scholarly journals Severe/Life-Threatening/Fatal Chronic Health Conditions (CHCs) after Allogeneic Blood or Marrow Transplantation (BMT) in Childhood - a Report from the BMT Survivor Study (BMTSS)

Blood ◽  
2020 ◽  
Vol 136 (Supplement 1) ◽  
pp. 12-13
Author(s):  
Anna Sallfors Holmqvist ◽  
Yanjun Chen ◽  
Jessica Wu ◽  
Lindsey Hageman ◽  
Kevin D. Battles ◽  
...  
Keyword(s):  
Joint Replacement ◽  
Cumulative Incidence ◽  
Research Funding ◽  
Chronic Gvhd ◽  
Health Conditions ◽  
Limited Information ◽  
Allogeneic Bmt ◽  
Life Threatening ◽  
Grade 3

Background: Allogeneic BMT is a curative option for children with malignant and non-malignant diseases. Nonetheless, the high intensity of therapeutic exposures at a young age increases the risk of organ compromise and thereby the risk of developing CHCs. Yet, there is limited information regarding CHC risk after allogeneic BMT performed in childhood. We address this gap in patients undergoing allogeneic BMT between 1974 and 2014 at 3 participating transplant centers. Methods: BMT recipients and a sibling comparison group (or the parents of participants <18y) completed a 255-item questionnaire that included sociodemographics and health conditions. A severity score (grades 3 [severe] or 4 [life-threatening]) was assigned to CHCs using CTCAE, v. 5.0. Deceased BMT recipients received a CHC-specific grade 5. Risk of severe/life-threatening CHC in BMT survivors vs. siblings: We calculated the cumulative incidence of CHCs for survivors and siblings as a function of attained age. We used logistic regression for estimating the risk of grade 3-4 conditions in survivors compared to siblings, adjusting for sex, age at study, race/ethnicity, education, household income, and health insurance. Risk of severe/life-threatening/fatal CHC in BMT recipients: We used proportional subdistribution hazards model (Fine-Gray) for competing risks to identify predictors of grade 3-5 CHCs, adjusting for demographics, primary disease, conditioning agents, disease status at BMT and chronic GvHD status. Results: 848 patients had received allogeneic BMT at age ≤22 and survived ≥2y after BMT (563 alive at study; 285 deceased after surviving ≥2y). Primary diagnoses included ALL (29%), AML/MDS (28%), SAA (13%), other (30%); median age at BMT: 11.5y (range: 0.4-22.0); median length of follow-up 10.7y (2.0-41.4). Risk of severe/life-threatening CHC in 563 BMT survivors vs. 515 siblings: Cumulative incidence of grade 3-4 condition by age 30y among BMT recipients was significantly higher than that among siblings (38.5±2.7% vs. 5.4±1.0%, p<0.0001), Figure 1. The adjusted odds of developing grade 3-4 CHCs were 8.9-fold higher in BMT survivors (95%CI 6.4-12.5). Higher odds were observed for developing cataracts (OR=48.2; 95%CI 17.9-129.5), heart disease (OR=11.4, 95%CI, 3.9-33.3), diabetes (OR=11.1; 95%CI 3.5-34.8), thyroid nodules (OR=6.6, 95%CI, 2.6-17.0), joint replacement (OR=4.4, 85%CI, 1.7-10.9), and sensorineural disorders (hearing loss/balance disorder/legally blind); OR=3.2, 95%CI, 1.5-6.8). Risk of severe/life-threatening/fatal CHCs in 848 BMT recipients: cumulative incidence of grades 3-5 CHCs was 60.5±3.0% at 40y (Figure 2). The most prevalent grade 3-5 CHCs were second malignancy (11.8%), cataract (5.9%), cardiovascular disease (5.8%), sensorineural disorder (4.4%), diabetes (3.4%), and joint replacement (2.9%). The risk of grades 3-5 CHCs was higher among females (HR=1.3, 95%CI 1.0-1.6), age >12y at BMT (HR=1.4, 95%CI 1.1-1.8) and among those exposed to TBI (HR=1.7, 95%CI 1.2-2.3). Conclusions: Two-year survivors of allogeneic BMT performed in childhood had an almost 10-fold higher risk of severe/life-threatening CHCs compared to siblings. By age of 30, 39% of the survivors had developed a severe or life-threatening CHC. The results of the present study call for close follow-up, from the time of transplantation continuing throughout life. Disclosures Weisdorf: Incyte: Research Funding; FATE Therapeutics: Consultancy. Arora:Fate Therapeutics: Consultancy; Syndax: Research Funding; Kadmon: Research Funding; Pharmacyclics: Research Funding.

scholarly journals A Phase II Study of Ruxolitinib Pre-, during- and Post-Hematopoietic Celltransplantation for Patients with Primary or Secondary Myelofibrosis

Blood ◽  
2021 ◽  
Vol 138 (Supplement 1) ◽  
pp. 169-169
Author(s):  
Gabriela Hobbs ◽  
Haesook T. Kim ◽  
AJ S. Bottoms ◽  
Michael T. Byrne ◽  
Mark A. Schroeder ◽  
...  
Keyword(s):  
Phase Ii ◽  
Cumulative Incidence ◽  
Interim Analysis ◽  
Research Funding ◽  
Acute Gvhd ◽  
Chronic Gvhd ◽  
Free Survival ◽  
Grade 3 ◽  
Neutrophil Engraftment

