Search

This is a consensus-based Canadian guideline whose primary purpose is to standardize and facilitate the management of chronic graft-versus-host disease (cGvHD) across the country. Creating uniform healthcare guidance in Canada is a challenge for a number of reasons including the differences in healthcare authority structure, funding and access to healthcare resources between provinces and territories, as well as the geographic size. These differences can lead to variable and unequal access to effective therapies for GvHD. This document will provide comprehensive and practical guidance that can be applied across Canada by healthcare professionals caring for patients with cGvHD. Hopefully, this guideline, based on input from GvHD treaters across the country, will aid in standardizing cGvHD care and facilitate access to much-needed novel therapies. This consensus paper aims to discuss the optimal approach to the initial assessment of cGvHD, review the severity scoring and global grading system, discuss systemic and topical treatments, as well as supportive therapies, and propose a therapeutic algorithm for frontline and subsequent lines of cGvHD treatment in adults and pediatric patients. Finally, we will make suggestions about the future direction of cGvHD treatment development such as (1) a mode-of-action-based cGvHD drug selection, according to the pathogenesis of cGvHD, (2) a combination strategy with the introduction of newer targeted drugs, (3) a steroid-free regimen, particularly for front line therapy for cGvHD treatment, and (4) a pre-emptive approach which can prevent the progression of cGvHD in high-risk patients destined to develop severe and highly morbid forms of cGvHD. [ABSTRACT FROM AUTHOR]

Introduction: Pneumocystis jirovecii pneumonia (PJP) is a rare complication of hematopoietic stem cell transplantation (HSCT). Primary prophylaxis for 6–12 months post‐HSCT is the standard approach. However, there is no consensus regarding the optimal duration of prophylaxis. Methods: We identified patients who developed PJP more than 1‐year post‐HSCT. All patients had previously received 12 months of PJP prophylaxis. PJP was diagnosed based on clinical findings and the detection of P. jirovecii in bronchoalveolar lavage (BAL) using polymerase chain reaction (PCR). The CD4+ T‐cell percentage was determined using flow cytometry. Data expressed as median (interquartile range). Results: Ten patients developed PJP at 17.5 months (16–24 months) post‐HSCT. PJP diagnosis occurred 5.5 months (3–15 months) after discontinuing prophylaxis. Eight patients received anti‐thymocyte globulin (ATG) as graft versus host disease (GVHD) prophylaxis. At diagnosis, only one patient had lymphopenia; all patients had CD4+ T‐lymphocyte counts ≥0.2 × 109/L (median 0.337 × 109/L). Three patients had concomitant bacterial infections. The clinical presentation was mild; only three required hospitalization, none of them required intensive care and there were no deaths. Conclusion: There is a need to develop risk‐adapted prophylactic strategies in the contemporary era using ATG‐based GVHD prophylaxis. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

Objectives: Hepatic grading systems for categorizing severity in chronic graft‐versus‐host disease (cGvHD) were determined arbitrarily, leading us to initiate the present study to provide objective evidence for the determination of optimal cutoff values and devise a hepatic grading system to predict prognosis. Methods: Of 842 patients who received allogeneic hematopoietic stem transplant (HCT), 336 patients diagnosed with cGvHD were evaluated for overall survival (OS) and non‐relapse mortality (NRM) after cGVHD development. Multiple statistical parameters were evaluated to define optimal cutoff values of liver profile, including negative predictive value (NPV), positive predictive value (PPV), accuracy, and p‐values as measures of risk stratification power. Results: We found that alkaline phosphatase (ALP) ≥ 146 IU/L (NPV: 83.4%; PPV: 32.8%; accuracy: 52.7%) and bilirubin ≥ 14 µmol/L (NPV: 81.8%; PPV: 39.4%; accuracy 68.1%) significantly correlated with OS. We developed a refined hepatic cGvHD grading score (RHS), stratifying patients into a low‐RHS group with RHS score 0, OS at 3 years (n = 162) to 80.5%, compared to high‐RHS group with score 1‐2 (n = 172) 62.7%. Regarding NRM, score 0 segregated NRM at 3 years to 11.9%, compared with score 1‐2 19.6%, P =.1. Conclusions: Refined hepatic score is promising for stratifying patients with cGVHD and liver involvement according to long‐term outcomes. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

