The Joint Role of Comorbidity and Performance Status (PS) in Predicting Morbidity after Allogeneic Nonmyeloablative Hematopoietic Cell Transplantation (HCT).

Blood ◽  
2006 ◽  
Vol 108 (11) ◽  
pp. 596-596 ◽  
Author(s):  
Mohamed Sorror ◽  
Barry Storer ◽  
Brenda M. Sandmaier ◽  
David G. Maloney ◽  
Michael Pulsipher ◽  
...  
Keyword(s):  
Hematopoietic Cell Transplantation ◽  
Disease Risk ◽  
Strong Predictor ◽  
Performance Status ◽  
Composite Index ◽  
Inverse Correlation ◽  
Risk Groups ◽  
Hematologic Malignancies ◽  
Total Body ◽  
And Performance

Abstract An HCT-specific comorbidity index (HCT-CI) was developed to capture comorbidities among patients (pt) given HCT. Here, we asked whether HCT-CI could provide information independent from current measures, notably PS. PS before and toxicities after HCT were prospectively graded per Karnofsky and Common Toxicity Criteria, respectively, while comorbidities were retrospectively evaluated per HCT-CI. Spearman rank was used to evaluate correlations. This study included pts (n=107) diagnosed with hematologic malignancies and conditioned with nonmyeloablative regimen of 2 Gy total body irradiation alone (15%) or with 90 mg/kg of fludarabine (85%) before related (44%) or unrelated HCT (56%). There were no exclusion criteria for HCT-CI scores but pts with PS of <60% were excluded from HCT. Pretransplant parameters included age (median=56 years); prior regimens (median=4); interval between diagnosis and HCT (median=24.5 months); prior HCT (34%); low, standard, and high disease risks (10%, 63%, and 27%) as described (Kahl et al. Blood-2005).; PS scores (median=90% and range=60–100%); and HCT-CI scores (median=3 and range=0–7). After HCT, 44%, 9%, and 2% of pts developed grades II, III, and IV acute graft-versus-host disease (GVHD) and 24% and 15% developed overall grades III and IV toxicities of solid organs, respectively. There were no correlations between PS and age, prior regimens, interval before HCT, prior HCT, or disease risk. HCT-CI scores had weak correlations with prior regimens (r =0.16, p=0.09) and disease risk (p=0.03) and no correlations with age, interval before HCT, and prior HCT. Pts with high-risk disease and HCT-CI scores of 0–2 vs ≥3 had median prior regimens of 3 vs 5. There was inverse correlation between HCT-CI and PS scores (r = −0.32, p=<0.001). Both higher HCT-CI and PS scores predicted increased incidences of grades II-IV acute GVHD and grades III-IV HCT-related toxicities while only HCT-CI scores predicted increased risks of 1-year NRM and worse survival (Table 1). Table 2 illustrates a composite scale combining the HCT-CI and PS scores and its relationship with short-term morbidity. We conclude that the HCT-CI and PS are only weakly correlated and therefore both should be assessed at HCT. HCT-CI was a strong predictor of morbidity and mortality, while PS predicted morbidity only. The consolidation of both scales could provide a refined stratification of risk groups for HCT-related morbidity. Larger pt cohorts are required to better define such risk groups. Table 1: Impacts of HCT-CI and PS scores on 1-year HCT outcomes HCT-CI scores PS scores 0–2 ≥3 p >80% ≤80% p % % Grades II-IV GVHD 43 67 0.01 48 62 0.02 Grades III-IV toxicities 25 53 0.004 30 52 0.02 Grade IV toxicities 8 23 0.03 12 20 0.2 NRM 11 30 0.01 20 22 0.5 survival 84 50 0.0006 68 64 0.2 Table 2: Composite index of HCT-CI and PS scores Groups Grades II-IV GVHD Grades III-IV toxicities Grade IV toxicities % A HCT-CI=0–2 and PS=≥80% 37 20 6 B HCT-CI=0–2 and PS=<80% 56 37 13 C HCT-CI=≥3 and PS=≥80% 64 44 20 D HCT-CI=≥3 and PS=<80% 69 61 25 p 0.02 0.009 0.1

Applying the Hematopoietic Cell Transplantation-Comorbidity Index (HCT-CI) in Myeloablative MUD Transplants Predicts NRM and OS Using a Modified 2-Tier Scoring System.