Abstract Background: Myelofibrosis (MF) is a lethal hematological malignancy associated with somatic mutations in JAK2, CALR or MPL. Ruxolitinib is the first JAK1/2 inhibitor approved for treatment of MF. Ruxolitinib does not prevent disease progression and thus, allogeneic hematopoietic stem cell transplantation (HSCT) remains the recommended therapy for eligible patients treated with curative intent. Ruxolitinib discontinuation, in preparation for HSCT is challenging as patients experience return of symptoms/splenomegaly. Therefore, ruxolitinib is often continued during and after HSCT in an off-label fashion, yet little is known about the safety of this approach. In addition, ruxolitinib is now utilized to treat steroid refractory acute and chronic graft versus host disease (GVHD) irrespective of underlying disease. Methods: This is a phase II, multi-center, investigator-initiated trial investigating ruxolitinib given pre-, during- and post-HSCT for patients with primary or secondary MF (NCT03427866). The study utilizes ruxolitinib during and after HSCT in MF patients for one year after HSCT. The accrual goal is 48 patients with 1-year GVHD free and relapse free survival (GRFS) as the primary endpoint. Secondary endpoints include overall and progression free survival, engraftment and incidence of acute and chronic GVHD, respectively. Patients are treated with reduced intensity conditioning with fludarabine (30mg/m 2/day x 5 days) and melphalan (100mg/m 2 or 140mg/m 2 x 1). HSCT grafts are with 7/8 or 8/8 HLA-matched peripheral blood stem cells with tacrolimus and methotrexate as standard GVHD prophylaxis. Results: This pre-planned interim analysis includes 26 MF patients who underwent HSCT between September 2018 and January 2021. An interim analysis was included in the trial design to ensure safety of this approach midway through accrual. Median age was 66 (range, 46-75) and 65% were male. 88% had 8/8 matched related grafts, and 92% had intermediate-2 or high DIPSS risk at the time of transplant. 14 (54%) patients were previously treated with ruxolitinib. At HSCT, 58% had JAK2, 12% CALR, 12% MPL, and 35% ASXL1 mutations (Figure A). There were no unexpected toxicities related to ruxolitinib therapy. The most common grade 3/4 hematologic adverse events (AE) were anemia (n=4), thrombocytopenia (n=3). There were few observed grade 3/4 non hematologic AEs and included infection (n=2) and hypertriglyceridemia (n=1). Median time to neutrophil engraftment was 15 days (range 11-38) after HSCT. All but one patient achieved successful neutrophil engraftment. Median day 30 donor all cell chimerism was 100% (range 95-100). Clinical outcomes are summarized in Figure B. With median follow-up among survivors of 12 months (range 3-24), 1-yr GRFS was 65%. OS, PFS, and cumulative incidence of NRM and disease relapse were 77%, 71%, 13% and 17%, respectively (Figure C). There was no grade IV acute GVHD and only one case of grade III acute GVHD. Cumulative incidence of all chronic GVHD and moderate-severe chronic GVHD was 14% and 5%, respectively. There was no severe chronic GVHD and only one patient developed moderate chronic GVHD. As part of the study, next generation sequencing (NGS) was obtained pre- and 100 days post-HSCT. 14 patients have paired samples, including 6 with ASXL1 mutations. All but one patient, who remains in remission at last follow up, no longer had mutations detected by NGS at day 100 (Figure D). Ongoing studies will assess for the presence of low-level mutation not detectable by clinical NGS testing. Discussion: The interim results of our multicenter study demonstrate safety of ruxolitinib administration pre, during and post-HCT with very favorable engraftment rates and no unexpected toxicities of ruxolitinib use. In addition, we demonstrate superior PFS, OS and GRFS compared to historical observations. Incidence of severe acute and chronic GVHD are thus far minimal, indicating excellent GVHD control with prophylactic and continued ruxolitinib use. Figure 1 Figure 1. Disclosures Hobbs: Bayer: Research Funding; Incyte Corporation: Research Funding; Celgene/Bristol Myers Squibb: Consultancy; AbbVie.: Consultancy; Merck: Research Funding; Novartis: Consultancy; Constellation Pharmaceuticals: Consultancy, Research Funding. Byrne: Karyopharm: Research Funding. Defilipp: Incyte Corp.: Research Funding; Regimmune Corp.: Research Funding; Omeros, Corp.: Consultancy; Syndax Pharmaceuticals, Inc: Consultancy. Chen: Gamida: Consultancy; Incyte: Consultancy. OffLabel Disclosure: Will describe the use of ruxolitinib in the ongoing clinical trial.

scholarly journals Burden of Long-Term Morbidity Borne By Survivors of Acute Myeloid Leukemia (AML) Treated with Blood or Marrow Transplantation (BMT) - a Report from the BMT Survivor Study (BMTSS)

Blood ◽  
2019 ◽  
Vol 134 (Supplement_1) ◽  
pp. 707-707
Author(s):  
Saro H. Armenian ◽  
Yanjun Chen ◽  
Lindsey Hageman ◽  
Jessica Wu ◽  
Liton F. Francisco ◽  
...  
Keyword(s):  
Joint Replacement ◽  
Cumulative Incidence ◽  
Comparison Group ◽  
Health Conditions ◽  
Malignant Neoplasms ◽  
Chronic Health ◽  
Life Threatening ◽  
Grade 3 ◽  
Hispanic White

Background: BMT is now an integral part of consolidation and/or salvage for patients with AML. With the growing population survivors, there is a need to understand the quality of survival. This would allow for appropriate resource allocation and implementation of risk-based screening for early detection of chronic health conditions over time. Yet, a comprehensive evaluation of the long-term burden of morbidity borne by AML patients treated with BMT remains unknown. We addressed this gap by evaluating long-term severe/life-threatening/fatal chronic health conditions (CHCs) in AML patients treated with BMT using the BMTSS. Methods: Patients were eligible if they had undergone an allogeneic or autologous BMT for AML between 1974 and 2014 at one of 3 BMT centers in the US, had survived for ≥2y after BMT, and were ≥21y of age at BMT. Of the 1,113 eligible subjects, 711 (64%) participated. BMT survivors identified a nearest-age sibling to constitute an unaffected comparison group (N=1,136). Survivors and siblings completed a 231-item BMTSS survey that included questions regarding CHC diagnosis by their healthcare provider, including age at onset of CHC. Scoring was based on Common Terminology Criteria for Adverse Events ([CTCAE] v 5.0) to determine the severity of CHCs. Using multivariable logistic regression, we determined the risk of any severe (CTCAE grade 3) or life-threatening (CTCAE grade 4) CHC in survivors compared with siblings, adjusting for age at study, sex, race/ethnicity, education, annual household income and insurance status. Information regarding therapeutic exposures (pre-BMT and transplant-related) was abstracted from medical records. Cumulative incidence of CHCs (including fatal [CTCAE grade 5] CHCs) were calculated for BMT survivors, treating relapse-related death as a competing risk. Results: Mean age at BMT was 48.6±13.8y and at survey was 58.2±11.5y. Mean interval between BMT and study participation was 9.7±6.8y; 53% were females, and 78% were non-Hispanic white; 86% received allogeneic BMT (48% from an unrelated donor). Conditioning was Fludarabine/Melphalan-based in 53% and TBI-based in 35%; stem cell source was peripheral blood (70.3%), bone marrow (19.3%), and cord (10.4%). For the siblings, the mean age at survey was 56.9+13.4y; 61% were females, and 88% were non-Hispanic white. BMT survivors vs. sibs: 53.3% of the BMT survivors and 30.4% of the sibs reported grades 3-4 CHCs, placing the survivors at a 3.0-fold higher odds of grades 3-4 CHC (95%CI, 2.4-3.7, p<0.0001). The odds of developing the following CHCs were significantly higher in BMT survivors when compared with siblings: subsequent malignant neoplasms (SMNs: odds ratio [OR]=10.0, 95% CI, 5.5-17.9, p<0.0001), diabetes (OR=5.3, 95% CI, 3.0-9.3, p<0.0001), venous thromboembolism (OR=3.8, 95%CI, 2.5-5.8 p<0.0001), cataracts (OR=3.7; 95%CI, 2.7-5.0, p<0.0001), and major joint replacement (OR=1.5, 95% CI, 1.1-2.1, p=0.02). Among BMT survivors: The 10- and 20y cumulative incidence of a grade 3-5 CHC was 52.0%±1.4% and 66.2%±1.6%, respectively (Figure 1). 75 survivors had developed SMNs: skin (melanoma/ squamous cell [56%]), breast (13%), colon (7%), prostate (7%), and other cancers (24%). The 10- and 20y-cumulative incidence of the most common CHCs were as follows (Figure 2): SMN (10y: 17.9%±1.7%, 20y: 32.1%±2.9%), cataract (10y: 21.5%±1.9%, 20y: 31.5%±3.0%), major joint replacement (10y: 12.5%±0.9%, 20y: 17.5%±3.4%), venous thromboembolism (10y: 8.6%±1.1%, 20y: 13.2%±2.1%), and diabetes (10y: 6.0%±1.9%, 20y: 8.0%±1.5%). Conclusion: The burden of severe/life-threatening CHCs is substantially higher in BMT survivors when compared with an unaffected comparison group. The incidence of severe/ life-threatening/ fatal chronic health condition following BMT for AML exceeds 50% at 10y, and continues to increase with time, approaching 70% at 20y post-BMT. Subsequent malignant neoplasms, diabetes, thrombo-embolic events, cataracts, and major joint replacement constitute the largest burden of morbidity. These findings suggest the need for increased awareness of the long-term burden of morbidity, to ensure close monitoring of these survivors to anticipate and manage morbidity. Disclosures Weisdorf: Incyte: Research Funding; Fate Therapeutics: Consultancy; Pharmacyclics: Consultancy.

