortality post‐HSCT.

Quality of life following completion of treatment for adult acute lymphoblastic leukemia with a pediatric-based protocol

Using multiple validated self-report instruments, we evaluated the health-related quality of life (HRQoL) of 29 adult ALL patients a median of 28 months after completing a pediatric-based treatment regimen. Global health was similar to normative data, but leukemia survivors had lower cognitive and social function, and reported more financial difficulty. Fatigue and pain affected 83% and 53% of patients, respectively, and both showed significant inverse correlation with overall health and all functional scales. Vincristine-related peripheral neuropathy was reported by 43%. Although therapy-related symptoms were persistent, long-term ALL survivors have a global HRQoL similar to the general population.

Efficacy of Cidofovir in Treatment of BK Virus–Induced Hemorrhagic Cystitis in Allogeneic Hematopoietic Cell Transplant Recipients

BK virus-associated hemorrhagic cystitis (BK-HC) is a common complication after allogeneic hematopoietic stem cell transplantation (allo-HCT), with incidences up to 70%. Cidofovir is an antiviral agent with growing evidence as a therapeutic intervention. To assess the safety profile and efficacy of intravenous and intravesical cidofovir in allo-HCT patients with BK-HC, a retrospective study was undertaken of the allo-HCT cohort who received cidofovir for symptomatic BK-HC (hematuria with BK viruria or viremia) from January 2010 until March 2017 in a single transplant center in Ontario, Canada. The primary outcome measure was a reduction in BK-HC severity (graded from 1 to 4); secondary outcomes included overall survival, BK virus titers, and the onset of acute kidney injury. Twelve allo-HCT patients received cidofovir for BK-HC, with pretreatment clinical severity of 3 (50%) or 4 (50%). Cidofovir was administered via intravenous (33%), intravesical (58%), or both modalities (8%). After a median cumulative dose of 10 mg/kg (range, 1 to 37), mean BK-HC grade decreased significantly by 1.8 (3.5 precidofovir, 1.7 postcidofovir, P < .01). Sixty-six percent of patients had at least partial response to cidofovir, with similar response rates between intravenous (66%) and intravesical (62%) administration. Sixty-seven percent of patients died, and 33% of patients experienced renal toxicity, including 2 patients receiving intravesical therapy. In this retrospective series, there was a significant reduction in BK-HC severity after cidofovir administration; most patients achieved at least partial response after cidofovir administration. Even with intravesical instillation, acute kidney injury remains a potential complication of cidofovir. Although cidofovir may be an efficacious therapy for BK-HC, albeit with potential demonstrated toxicities, further prospective trials are needed.

Outcome following second allogeneic hematopoietic cell transplantation: A single-center experience

Second allogeneic hematopoietic cell transplantation (HCT) may be indicated following relapse or graft failure following first HCT. Our retrospective single‐center study sought to investigate parameters that influence post‐second allogeneic HCT survival.

Reduction of severe acute graft-versus-host disease using a combination of pre transplant anti-thymocyte globulin and post-transplant cyclophosphamide in matched unrelated donor transplantation

Use of Post-transplant Cyclophosphamide (PTCy) has recently been introduced specifically in the haplo-identical transplant setting with promising results [1]. This intervention has also shown a significant reduction of acute graft versus host disease (aGVHD) and a trend towards improving chronic graft versus host disease (cGVHD) [2]. The efficacy of PTCy has mainly been demonstrated in patients with bone marrow (BM) as the stem cell source [3]; and has been associated with clinically significant acute and chronic GVHD in patients with peripheral blood as the stem cell source (PBSC) [4]. Anti-thymocyte globulin (ATG) has previously been shown to reduce the incidence of cGVHD at around 1 year post transplantation [5], without increasing the incidence of relapse [6]. The incidence of Gr III-IV aGVHD was 28% using ATG, cyclosporine and mycophenolate mofetil (ATG-CSA-MF), as the GVHD prophylaxis regimen, in the recently concluded randomized trial [7]. We hypothesized that a combination of both ATG and PTCy would reduce the incidence of both acute and chronic GVHD in our patient cohort; effectively reducing the morbidity and mortality associated with severe forms of GVHD. Here we present the preliminary outcome in our unrelated patients using this regimen. This is a retrospective study of the patient cohort treated from 1 October 2015 until 31 March 2016 in a single center. This study was approved by the institutional Research Ethics Board. This study cohort was compared to the earlier historical study cohort of patients who received pre transplant ATG as part of GVHD prophylaxis at our center [7]. Patients received transplant from HLAMatched (10/10) or mismatched (9/10) unrelated donors. The graft source was Filgrastim stimulated PBSC. The treatment schema initially for ages<60 years was a myeloablative regimen using the FBT400 protocol and for ages>60 years consisted of FBT200 as the reduced intensity conditioning (RIC) regimen [8]. The FBT400 regimen consisted of a combination of Fludarabine (50 mg/m2 on days −5,−4,−3,−2), Busulphan (once daily dose of 3.2 mg/kg on days −5,−4,−3,−2) along with 2 doses of total body irradiation (TBI) of 200 cGy on Day −1. The regimen of FBT200 comprised of reduced dose of Fludarabine at 30 mg/m2 on same days but with only 2 days of Busulphan (on days −2,−1) and only one dose of 200 cGy TBI on day −1 [9]. We subsequently decided to use FBT200 for all patients in view of increased liver and kidney toxicities observed with FBT400 regimen with post-transplant cyclophosphamide. The GVHD prophylaxis consisted of ATG (rabbit, Thymoglobulin; Genzyme-Sanofi, Lyon, France) on days −3, −2 and −1 with a total dose of 4.5 mg/kg. Patients additionally received 50 mg/kg/day IV cyclophosphamide on days +3 and +4 (PTCy), with the first dose starting 72 h after PBSC infusion. This was further followed by post transplant administration of IV cyclosporine (2.5 mg/kg twice daily) on day+ 5 onwards, with change to oral route when the patient was able to tolerate orally. Presented in part at the 58th American Society of Hematology Annual Meeting in San Diego, California, 2–6 December 2016 and at the American Society of Blood and Marrow Transplantation meeting at Orlando, Florida, 22–26 February 2017.