Blood ◽  
2007 ◽  
Vol 110 (11) ◽  
pp. 1988-1988
Author(s):  
Tibor Kovacsovics ◽  
Byung Park ◽  
Brandon Hayes-Lattin ◽  
Jose F. Leis ◽  
Peter T. Curtin ◽  
...  
Keyword(s):  
High Risk ◽  
Cell Transplantation ◽  
Cumulative Incidence ◽  
Scoring System ◽  
Clinical Decision Making ◽  
Hematopoietic Cell Transplantation ◽  
Disease Risk ◽  
Risk Groups ◽  
Hematopoietic Stem ◽  
Gvhd Prophylaxis

Abstract Background: The HCT-CI is a recently developed comorbidity score which has been adapted to hematopoietic stem cell transplantation, and identified 3 risk groups with increased non-relapse mortality (NRM) and lower overall survival (OS) (Blood2005;106:2912). We determined the HCT-CI score in a cohort of patients who underwent myeloablative MUD transplantation in a single arm, institutional trial assessing the efficacy of a combination of cyclosporine, methotrexate and prednisone for GVHD prophylaxis. Methods: The analysis included all patients undergoing MUD transplant from 1996–2006 who received GVHD prophylaxis with cyclosporine 2 mg/kg iv BID from day −2, methotrexate 15 mg/m2 iv on day +1 and 10 mg/m2 iv on days +3 and +6, and methylprednisolone 0.25 mg/kg iv BID beginning on day +7 and tapering from day +28. Patients were stratified by disease risk per CIBMTR classification. The comorbidities were obtained by retrospective chart review and scored according to the HCT-CI score. Results: 150 patients (median age 40) received the 3 drug-regimen, including 38% with low-, 34% with intermediate- and 28% with high-risk disease. Diagnoses included acute leukemia in 50%, MDS in 12%, CML in 15%, lymphoma in 18%, and multiple myeloma in 3.0%. Conditioning regimens included Cy-TBI in 64% and Bu-Cy in 21%. Source of stem cells was PBSC in 47.3% and marrow in 50.7%. HCT-CI scores of 0, 1–2 or ≥3 were found in 17%, 30% and 53% of patients evaluated. The majority of comorbidities were pulmonary (72%). With a median follow-up of 46 weeks, day 100 and 5-year OS were 82.7 and 33%, with a 23% and 50.4% cumulative incidence of NRM. Five year relapse-related mortality was 15.8%. Although higher HCT-CI scores were associated with increased NRM and decreased OS, no statistically significant differences were detected when using the published HCT-CI grouping of 0, 1–2 and ≥3. Unadjusted hazard ratio (HR) for inferior survival were 0.9 (CI 0.47–1.85, P=.79) and 1.65 (CI 0.885–3.090, P=.11) for scores 1–2 and ≥3, respectively. We then determined an alternate prognostic model based on 2 groups. Statistical modeling separated patients with a score of 0–3 (n=97, 64%) and ≥4 (n=53, 35.6%), with a 3 month and 5 year OS of 84% and 45% versus 52% and 10%, respectively (P<.0001). Cumulative incidence of day 100 and 5-year NRM was 16% and 38% versus 43% and 73%, respectively. Unadjusted HR for inferior survival was 2.77 (CI 1.816–4.225, P<.0001) for a score of ≥4. By multivariate analysis, only the HCT-CI score (P<.0001) and the disease risk per CIBMTR (P=.0058) were predictive of OS and NRM, but not age, CMV positivity, sex- or HLA-mismatch, or regimen. Conclusions: While our data confirm that the HCT-CI score is predictive of NRM and OS in a high-risk MUD transplant cohort, we were unable to detect statistically significant differences between the 3 risk groups defined in the original score. A modified 2-group scoring system readily stratified the patient population into low-risk and high-risk risk groups with scores of 0–3 and ≥4, respectively, that was predictive of OS and NRM. This simplified, 2-tiered scoring system will have utility in clinical decision-making and in defining patient populations eligible for clinical trials. Additional single and multi-institutional analyses will ultimately determine the optimal applications of the HCT-CI score.

Development and validation of a pediatric disease risk index for allogeneic hematopoietic cell transplantation.

2020 ◽  
Vol 38 (15_suppl) ◽  
pp. 7503-7503
Author(s):  
Muna Qayed ◽  
Carrie L Kitko ◽  
Kwang Woo Ahn ◽  
Mariam H Johnson ◽  
Kirk R. Schultz ◽  
...  
Keyword(s):  
High Risk ◽  
Hematopoietic Cell Transplantation ◽  
Proportional Hazards ◽  
Proportional Hazards Model ◽  
Disease Risk ◽  
Risk Index ◽  
Risk Groups ◽  
The United States ◽  
Cox Proportional Hazards ◽  
Cox Proportional Hazards Model