scholarly journals Long-Term Morbidity and Mortality Experienced By Chronic Myeloid Leukemia (CML) Patients after Allogeneic Hematopoietic Cell Transplantation (HCT) - a Report from BMTSS-2

Blood ◽  
2016 ◽  
Vol 128 (22) ◽  
pp. 823-823
Author(s):  
Jessica Wu ◽  
Yanjun Chen ◽  
Lindsey Hageman ◽  
Can-Lan Sun ◽  
Liton F. Francisco ◽  
...  
Keyword(s):  
Board Of Directors ◽  
Cumulative Incidence ◽  
Chronic Gvhd ◽  
Chronic Health Conditions ◽  
Health Conditions ◽  
Advisory Committees ◽  
Chronic Health ◽  
Life Threatening ◽  
Related Mortality

Abstract Background: Tyrosine kinase inhibitors have become the treatment of choice for CML. However, the high cost and need for life-long treatment contribute to non-adherence and represent a major challenge in their use. Allogeneic HCT is potentially curative, but the very long-term health of the survivors is not known. It is also not clear whether a subgroup of CML patients carries a relatively low risk of long-term morbidity. Methods: We addressed these gaps by studying long-term outcomes in 637 CML patients treated with allogeneic HCT between 1981 and 2010 at City of Hope or Univ MN, and surviving for at least 2y after HCT (median follow-up: 16.7y from HCT); 80% of the cohort was <45y at HCT; 68% received HCT in 1st chronic phase (CP); 63% received matched related [MRD], 34% matched unrelated donor (MUD) and 3% non-myeloablative HCTs; 79% received TBI; 65.8% developed chronic GvHD. Vital status information was collected as of May, 2016, using medical records, National Death Index and Lexis Nexis. US mortality rates were obtained from CDC's National Center for Health Statistics. Thirty percent (n=192) died after having survived at least 2 years after HCT; median time between HCT and death was 8.3y. Of the 445 patients alive at study, 288 (65%) completed the BMTSS health questionnaire used to examine the risk of CTCAE grade 3 (severe) or 4 (life-threatening) chronic health conditions. A sibling comparison group (n=404) also completed the BMTSS questionnaire. Results: Late Mortality: Overall survival was 72.1% at 20y and 69.9% at 30y from HCT. The 20y cumulative incidence of relapse-related mortality was 3.9% (95% CI, 2.6-5.8%) and of non-relapse-related mortality was 18.2% (95% CI, 19.8-28.1%) (Figure 1). 20y cumulative incidence of mortality by cause of death was as follows: infection (7%), chronic GvHD (6%), subsequent malignant neoplasms (SMNs: 3%). HCT recipients were at 4.4-fold increased risk of death (95% CI, 3.8-5.1, p<0.0001) than age-, race-, and sex-adjusted normal populations. For patients transplanted in 1st CP and surviving 15y, mortality rates became comparable with the general population (SMR, 1.5, 95% CI, 0.9-2.3, p=0.1). Among CML patients receiving HCT at <45y with Bu/Cy (n=70), overall survival was 81.5% at 20y from HCT; the 20y cumulative incidence of relapse-related mortality was 2.9% and of non-relapse-related mortality was 14%. This cohort was at 3.3-fold higher risk of death when compared with the general population (95% CI=1.7-5.7, p<0.0001). Late Morbidity: The 20y cumulative incidence of a severe/life-threatening chronic health condition among HCT survivors was 47.2% (95% CI, 39.0-54.9%); the incidence was higher (p=0.0006) for MUD vs. MRD recipients (Figure 2). After adjusting for age, sex, race and SES, HCT survivors were at 2.7-fold higher risk for severe/life-threatening chronic health conditions as compared with siblings (95% CI, 1.8-3.9, p<0.0001). The 20y cumulative incidence of specific conditions experienced by survivors and siblings were: SMNs (10.1% vs. 1.7%, p<0.001); diabetes (11.1% vs. 1.5%, p<0.001) and coronary artery disease (6.9% vs. 3.2%, p<0.001). CML patients receiving MRD HCT at <45y with Bu/Cy were not at increased risk of severe/life-threatening chronic health conditions when compared with the sibling comparison group (HR=0.81, 95% CI, 0.26-2.54, p=0.7). Conclusions: Conditional on surviving the first 2y after HCT, the overall survival exceeds 70% at 20y and remains stable at 70% at 30y after HCT. Non-relapse related mortality (infections, chronic GvHD, SMNs) is by far the major contributor to the late mortality. Conditional on surviving the first 15y, mortality rates are similar to those observed in the general population. HCT survivors are at a 2.7-fold higher risk of severe/life-threatening morbidity when compared with siblings. The more common morbidities include SMNs, diabetes and coronary artery disease. However, CML patients receiving HCT at <45y with Bu/Cy conditioning enjoy survival rates exceeding 81% at 20y from HCT, and their burden of long-term morbidity is comparable to that experienced by siblings. These findings could help inform decisions regarding therapeutic options for management of CML. Disclosures Snyder: BMS: Membership on an entity's Board of Directors or advisory committees; Ariad: Membership on an entity's Board of Directors or advisory committees; Incyte: Membership on an entity's Board of Directors or advisory committees. Forman:Mustang Therpapeutics: Other: Construct licensed by City of Hope.

scholarly journals Impact of Chronic Graft-Versus-Host Disease on Long-Term Outcomes of Reduced-Intensity Conditioning Allogeneic Hematopoietic Cell Transplantation for Adults with High-Risk Acute Lymphoblastic Leukemia in First Remission

Blood ◽  
2016 ◽  
Vol 128 (22) ◽  
pp. 3980-3980
Author(s):  
Jae-Ho Yoon ◽  
Sung-Soo Park ◽  
Young-Woo Jeon ◽  
Sung-Eun Lee ◽  
Byung-Sik Cho ◽  
...  
Keyword(s):  
High Risk ◽  
Board Of Directors ◽  
Median Time ◽  
Cumulative Incidence ◽  
Research Funding ◽  
Chronic Gvhd ◽  
Unrelated Donor ◽  
Advisory Committees