Incidence and Risk Factors for Nontuberculous Mycobacterial Infection after Allogeneic Hematopoietic Cell Transplantation

Allogenic hematopoietic stem cell transplant (HCT) recipients are at risk of many infections. Nontuberculous mycobacteria (NTM) are increasingly recognized as clinically significant pathogens in this population. We investigated the incidence and risk factors for NTM infection after allogeneic HCT. This retrospective cohort study included all patients with allogeneic HCT at our institution during 2001 to 2013. Patients who developed significant NTM infection (NTM disease) were identified. Multivariable modeling was used to identify risk factors for NTM disease, and a risk score model was constructed to identify high-risk patients. Of 1097 allogeneic HCT patients, 45 (4.1%) had NTM isolated and 30 (2.7%) had NTM disease (28 [93.3%] exclusively pulmonary, 2 [6.7%] pulmonary plus another site). Incidence of NTM infection by competing risk analysis was 2.8% at 5 years (95% CI, 1.9% to 4.0%). The median time to diagnosis was 343 days (range, 19 to 1967). In Fine-Gray proportional hazards modeling, only global severity of chronic graft-versus-host disease (cGVHD) (HR, 1.99; 95% CI, 1.12 to 3.53; P = .019,) and cytomegalovirus (CMV) viremia (HR, 5.77; 95% CI, 1.71 to 19.45; P = .004) were significantly associated with NTM disease. Using these variables a risk score was calculated: 1 point for CMV viremia or moderate cGVHD and 2 points for severe cGVHD. The score divided patients into low risk (0 to 1 points, n = 820 [77.3%], 3-year NTM risk 1.2%), intermediate risk (2 points, n = 161 [15.4%], 3-year NTM risk 7.1%), and high risk (3 points, n = 56 [5.4%], 3-year NTM risk 14.3%). NTM disease after allogeneic HCT is common. Severe cGVHD and CMV viremia are associated with increased risk, permitting risk stratification.

Extramedullary disease at diagnosis of AML does not influence outcome of patients undergoing allogeneic hematopoietic cell transplant in CR1

Extramedullary disease (EMD) at diagnosis of acute myeloid leukemia (AML) has been associated with increased risk of relapse and worse outcomes post‐chemotherapy. This study sought to investigate the association of EMD with outcomes following allogeneic hematopoietic cell transplantation (allo‐HCT).

Prolonged granulocyte colony stimulating factor use in glycogen storage disease type 1b associated with acute myeloid leukemia and with shortened telomere length

ABSTRACT Glycogen storage disease (GSD) type 1 is a rare autosomal recessive inherited condition. The 1b subtype comprises the minority of cases, with an estimated prevalence of 1 in 500,000 children. Patients with glycogen storage disease type 1b are often treated with granulocyte colony stimulating factor (G-CSF) for prolonged periods to improve symptoms of inflammatory bowel disease (IBD) and in the face of severe neutropenia to decrease risk of infection. Long-term G-CSF treatment may result in an increased risk of myelodysplastic syndrome (MDS) or acute myeloid leukemia (AML) possibly due to increased marrow stress resulting in telomere shortening. To our knowledge, there have been two published cases of AML in GSD type 1b patients following long-term G-CSF exposure. Here, we report two further cases of AML/MDS-related changes in patients GSD type 1b treated with G-CSF. One patient developed AML with complex karyotype after 20 years of G-CSF treatment. The second patient was found to have short telomeres after 10 years of G-CSF exposure, but no evidence of acute leukemia at present. The third patient developed AML/MDS after 25 years of G-CSF use, with short telomeres prior to bone marrow transplant. Together these cases suggest that GSD type 1b patients with prolonged G-CSF exposure may be at an increased risk of MDS/AML states associated with G-CSF-induced shortened telomeres. We recommend that any GSD1b patients with prolonged G-CSF should have routine telomere assessments with monitoring for MDS if telomere shortening is observed, and with particular attention warranted if there is unexplained loss of G-CSF responsiveness.