An increase in large granular lymphocytes ( LGL) is frequently seen in patients following allogeneic hematopoietic cell transplantation (allo- HCT) and it has been associated with better outcomes in some reports. We assessed 826 consecutive patients at our institution with over 12 years of follow-up for the occurrence of LGL lymphocytosis after allo- HCT. The 3-year cumulative incidence of LGL lymphocytosis was 14.5% with a median duration of over 3.5 years. The development of LGL lymphocytosis was strongly correlated with CMV viremia and GVHD. The clinical course of patients with LGL lymphocytosis after allo- HCT was indolent, with the majority of these patients not displaying any clinical signs or symptoms related to the LGL proliferation. LGL lymphocytosis was associated with better outcomes, including higher overall survival ( OS 86.6% vs 44.7% at 3 years), lower non-relapse mortality ( NRM 5.5% vs 30.4% at 3 years), and lower risk of relapse (8.9% vs 22.9% at 3 years). A time-dependent multivariable analysis confirmed the favorable impact of LGL lymphocytosis on OS and NRM, but not on the risk of relapse. In multivariable analysis, a longer duration of LGL lymphocytosis was associated with better OS and NRM. Improved immunomodulatory properties of these cells, regulating GVHD and infections, may explain the observed favorable outcomes of patients who developed LGL lymphocytosis following allo- HCT. [ABSTRACT FROM AUTHOR]

The CIBMTR chronic graft-versus-host disease (cGVHD) risk score can be refined and improved for better prognostic stratification. Three hundred and seven consecutive patients diagnosed with cGVHD by the NIH consensus criteria were retrospectively reviewed and had the CIBMTR risk score applied and analyzed. The CIBMTR risk score was successfully validated in our cohort (n = 307). The 3-year overall survival (OS) rates in each risk group (RG) were 82.5 ± 11.3% (RG1), 79.4 ± 3.0% (RG2), 71.8 ± 6.3% (RG3), and 27.3 ± 13.4% (RG4). A significantly lower OS rate and higher non-relapse mortality (NRM) were noted in RG4 compared to the other RGs. However, there were no differences in OS or NRM among RG1 to 3. To improve prognostic stratification power of the CIBMTR risk score, we incorporated the absolute lymphocyte (ALC) and eosinophil count (EC) at time of cGVHD into the CIBMTR risk score. Lower ALC (<1.0 × 109/L, HR 1.94, p = 0.014) and lower EC (<0.5 × 109/L, HR 3.27, p = 0.014) were confirmed as adverse risk factors for OS. Patients were stratified into four revised risk groups (rRG). The 3-year OS rates were 93.3 ± 6.4% (rRG1, score 0-3), 84.9 ± 3.4% (rRG2, score 4-6), 70.9 ± 4.4% (rRG3, score 7-9), and 32.0 ± 1.1% (rRG4, score ≥ 10) (p < 0.001). The 3-year NRM rates were 0.0% (rRG1), 6.7 ± 0.4% (rRG2), 18.4 ± 0.7% (rRG3), and 57.7 ± 5.1% (rRG4) (p < 0.001). The revised CIBMTR risk score was superior to the original CIBMTR risk score for OS (p < 0.001). The revised CIBMTR risk score including ALC and EC at the onset of cGVHD improved the prognostic stratification power of the CIBMTR risk score for long-term outcomes. [ABSTRACT FROM AUTHOR]

Extracorporeal photopheresis (ECP) is recommended as a second- or later-line therapy for chronic GvHD (cGvHD). Benefits include reasonable response with avoidance of intense systemic immunosuppression, which can translate into lowering the risk of systemic toxicity and opportunistic infection. We evaluated 75 patients treated with ECP for cGvHD from 2007 to 2021 at Princess Margaret Cancer Centre, and analyzed overall response rate (ORR) and clinical benefit (CB) at 3, 6 and 12 months plus other long-term treatment outcomes. With a median follow-up of 72 months, a gradual increase in ORR was noted over time: 21% (16 out of 75 patients), 57% (36/63) and 70% (32/46) at month 3, 6 and 12, respectively. Gradual increase in CB was also observed over time with CB rate of 23% (17/75), 62% (39/63), and 76% (35/46) at months 3, 6 and 12, respectively. A total of 27 failures (36%) were noted, due to: 1) ECP resistance requiring switch to other therapy (n = 14, 19%), 2) non-relapse mortality (n = 10, 13%), 3) relapse of primary disease (n = 1, 1%) or 4) ECP procedure-related complication (n = 1, 1%, line infection), with 20 deaths (27%) observed. Failure-free survival (FFS) and overall survival (OS) rates were 68.3% and 85.9% at 12 months, respectively. After starting ECP, the proportions of patients who completely discontinued steroids were 17%, 32%, and 64% at months 3, 6 and 12, respectively. ECP is an effective treatment option for heavily pre-treated cGvHD patients. • ECP is a highly effective treatment in cGvHD, even in patients who had been heavily pre-treated and failed other GVHD therapy. • ECP induce durable responses and clinical benefit in cGvHD. • Steroid-sparing efficacy of ECP reduced systemic toxicity from prolonged use of corticosteroids. • Failure free survival of ECP comparable with ruxolitinib treatment in cGvHD. [ABSTRACT FROM AUTHOR]