Abstract Background : The role of reduced-intensity conditioning allogeneic hematopoietic cell transplantation (RIC-HCT) in adult acute lymphoblastic leukemia (ALL) remains unclear because the interpretation of transplantation outcome is mainly limited by the small sample size, short follow-up duration, various regimens for conditioning and graft-versus-host disease (GVHD) prophylaxis, and the heterogeneity of the criteria used to select patients for RIC-HCT. Previously, we conducted a phase 2 trial of RIC-HCT in adults with high-risk ALL who were ineligible for myeloablative conditioning and showed the potential role of this strategy, especially in patients in first complete remission (CR1). Here, we report the long-term outcomes of RIC-HCT by analyzing 122 consecutive adults with high-risk ALL in CR1, particularly focusing on the prognostic relevance of chronic GVHD. Methods: During the period between 2000 and 2014, 122 patients in CR1 (median age, 52 years [range, 15-65 years]; 54 Ph-negative ALL and 68 Ph-positive ALL) were given an identical RIC regimen consisting of fludarabine (150 mg/m2 in total) and melphalan (140 mg/m2in total). The indications for RIC-HCT were advanced age (≥50 years; n=79; 64.8%) and comorbid conditions (n=43; 35.2%). Graft sources were peripheral blood stem cells (n=118; 66 matched sibling donor, 23 matched unrelated donor, 29 mismatched unrelated donor) and bone marrow (n=4; 1 matched sibling donor, 1 matched unrelated donor, 2 mismatched unrelated donor). The median time to transplantation was 155.5 days (range, 103-291 days). GVHD prophylaxis was attempted by administering calcineurin inhibitors (cyclosporine for sibling donor transplants, tacrolimus for unrelated donor transplants) plus methotrexate. Antithymocyte globulin was administered to the patients who received mismatched unrelated donor grafts. If residual leukemia was detected in the absence of GVHD at 3 months after transplantation, calcineurin inhibitors were rapidly discontinued. Results: The median time for neutrophil and platelet recovery was 12 days (range, 8-30 days) and 13 days (range, 5-60 days) after RIC-HCT. Sixty-two patients developed acute GVHD (53 grade II, 5 grade III, 4 grade IV). The cumulative incidence of acute GVHD at 1 year was 50.8% (42.6% for Ph-negative and 57.4% for Ph-positive, P=0.152). Except for 11 patients with early deaths within 100 days, 77 developed chronic GVHD (30 mild, 29 moderate, 18 severe), resulting in a 5-year cumulative incidence of 63.6% (69.1% for Ph-negative ALL and 58.8% for Ph-positive ALL, P=0.319). The median time to onset of chronic GVHD was 140 days (range, 37-843 days) after transplantation. Cytomegalovirus reactivation >10,000 copies/mL was observed in 40.2% (44.4% for Ph-negative ALL and 36.8% for Ph-positive ALL, P=0.447). After a median follow-up duration of 57.9 months (range, 17.7-206.8 months), the 5-year cumulative incidence of relapse (CIR) and non-relapse mortality (NRM) were 27.5% (23.9% for Ph-negative ALL and 30.2% for Ph-positive ALL) and 19.0% (17.4% for Ph-negative ALL and 20.3% for Ph-positive ALL), respectively, and the 5-year disease-free survival (DFS) and overall survival (OS) rates were 53.5% (58.4% for Ph-negative ALL and 49.7% for Ph-positive ALL) and 59.8% (60.2% for Ph-negative ALL and 59.3% for Ph-positive ALL). In multivariate analysis, the presence of chronic GVHD lowered CIR (HR, 0.23; 95% CI, 0.10-0.48; P<0.001), but severe chronic GVHD increased NRM (HR, 8.76; 95% CI, 3.39-22.6; P<0.001). Thus, the presence of mild to moderate chronic GVHD was closely related to better outcomes in terms of DFS (HR, 0.45; 95% CI, 0.32-0.64; P<0.001) and OS (HR, 0.44; 95% CI, 0.30-0.64; P<0.001) in all patients as well as in both subgroups of patients. In Ph-positive ALL subgroup of patients, patients without achievement of major molecular response until the time of transplantation had also significantly higher CIR (HR, 7.42; 95% CI, 3.04-18.10; P<0.001) and poorer DFS (HR, 3.47; 95% CI, 1.48-8.14; P=0.004) and OS (HR, 2.58; 95% CI, 1.03-6.47; P=0.043). Conclusion: Our long-term follow-up data with a uniform treatment strategy suggest that RIC-HCT is a valid alternative choice for providing a long-term disease control for adult high-risk ALL patients in CR1. Minimal residual disease-based treatment strategies to reduce leukemia cell burden before HCT and to enhance the graft-versus-leukemia effect are needed in the future. Disclosures Kim: ILYANG: Consultancy, Honoraria, Research Funding; Pfizer: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Novartis: Consultancy, Honoraria, Research Funding, Speakers Bureau; BMS: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau. Lee:Alexion Pharmaceuticals, Inc.: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau.

Burdern of Long-Term Morbidity after Hematopoietic Cell Transplantation: A Report from the Bone Marrow Transplant Survivor Study (BMTSS).

Blood ◽  
2007 ◽  
Vol 110 (11) ◽  
pp. 832-832 ◽  
Author(s):  
Can-Lan Sun ◽  
Liton Francisco ◽  
Toana Kawashima ◽  
Leslie L. Robison ◽  
K.S. Baker ◽  
...  
Keyword(s):  
Health Condition ◽  
Chronic Health Conditions ◽  
Health Conditions ◽  
Unrelated Donor ◽  
Chronic Health ◽  
Threatening Condition ◽  
Life Threatening ◽  
Grade 3

Abstract Long-term survival is an expected outcome after HCT. However, no study has assessed the burden of long-term morbidity in these survivors, or attempted to identify subpopulations at highest risk for severe, debilitating conditions. In this study, we determined the prevalence and severity of chronic health conditions in a large population of long-term HCT survivors and compared these outcomes with their siblings. BMTSS, a collaborative effort between City of Hope National Medical Center and University of Minnesota, examined self-reported chronic health conditions in individuals who underwent HCT between 1976 and 1998, and survived two or more years. A severity score (grade 1 through 4, ranging from mild to life-threatening or disabling) was assigned to each health condition according to the Common Terminology Criteria for Adverse Events (version 3). A partial list of conditions graded as severe or life-threatening (grade 3 or 4) included congestive heart failure, second malignant neoplasms, coronary artery disease, cerebrovascular accident, renal failure/dialysis/renal transplant, and active chronic graft vs. host disease. Adverse psychosocial outcomes were not included. Cox proportional-hazard models were used to estimate hazard ratios and their 95% confidence intervals. We compared the prevalence and severity of chronic conditions in 1013 HCT survivors (455 autologous, 460 related donor, and 98 unrelated donor HCT survivors) with 309 siblings. The median age at study participation was 44 (range 18–73) and 45 years (range 17–79) for survivors and siblings, and the median follow-up for the survivors was 7.3 years (range 2–28) from HCT. Among the 1013 survivors, 69% had at least one chronic condition, and 29% had a severe or life-threatening condition (grade 3 or 4). The comparable figures in siblings were 39% and 7%, respectively (p<0.001 compared to survivors). After adjustment for age at HCT, sex and race/ethnicity, survivors were 2.4 times as likely as their siblings to develop any chronic health conditions (95%CI, 2.0–2.9), and 4.5 times more likely to develop severe/life threatening conditions (95%CI, 3.0–6.7). Groups at highest risk for a severe or life-threatening condition are summarized in the Table. Among survivors, the cumulative incidence of a chronic health condition reached 84% at 20 years post HCT, with a cumulative incidence of 55% for severe/life threatening conditions at 15 years after HCT. The chronic health burden of this population is significant, and life-long follow-up of patients who receive transplantation is recommended. Table: Groups at highest risk for severe or life-threatening condition Risk Factors Relative Risk 95% CI Siblings 1.0 __ CML 5.8 3.8–8.9 AML 4.9 3.2–7.5 ALL 5.2 3.3–8.3 Allogeneic sibling donor 5.9 3.9–8.7 Unrelated donor 7.4 4.9–11.1 TBI 5.0 3.4–7.5

scholarly journals Bosutinib Vs Imatinib for Newly Diagnosed Chronic Myeloid Leukemia (CML) in the BFORE Trial: 18 Month Follow-up