Characteristics, treatment and outcomes of nontuberculous mycobacterial pulmonary disease after allogeneic haematopoietic stem cell transplant

Allogeneic haematopoietic stem cell transplant (alloHCT) recipients are at risk for a variety of opportunistic infections. While typical bacterial infections occur most frequently, nontuberculous mycobacteria (NTM) are becoming increasingly recognised as pathogens after alloHCT [1]. The prevalence of NTM pulmonary disease (NTM-PD) is increasing worldwide, with a rise in Ontarios period prevalence from 29.3 per 100 000 in 1998–2002 to 41.3 per 100 000 in 2006–2010 [2]. Likewise, the incidence of NTM-PD post alloHCT increased from 0.11–0.23% [3, 4] in early studies to 2.7–3.15% in recent investigations [5, 6]. Despite the incidence of NTM-PD after alloHCT being far higher than in the general population [6], there are few reports addressing management and treatment outcomes of NTM-PD after alloHCT. We reviewed the experience with NTM-PD among alloHCT recipients at our institution to better characterise clinical features and treatment outcomes. Nontuberculous mycobacterial pulmonary disease in allogeneic haematopoietic stem cell transplant recipients http://ow.ly/5epj30j6bfy

Therapeutic efficacy of azathioprine in addition to prednisone-based regimens as first-line chronic graft-versus-host disease treatment

Chronic graft-versus-host disease (cGVHD) is a major complication of allogeneic hematopoietic stem cell transplantation (allo-HCT) that is related to higher mortality and morbidity [1, 2]. Glucocorticoids has been the mainstay of the treatment for cGVHD, while it also has been widely used to treat the variety of autoimmune diseases as the combination with other immunosuppressive agents including azathioprine (AZP) to reduce long-term complications of glucocorticoids such as diabetes mellitus, iatrogenic Cushing’s syndrome, avascular necrosis of joints and osteoporosis, etc. [3–6]. Although a previous clinical trial suggested that prednisone (PRD) based regimen plus AZP (PRD+AZP) resulted in worse survival than PRD-based regimen in a standard risk group of cGVHD patients due to higher nonrelapse (infection-related) mortality (NRM) [7], the therapeutic efficacy of AZP might deserve to be looked at again because there have been advances in the allo-HCT field for over the last decades, including significant improvement in supportive care such as infectious prophylaxis and treatment, as well as in evaluating cGVHD systematically. The National Institutes of Health (NIH) first proposed consensus criteria for the diagnosis of cGVHD, and tools for scoring cGVHD organ involvement and assessing overall severity in 2005, which are now widely used in clinical practice [8, 9]. In addition, a new statistical endpoint for evaluating the efficacy of cGVHD treatment, i.e. failure free survival (FFS), has been introduced and suggested to be a potential surrogate of overall survival (OS) for cGVHD treatment [10, 11]. Therefore, we retrospectively reviewed 668 consecutive patients who underwent allo-HCT between 2004 and 2012 at Princess Margaret Cancer Centre, Toronto, Canada in order to compare the efficacy of PRD+AZP and PRD-based regimens with respect to FFS as well as OS, NRM, and the incidence of relapse. Chronic GVHD was defined, reclassified and graded by the NIH consensus criteria [8]. Among 313 patients with redefined cGVHD, we then identified 240 patients who received PRD or PRD+AZP as first line treatment for cGVHD. Late onset acute GVHD was excluded from the analysis. The FFS was defined as time from the initiation of frontline treatment for cGVHD to treatment failure (TF), NRM or relapse of disease. TF was defined as initiation of the next line of IST for cGVHD [11] or an escalation of the dose of PRD to ≥1 mg/kg/day regardless of the target organ. OS and FFS were calculated by the Kaplan–Meier method and compared using the log rank test. The cumulative incidences of NRM, disease relapse, and the TF rate (TFR) for front line cGVHD treatment were estimated considering competing risks, with disease relapse, NRM and TFR considered as mutually-competing risks. The transplant-related characteristics were analyzed to compare the PRD and PRD+AZP groups using Pearson’s Χ or Fisher’s exact test. The univariate and multivariate analyses performed to compare OS, NRM, relapse incidence, and FFS between two treatment groups. OS and FFS were compared using the log rank test. Univariate analyses for incidence with competing risks were performed by Gray’s method. Cox proportional hazard regression model was used for multivariate analysis of survivals. Since the characteristics of cGVHD of two treatment groups were imbalanced (Table 1), we performed a propensity score matching (PSM) analysis as a case-control study in order to adjust the potential confounding effects of the clinical features of cGVHD on treatment outcome. The * Dennis (Dong hwan) Kim dr.dennis.kim@uhn.ca