• The Centre for International Blood and Marrow Transplant Registry (CIBMTR) score classifies most patients with chronic graft-versus-host disease (GVHD) into low-risk groups. • A novel prognostic risk score further refines the CIBMTR low-risk groups. • The novel risk score improves on the CIBMTR in identifying high-risk chronic GVHD. • The novel risk score classifies patients with respect to failure-free survival. • The novel risk score groups patients according to other relevant clinical outcomes. 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. [ABSTRACT FROM AUTHOR]

Highlights • HaploHSCT after RIC with ATG, PTCy, and cyclosporine is a feasible transplant regimen. • Low rates of grade II to IV acute GVHD were observed. • ATG use leads to higher rates of viral reactivation, particularly CMV and EBV. Abstract 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/m2/day on days –5 to –2), busulfan (3.2 mg/m2/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. [ABSTRACT FROM AUTHOR]

Highlights • Twelve transplant recipients received cidofovir for BK virus hemorrhagic cystitis. • Mean hemorrhagic cystitis severity decreased significantly after cidofovir. • Two-thirds achieved partial response, which was similar between intravenous and intravesical. • One-third experienced renal toxicity, including 2 receiving intravesical therapy. Abstract 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. [ABSTRACT FROM AUTHOR]

Sclerotic chronic graft-versus-host disease (sclGVHD) is associated with significant morbidity and a poor quality of life. We reviewed 502 patients diagnosed with chronic GVHD and analyzed the incidence and risk factors of sclGVHD and long-term outcomes and immunosuppressive therapy (IST) cessation in patients with sclGVHD. With a median onset at 18 months the cumulative incidence of sclGVHD was estimated at 22.6% at 5 years (95% confidence interval, 18.6% to 26.8%). Univariate and multivariate analysis identified 2 risk factors for sclGVHD: non-T cell depletion (hazard ratio [HR] 9.09, P < .001) and peripheral blood stem cell (HR 3.87, P < .001). Overall survival (OS) at 5 years was significantly better in the sclGVHD group (88.1%) compared with the non-sclGVHD group (62.7%; P < .001), as were nonrelapse mortality (7.3% versus 21.5% at 5 years) and relapse rates (9.1% versus 19.3% at 5 years). There was no difference in the rate of IST cessation at 5 years (44.8% versus 49.9%, P = .312), but there was a trend of longer IST duration in the sclGVHD group compared with the non-sclGVHD group (median 71.6 months versus 62.9 months). In conclusion, T cell depletion and graft source affect the risk of sclGVHD. SclGVHD did not adversely affect long-term outcomes or IST duration. [ABSTRACT FROM AUTHOR]

The risk factors for lung chronic graft-versus-host disease (cGVHD) are not fully elucidated. We attempted to identify clinical risk factors for lung cGVHD after allogeneic hematopoietic cell transplantation (HCT). A total of 401 patients who underwent allogeneic HCT between 2000 and 2007 at Princess Margaret Hospital, Toronto, Canada, were evaluated for lung cGVHD serially starting on day 120 and then annually therafter. The stem cell source for HCT was peripheral blood stem cells (PBSCs) in 280 patients (69.8%) and bone marrow (BM) in 121 patients (30.2%). With a median follow-up of 36.8 months, 68 patients (17%) had a diagnosis of lung cGVHD, with a median time of onset of 11.4 months after HCT. Stem cell source was the sole risk factor identified in univariate analyses. The incidence of lung cGVHD was significantly higher in the patients receiving PBSCs (14.2% at 1 year and 22.7% at 2 years) compared with those receiving BM (6.8 at 1 year and 14.9% at 2 years; hazard ratio, 1.937; P = .02). Multivariate analyses also confirmed the use of PBSCs as an independent risk factor for lung cGVHD (hazard ratio, 2.408; 95% confidence interval, 1.289-4.496; P = .0058). The use of PBSCs is associated with an increased risk of lung cGVHD compared with the use of BM for allogeneic HCT. [Copyright &y& Elsevier]