Blood ◽  
2017 ◽  
Vol 130 (Suppl_1) ◽  
pp. 896-896
Author(s):  
Carlo Gambacorti-Passerini ◽  
Michael W. Deininger ◽  
Michael J. Mauro ◽  
Charles Chuah ◽  
Dong-Wook Kim ◽  
...  
Keyword(s):  
Board Of Directors ◽  
Primary Endpoint ◽  
Cumulative Incidence ◽  
Research Funding ◽  
Newly Diagnosed ◽  
Employment Equity ◽  
Advisory Committees ◽  
Equity Ownership ◽  
Grade 3

Abstract Introduction: Bosutinib is a potent SRC/ABL tyrosine kinase inhibitor approved for treatment of adults with CML resistant or intolerant to prior therapy. Here we compare the efficacy and safety of first-line bosutinib versus imatinib in patients with chronic phase (CP) CML enrolled in BFORE after ≥18 months of follow-up. Methods: BFORE (NCT02130557) is an ongoing, multinational, open label phase 3 study that randomized 536 patients 1:1 to 400 mg QD bosutinib (n=268) or 400 mg QD imatinib (n=268 [3 not treated]). The prespecified primary endpoint was major molecular response (MMR) rate at 12 months in the modified intent-to-treat (mITT) population, defined as Philadelphia chromosome‒positive (Ph+) patients with e13a2/e14a2 transcripts, and excluding Ph- patients and those with unknown Ph status and/or BCR-ABL transcript type (mITT: BOS, n=246; IM, n=241). Efficacy results refer to the mITT population unless otherwise noted. Results: MMR rate was higher with bosutinib versus imatinib at 18 months (56.9% vs 47.7%; P=0.042). Among all randomized patients (ITT) 18-month MMR rates were higher for bosutinib (56.7% vs 46.6%; P &lt;0.02). Earlier analyses (Table) showed complete cytogenetic response (CCyR) rate by 12 months (77.2% vs 66.4%; P=0.0075) was significantly higher with bosutinib versus imatinib. Rates of BCR-ABL1 transcript ratio ≤10% (International Scale) at 3 months (75.2% vs 57.3%), as well as MR4 at 12 months (20.7% vs 12.0%) and MR4.5 at 12 months (8.1% vs 3.3%), were all higher with bosutinib versus imatinib (all P &lt;0.025). By comparison at 18 months, rates of MR4 (24.4% vs 18.3%) and MR4.5 (11.4% vs 7.1%) were consistent with this trend. Also after ≥18 months follow-up, time to MMR (hazard ratio=1.36, based on cumulative incidence; P=0.0079) and time to CCyR (hazard ratio=1.33; P=0.0049) were shorter for bosutinib (Figure). Cumulative incidence of transformation to accelerated/blast phase disease at 18 months was 2.0% and 2.9% for bosutinb and imatinib, respectively, of which 2 bosutinib and 4 imatinib patients discontinued treatment due to transformation. Additional treatment discontinuations due to suboptimal response/treatment failure occurred in 11 (4.1%) and 35 (13.2%) of bosutinib and imatinib patients, respectively. Dose increases happened in 20% of bosutinib-treated and 31% of imatinib-treated pts There were 2 deaths and 9 deaths in the bosutinib and imatinib arms, respectively. One patient taking bosutinib died within 28 days of last dose, while 4 patients taking imatinib died with that period from last dose. Overall survival at 18 months was 99.6% vs. 96.6% for bosutinib and imatinib groups, respectively. Grade ≥3 diarrhea (8.2% vs 0.8%) and increased alanine (20.9% vs 1.5%) and aspartate (10.1% vs 1.9%) aminotransferase levels were more frequent with bosutinib. Cardiovascular, peripheral vascular, and cerebrovascular events were infrequent in both arms (3.4%, 1.9%, and 0.4% bosutinib vs 0.0%, 1.1%, and 0.8% imatinib; grade ≥3: 1.5%, 0%, and 0.4% vs 0%, 0%, and 0.4%). There were no deaths in the bosutinib arm and 1 death in the imatinib arm due to treatment-emergent vascular events. Treatment discontinuations due to drug-related toxicity occurred in 15.3% and 9.4% of bosutinib and imatinib patients, respectively. Conclusion: After 18 months of follow-up,the MMR benefit seen with bosutinib over imatinib was sustained. These results are in line with observations at 12 months where patients taking bosutinib had significantly higher response rates (primary endpoint) and achieved responses sooner than those on imatinib. Safety data were consistent with the known safety profiles. These results suggest that bosutinib may be an important treatment option for patients with newly diagnosed CP CML. Disclosures Gambacorti-Passerini: Pfizer: Consultancy, Honoraria, Research Funding; BMS: Consultancy. Deininger: Novartis: Consultancy, Research Funding; Pfizer: Consultancy; Celgene: Research Funding; BMS: Consultancy, Research Funding; Gilead: Research Funding; ARIAD: Consultancy; Ariad Pharmaceuticals, Bristol Myers Squibb, CTI BioPharma Corp, Gilead, Incyte, Novartis, Pfizer, Celgene, Blue Print, Galena: Consultancy, Membership on an entity's Board of Directors or advisory committees; Incyte: Consultancy. Mauro: Bristol-Myers Squibb: Consultancy. Chuah: Avillion: Honoraria; Chiltern: Honoraria; BMS: Honoraria, Other: Travel; Novartis: Honoraria. Kim: Novartis: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Pfizer: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Takeda: Membership on an entity's Board of Directors or advisory committees, Research Funding; Il-Yang: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; BMS: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding. Milojkovic: Novartis: Consultancy, Honoraria; Incyte: Honoraria, Speakers Bureau; Pfizer: Consultancy, Honoraria; BMS: Consultancy, Honoraria; ARIAD: Consultancy, Honoraria. le Coutre: BMS: Honoraria; Pfizer: Honoraria; Incyte: Honoraria; Novartis: Honoraria, Research Funding; ARIAD: Honoraria. García Gutiérrez: Pfizer: Consultancy, Honoraria, Research Funding; BMS: Consultancy, Honoraria, Research Funding; Incyte: Consultancy, Honoraria, Research Funding; Novartis: Consultancy, Honoraria, Research Funding. Crescenzo: Pfizer: Employment, Equity Ownership. Leip: Pfizer: Employment, Equity Ownership. Bardy-Bouxin: Pfizer: Employment, Equity Ownership. Hochhaus: Novartis: Research Funding; Pfizer: Research Funding; Incyte: Research Funding; Ariad: Research Funding; MSD: Research Funding; BMS: Research Funding. Brümmendorf: Pfizer: Consultancy, Research Funding; Novartis: Consultancy, Research Funding. Cortes: Sun Pharma: Research Funding; ARIAD: Consultancy, Research Funding; Novartis Pharmaceuticals Corporation: Consultancy, Research Funding; Pfizer: Consultancy, Research Funding; BMS: Consultancy, Research Funding; ImmunoGen: Consultancy, Research Funding; Teva: Research Funding.

scholarly journals Effect of Age on Outcomes of Allogeneic Transplantation in Patients with Acute Myeloid Leukemia and Myelodysplastic Syndrome

Blood ◽  
2021 ◽  
Vol 138 (Supplement 1) ◽  
pp. 3933-3933
Author(s):  
Audrey M. Sigmund ◽  
Justin Jiang ◽  
Qiuhong Zhao ◽  
Patrick Elder ◽  
Ashley E. Rosko ◽  
...  
Keyword(s):  
Acute Myeloid Leukemia ◽  
Board Of Directors ◽  
Cumulative Incidence ◽  
Older Patients ◽  
Myeloid Leukemia ◽  
Research Funding ◽  
Chronic Gvhd ◽  
Advisory Committees ◽  
Acute Myeloid

Abstract Background: Allogeneic stem cell transplantation (allo-SCT) has become an increasingly important consolidation treatment option for patients with acute myeloid leukemia (AML) and as upfront therapy for patients with high-risk myelodysplastic syndrome (MDS). Although the median age at diagnosis for both diseases is above 65 years, studies evaluating allo-SCT as treatment option for patients aged 65 years or older are limited. Further, as the population ages, the number of patients above 65 years considered for allo-SCT will continue to rise. Thus, the aim of our current investigation was to analyze outcomes based on age in AML/MDS patients &lt;65 years old and ≥65 years old who received allo-SCT at the Ohio State University. Methods: A retrospective analysis was performed for all AML/MDS patients who received allo-SCT between January 1984 and December 2018 at our institution. Primary endpoints included progression free survival (PFS) and overall survival (OS). PFS was counted from the day of transplantation to relapse or death. OS was defined as survival from the day of allo-SCT until death from any cause, with censoring of patients known to be alive at the time of last follow-up. PFS and OS were calculated using Kaplan Meier Curves. Secondary endpoints included cumulative incidences of grade II-IV and III-IV acute GVHD (aGVHD), chronic GVHD (cGVHD), relapse, and non-relapse mortality (NRM). Cumulative incidence rates of aGVHD, cGVHD, relapse, NRM were estimated and compared using Gray's test accounting for competing risks. Results: The cohort consisted of 900 AML/MDS patients, with 150 patients ≥65 years and 750 patients &lt;65 years. The median age at transplant for the &lt;65 years group was 49 years (range: 18-64 years) and 68 years (range: 65-76 years) for the ≥65 years group. Gender, race, Karnofsky score, and comorbidity index were similar between the two groups. A higher proportion of patients received myeloablative (MA) conditioning (65.1%) in the &lt;65 years of age compared to 20% in the ≥65 years of age (p&lt;0.01). A higher proportion of older patients had matched unrelated donors (57.3%), and reduced intensity conditioning (RIC) regimens (80%). The median time from diagnosis to transplantation was 176 days (range: 55-4920) for age &lt;65 years and 168 days (range: 34-6079 days) for age ≥65 years. Median follow-up from allo-SCT was 5.9 years (range 0.8-35.9 years) and 3.4 years (range: 1.0-9.6 years) from transplantation among survivors. Neutrophil and platelet engraftment were similar among the groups (p=0.35; 0.11). 3 year OS of 42.3% (95% CI: 38.7-45.8%) and PFS of 38.3% (95% CI: 34.8%-41.9%) were observed for age &lt;65 years. The corresponding OS and PFS for age ≥65 years was 46.3% (95% CI: 37.9%-54.3%) and 43.0% (95% CI: 34.7%-51.0%), respectively (Figure 1a & 1b). Cumulative incidences of relapse at 1 year in &lt;65 and ≥65 years were 26.4% and 25.3%, respectively (p=0.43). The cumulative incidence of NRM at 1 year in &lt;65 and ≥65 years was 23.2% and 17.3%, respectively (p=0.12; Figures 1c and d). The incidences of acute and chronic GVHD were similar in the two age groups. The cumulative incidence of aGVHD at day 100 in &lt;65 and ≥65 years was 40.3% (95% CI: 36.4%-44.2%) and 43.0% (95% CI: 34.9%-50.7%), respectively. The cumulative incidence of cGVHD at day 365 in &lt;65 and ≥65 years was 40.8% (95% CI: 36.9%-44.6%) and 41.6% (95% CI: 33.6%-49.4%), respectively. Conclusion: Overall, our study suggests similar outcomes for elderly patients undergoing allo-HCT as compared to their counterparts, which is in line with prior studies. This likely is due to advancements in the transplant field, including the development of RIC and alternative donors, which have allowed greater access to transplant for older adults. Utilization of allo-HCT is feasible and should be considered for AML/MDS patients ≥65 years. Further research is underway to evaluate the important determinants of health status in older patients undergoing allo-HCT and to ultimately help predict NRM (BMT CTN 1704). Figure 1 Figure 1. Disclosures Bumma: Amgen, Sanofi: Speakers Bureau; Janssen, Oncopeptides, Sanofi: Consultancy. Vasu: Seattle Genetics: Other: travel support; Boehringer Ingelheim: Other: Travel support; Kiadis, Inc.: Research Funding; Omeros, Inc.: Membership on an entity's Board of Directors or advisory committees. Jaglowski: Takeda: Consultancy; Juno: Consultancy; Kite, a Gilead Company: Consultancy, Research Funding; CRISPR Therapeutics: Consultancy; Novartis: Consultancy, Research Funding. Mims: Syndax Pharmaceuticals: Consultancy; BMS: Consultancy; Jazz Pharmaceuticals: Consultancy; Abbvie: Consultancy; Genentech: Consultancy; Kura Oncology: Consultancy; Leukemia and Lymphoma Society: Consultancy; Glycomemetics: Research Funding; Aptevo: Research Funding; Xencor: Research Funding; Daiichi-Saynko: Consultancy. Brammer: Celgene: Research Funding; Seattle Genetics: Speakers Bureau; Kymera Therapeutics: Consultancy. Saad: Incyte Pharmaceuticals: Consultancy; careDx: Consultancy; Amgen: Research Funding; Kadmon: Research Funding; OrcaBio: Research Funding; Magenta Therapeutics: Consultancy. de Lima: Miltenyi Biotec: Research Funding; Incyte: Membership on an entity's Board of Directors or advisory committees; BMS: Membership on an entity's Board of Directors or advisory committees; Pfizer: Membership on an entity's Board of Directors or advisory committees.

Allogeneic Stem Cell Transplantation (allo-SCT) for Acute Myeloid Leukemia (AML): Low Incidence of Relapse and Graft Versus Host Disease (GVHD) in Patients (pts) Transplanted without Active Leukemia Using in-Vivo T-Cell Depletion with Rabbit Anti-Thymocyte Globulin (r-ATG)

Blood ◽  
2011 ◽  
Vol 118 (21) ◽  
pp. 4527-4527
Author(s):  
James L. Slack ◽  
Jose F. Leis ◽  
Craig B. Reeder ◽  
Joseph R. Mikhael ◽  
Raoul Tibes ◽  
...  
Keyword(s):  
T Cell ◽  
High Risk ◽  
Cumulative Incidence ◽  
Research Funding ◽  
Acute Gvhd ◽  
Chronic Gvhd ◽  
Cell Depletion ◽  
T Cell Depletion

Abstract Abstract 4527 Introduction: The prognosis for pts with intermediate or high risk AML remains dismal, with relapse rates typically in the 60–80% range after treatment with chemotherapy alone. While allo-SCT can decrease the risk of relapse to 10–20%, widespread use of this modality is limited by relatively high rates of non-relapse mortality (NRM), often due to severe acute and/or chronic GVHD. Attenuation of severe GVHD, without a concomitant increase in relapse or NRM, should improve outcomes and result in cure of a larger fraction of AML pts. We therefore investigated the use of in-vivo T-cell depletion with r-ATG in pts with intermediate- or high-risk AML but without active leukemia at the time of allo-SCT. Patients and Methods: Pts (n = 43) were included in this retrospective analysis if they were between 18 and 65 years of age and had no evidence of active AML at the time of allo-SCT (see Table). All pts had 1 or more high-risk features: 1) adverse or intermediate risk cytogenetics (without NPM1 mutation if cytogenetically normal); 2) therapy-related or secondary AML; 3) high WBC count at diagnosis; 4) failure to achieve CR after 1 cycle of induction; or 5) not in CR1 at allo-SCT. Among the 43 pts, 10 received grafts from related donors, 14 from 10/10 matched unrelated donors (URDs), and 19 from mismatched URDs (9/10, n = 11; 8/10, n = 8). All pts received r-ATG according to institutional standard operating policy, with doses ranging from 2.5 – 10 mg/kg depending on donor type and degree of mismatch. All transplants were performed using PBSC. Additional GVHD prophylaxis included tacrolimus plus either methotrexate or mycophenolate mofetil. Results: The median age was 47 (range 20 – 65), and median follow-up for surviving pts is 12 (range 1 – 66) months. As of 8/5/11, 39 pts were alive, and 4 had died from multiorgan failure (n = 1), relapse (n = 1), GVHD (n = 1), and veno-occlusive disease (n = 1). The 2-year estimate of PFS is 84.7% (Fig. 1). The 2-year cumulative incidence of relapse is 6.8% (2 pts, days 97 and 147), and of non-relapse mortality 9.4%. Three pts developed severe (grades III-IV) acute GVHD by day 100 (cumulative incidence 4.6% at day 100) with no additional cases of severe acute GVHD beyond day 100. To date, 4 pts have developed moderate/severe chronic GVHD (cumulative incidence 16.8% at 2 yrs), with one death at day 344 related to complications of acute and chronic GVHD. CMV reactivation occurred in 29 pts (56%), with no deaths related to CMV. Three pts have reactivated EBV, with one case of PTLD (all treated with Rituximab). Conclusions: In this retrospective analysis of single center data, the inclusion of r-ATG in the GVHD prophylactic strategy appeared to significantly attenuate the incidence and severity of both acute and chronic GVHD. Although follow-up is relatively early, the incidence of relapse and NRM does not appear to be increased compared to contemporaneous pts treated without ATG. Given that almost half of the pts received grafts from mismatched URDs, this abrogation in risk of GVHD is significant and clinically relevant. While randomized studies are needed, these data suggest that in-vivo T-cell depletion with r-ATG ameliorates severe GVHD, without increasing relapse or non-relapse mortality, in AML pts without overt leukemia at the time of allo-SCT. Using this strategy, cure rates of 70 – 80% may be realistic and attainable for younger (</= age 65) AML patients who achieve a leukemia-free state and who have a reasonably matched related or unrelated donor. Disclosures: Reeder: Celgene: Research Funding; Millennium Pharmaceuticals Inc.: Research Funding; Novartis: Research Funding.

scholarly journals Burden of Morbidity Borne By Survivors of Multiple Myeloma (MM) Treated with Autologous Blood or Marrow Transplant (BMT) — Results of the BMT Survivor Study (BMTSS)

Blood ◽  
2018 ◽  
Vol 132 (Supplement 1) ◽  
pp. 2127-2127
Author(s):  
Mukta Arora ◽  
Yanjun Chen ◽  
Lindsey Hageman ◽  
Jessica Wu ◽  
Liton F. Francisco ◽  
...  
Keyword(s):  
Cumulative Incidence ◽  
Older Age ◽  
Chronic Health Conditions ◽  
Health Conditions ◽  
Chronic Health ◽  
Increased Risk ◽  
Life Threatening ◽  
Race Ethnicity ◽  
Grade 3 ◽  
Hispanic White

Abstract Background: Autologous BMT (either as a planned procedure after completion of initial treatment or as salvage therapy for relapse) is considered standard of care for patients with MM. Therapeutic advances have resulted in significant improvement in survival, necessitating an understanding of the burden of morbidity borne by MM survivors - an understudied topic. We addressed this gap by conducting a comprehensive evaluation of chronic health conditions (CHCs) in MM patients treated with autologous BMT using BMTSS. Methods: Patients were eligible if they had undergone autologous BMT for MM between 1974 and 2014 at one of 3 BMT centers, had survived for ≥2y after BMT, and were ≥18y of age at participation. Of the 1,116 subjects approached, 630 (56.5%) participated. A nearest-age sibling was invited to participate in the study, and served as an unaffected comparison group (n=289). Survivors and siblings completed a 231-item BMTSS survey that included questions regarding CHCs, including age at onset of each CHC. Each CHC was scored (CTCAE v 4.03) to determine severity. Using multivariable logistic regression, we determined the risk of any severe (grade 3) or life-threatening (grade 4) CHC in survivors compared with siblings, adjusting for age at study, sex, race/ethnicity, education, annual household income and insurance status. Information on initial pre-BMT treatment exposures, conditioning regimens and post-BMT maintenance treatment was abstracted from medical records. Cumulative incidence of CHCs overall, and by specific types were calculated for BMT survivors, treating death as a competing risk. Cox regression was used to determine clinical, demographic and therapeutic predictors of CHCs in BMT survivors. Results: Mean age at BMT was 57.6±8.5y and at survey was 64.2±7.9y. Mean interval between BMT and study participation was 6.6±3.7y; 58% were males, and 62% were non-Hispanic white. Conditioning was melphalan based in 98%, TBI was used in only 5.5%. Mean age at survey for the siblings was 64±8.08y; 58% were male and 84% were non-Hispanic whites. BMT survivors vs. siblings: Overall, 43.3% of the survivors reported a grade 3-4 CHC, placing them at a 1.4-fold higher odds when compared with siblings (95%CI, 1.0-1.9, p=0.03). The odds of developing the following CHCs were significantly higher in BMT survivors when compared with siblings (Fig 1): cataracts (odds ratio [OR]=2.3; 95%CI, 1.4-3.7, p=0.0006), venous thrombo-embolism (VTE: OR=2.4, 95%CI, 1.2-4.6 p=0.01), and subsequent neoplasms (SNs: OR=4.4, 95% CI, 1.8-10.6, p=0.0009). BMT survivors only: 10y cumulative incidence of any grade 3-4 CHC in BMT survivors was 57.6% ± 3.2% (Fig 2). Cataracts: 10y cumulative incidence of cataracts was 24.8% ± 2.7%. Older age at BMT (≥60y: relative risk [RR]=3.3; 95%CI, 2.2-5.1, p <0.0001); TBI-based conditioning (RR=2.3; 95%CI, 1.1-4.8, p=0.02); and female sex (RR=1.6; 95%CI, 1.1-2.4, p=0.01) were associated with increased risk of cataracts. VTE: 10y cumulative incidence of thrombo-embolic events was 10.5% ± 1.6%. Older age at BMT (≥60y: RR=2.2; 95%CI, 1.2-3.9, p=0.007); non-Hispanic white race/ethnicity (RR=4.8; 95%CI, 2.0-11.2, p=0.0003); and pre-BMT exposure to doxorubicin (RR=2.1; 95%CI, 1.04-4.04, p=0.04) were associated with increased risk for VTE. SNs:10y cumulative incidence of SN was 14.0% ± 2.5%. Older age at BMT (≥60y: RR=2.2; 95%CI, 1.2-4.2, p=0.01), pre-BMT exposure to cyclophosphamide (RR=2.9, 95%CI,1.3-6.5, p=0.01) and IMiDs (thalidomide or lenalidomide: RR=3.8, 95%CI, 1.6-9.2, p=0.003); and non-Hispanic white race/ethnicity (RR=2.3; 95%CI, 1.1-4.8, p=0.03) were associated with increased risk for SNs. Conclusion: The 10y cumulative incidence of a severe/life-threatening chronic health condition approaches 60% in multiple myeloma patients treated with autologous BMT. Cataracts, thrombo-embolic events and subsequent neoplasms constitute the largest burden of morbidity. This study identifies demographic factors and treatment exposures associated with increased risk of chronic health conditions, and provides evidence for close monitoring of these survivors to anticipate and manage morbidity. Disclosures Weisdorf: Seattle Genetics: Consultancy; Pharmacyclics: Consultancy; FATE: Consultancy; SL Behring: Consultancy; Equillium: Consultancy. Forman:Mustang Therapeutics: Other: Licensing Agreement, Patents & Royalties, Research Funding.

scholarly journals Allogeneic Blood or Marrow Transplantation (BMT) with Post-Transplantation Cyclophosphamide (PTCy) Based Graft Versus Host Disease (GVHD) Prophylaxis for Myelodysplastic Syndrome/ Myeloproliferative Neoplasm-Overlap Syndromes (MDS/MPN)

Blood ◽  
2020 ◽  
Vol 136 (Supplement 1) ◽  
pp. 40-40
Author(s):  
Theodoros Karantanos ◽  
Hua-Ling Tsai ◽  
Lukasz P. Gondek ◽  
Mark Levis ◽  
Margaret M. Showel ◽  
...  
Keyword(s):  
Clinical Outcomes ◽  
Cumulative Incidence ◽  
Research Funding ◽  
Acute Gvhd ◽  
Chronic Gvhd ◽  
Univariate Analysis ◽  
Kaplan Meier ◽  
Gvhd Prophylaxis ◽  
Grade 3 ◽  
Myelomonocytic Leukemia

INTRODUCTION: MDS/MPN are a group of clonal hematopoietic disorders with overlapping features of MDS and MPN, and include chronic myelomonocytic leukemia (CMML), atypical chronic myeloid leukemia (aCML), MDS/MPN-unclassifiable along with juvenile myelomonocytic leukemia and MDS/MPN with ring sideroblast and thrombocytosis. Therapeutic options for MDS/MPN remain limited and BMT remains the only modality with curative potential. However, the overall survival of these patients following BMT remains poor marked by a high incidence of non-relapse mortality (NRM) and relapse. Moreover, most of the published cohorts consisted of patients receiving matched related donor grafts, with limited data on the outcomes of patients receiving grafts from alternative donors. In the current study, we aim to describe outcomes of BMT for MDS/MPN using PTCy as the GVHD prophylaxis platform and primarily haploidentical related (haplo) donors. PATIENTS AND METHODS: We performed a retrospective analysis of patients with MDS/MPN who underwent BMT with PTCy at Johns Hopkins between 1/2011-1/2019. Kaplan-Meier analysis was used to evaluate overall survival (OS), relapse-free survival (RFS), and GVHD/relapse-free survival (GRFS). Cumulative incidence of relapse and non-relapse mortality (NRM) were estimated non-parametrically in presence of competing events where NRM was a competing event of relapse, and vice versa. Univariate analysis was used to evaluate the impact of donor type, HCT-CI, and karyotype on these clinical outcomes via Cox proportional hazard models for OS/RFS/GRFS, and Fine-Gray's sub-distribution (s) hazard models for relapse/NRM/GVHD. RESULTS: Thirty-four consecutive patients (11 women and 23 men) with a median age of 63 years (range 51-74) at the time of BMT were identified. Of these, 21 (61.8%) had haplo donors and 31 (91%) received non-myeloablative conditioning with fludarabine, cyclophosphamide and total body irradiation. Median follow up was 3.9 years (range: 24 days - 8.4 years) based on reverse Kaplan-Meier approach. Other patient, disease and BMT related details are shown in Table 1. Time to neutrophil and platelet recovery was 22 days (range 19 - 28 days) and 31 days (range 22 - 67 days), respectively. Two (6%) patients had primary graft failure, both had received a marrow graft. At 3-years, probability of OS was 46% (95% CI: 31% - 68%), 3 RFS was 30% (17% - 51%), GRFS was 26% (14%-48%), cumulative incidence of relapse was 59% (95% CI: 41% - 77%) and incidence of NRM was 12% (95% CI: 1% - 23%). The incidence of grade 2-4 acute GVHD at 1 year following HCT was 24% but no patients had grade 3-4 acute GVHD. The cumulative incidence of any chronic GVHD at 3 years was 20% with 3 (9%) patients requiring systemic therapy. Univariate analysis showed that HCT-CI score at the time of HSCT was associated with higher incidence of relapse (sHR 5.22, 95% CI 2.26-12.08) and inferior RFS (HR 3.09, 95% CI 1.16-8.2). Other patient-, disease- and HCT-related factors were not statistically significantly associated with these clinical outcomes. The outcomes of patients with haplo donors (n=21) were also estimated at 3 years and estimates of OS were 56% (95% CI 38% - 82%), RFS 42% (95% CI 26% - 70%), GRFS 37% (21% - 66%), cumulative incidence of relapse 43% (95% CI 21% - 66%), NRM 14% (95% CI 1% - 30%), chronic GVHD 21% (95% CI 2% - 40%). No patients developed grade 3-4 acute GVHD. While the sample size is limited, comparison of K-M estimates for RFS and relapse with haplo donor (n=21) and matched related/unrelated donor (n=12), is shown in Figure 1. CONCLUSIONS: We report, for the first time, clinical outcomes of BMT for MDS/MPN with the PTCy based GVHD platform, and outcomes appear comparable with those previously described in other retrospective studies using conventional approach. Although limited by sample size for a statistical analysis, the outcomes with haplo donor BMT appear promising. The relatively high incidence of relapse in these patients appears to be the major factor contributing adversely to outcomes, while NRM and GVHD incidence with our non-myeloablative conditioning PTCy platform are low. We are currently exploring strategies to decrease relapse rates to further improve BMT outcomes in these patients. Disclosures Levis: Amgen: Honoraria; FujiFilm: Honoraria, Research Funding; Daiichi-Sankyo: Honoraria; Menarini: Honoraria; Astellas: Honoraria, Research Funding. DeZern:MEI: Consultancy; Astex: Research Funding; Abbvie: Consultancy; Celgene: Consultancy, Honoraria. Gojo:BMS: Membership on an entity's Board of Directors or advisory committees; Genentech: Research Funding; Amgen: Research Funding; Merck: Research Funding; Amphivena: Research Funding. Jain:Takeda: Consultancy, Honoraria; CareDx: Other: Advisory Board; Bristol Myer Squibb: Other: for advisory board participation.

Sign in / Sign up

Export Citation Format

Share Document