7503 Background: Characteristics such as disease, disease status and cytogenetic abnormalities impact relapse and survival after transplantation for acute myeloid (AML) and acute lymphoblastic (ALL) leukemia. In adults, these attributes were used to derive the disease risk index for survival. Thus, the current analysis sought to develop and validate a pediatric disease risk index (p-DRI). Methods: Eligible were patients aged <18 years with AML (n=1135) and ALL (n=1228) transplanted between 2008 and 2017 in the United States. Separate analyses were performed for AML and ALL. Patients were randomly assigned (1:1) to a training and validation cohort. Cox proportional hazards model with stepwise selection was used to select significant variables (2-sided p<0.05). The primary outcome was leukemia-free survival (LFS; relapse or death were events). Based on the magnitude of log(HR), a weighted score was assigned to each characteristic that met the level of significance and risk groups were created. Results: Four risk groups were identified for AML and three risk groups for ALL (Table). The 5-year probabilities of LFS for AML were 81% (68-91), 56% (51-61), 44% (39-49) and 21% (15-28) for good, intermediate, high and very high-risk groups, respectively. The 5-year probabilities of LFS for ALL were 68% (63-72), 50% (45-54) and 15% (3-34) for good, intermediate, high risk groups, respectively. Conclusions: This validated p-DRI successfully stratified children with AML and ALL for prognostication undergoing allogeneic transplantation. [Table: see text]

Reduced Intensity (RI) Allogeneic Hematopoietic Cell Transplantation (HCT) Improves Outcomes for Older (≥ 60 Yrs) Patients (Pts) with Acute Myeloid Leukemia (AML).

Blood ◽  
2007 ◽  
Vol 110 (11) ◽  
pp. 1089-1089
Author(s):  
Margaret R. O’Donnell ◽  
Anthony S. Stein ◽  
Ryotaro Nakamura ◽  
Marilyn L. Slovak ◽  
Nicole Tsai ◽  
...  
Keyword(s):  
Peripheral Blood ◽  
Dna Analysis ◽  
Hematopoietic Cell Transplantation ◽  
Performance Status ◽  
Chronic Gvhd ◽  
Disease Free Survival ◽  
Remission Induction ◽  
Gvhd Prophylaxis ◽  
Total Body ◽  
Induction Failure

Abstract The current paradigm of cytarabine-based induction chemotherapy followed by repetitive cycles of similar consolidation has yielded 2-year disease-free survival (DFS) of no more than 20% in older pts (≥60 yrs) who achieve remission. Induction failure (IF) is also high in this population (20–35%), depending on cytogenetic risk. Regimen-related toxicities have been a barrier to allogeneic HCT in older pts. RI conditioning provides a means to harness graft vs. leukemia in this group. Between 2/2000 and 3/1/2007, 46 pts ≥ 60 yrs (median 63 yr, range 60–71) received RI HCT from either related (26) or unrelated (20) HLA matched donors. In 23 pts, RI HCT was used as consolidation of remission (CR1 [19 pts] + CR2 [4 pts]) while 23 had active disease, including 10 IF. Karyotype was favorable in 9%, intermediate in 48% and poor in 41%. The median % marrow blasts for non-remission pts was 31% (6–80%) and peripheral blood blast was 5% (0–78%). The majority (41 pts) received fludarabine (FLU)/melphalan (MEL) for conditioning. Four pts received FLU with either 200G total body irradiation (TBI) (3 pts) or busulfan (1 pt) and one received TBI alone. Graft vs. host disease (GVHD) prophylaxis was based on either cyclosporine/mycophenolate mofetil alone or with methotrexate (MTX) (20/10) or tacrolimus/sirolimus +/− MTX (2/14 pts). The graft source was peripheral blood in 43 pts and marrow in 3 pts. Engraftment occurred at a median of 15 days (0–27 days) in 98% of recipients; graft failure occurred in one sibling HCT. Donor engraftment based on DNA analysis ranged from 30–100% at 4–6 wks post-HCT (median 100%) in the 33 analyzed pts. Mortality at day 100 was 10.8%. Acute GVHD (Grade 2–4) occurred in 61% of recipients and chronic GVHD has occurred in 23/33 evaluable pts. With a median follow-up of 24.5 months (m) for surviving pts (4–83 m), 25/46 (64.5%) pts are alive. For remission pts, the 2 yr DFS is 65% (CI 51–76%). For pts who received RI HCT as “salvage”, 34% are DF at 2 yrs. (CI 27–41%). Relapse rates were 11% for remission pts and 60% for non-remission pts. Deaths post HCT were attributed to relapse in 12 pts and treatment related mortality due to GVHD (6 pts) or infection (3 pts). Conclusion: DFS can be improved for older patients with the use of RI HCT as remission consolidation. RIC also provides a meaningful salvage option for pts with IF or early relapse. Evaluation of donor options including both siblings and unrelated donors should be considered during induction for patients with good performance status.

scholarly journals Incidence and impact of stroke following surgery for low-grade gliomas

2019 ◽  
pp. 1-9 ◽  
Author(s):  
Assaf Berger ◽  
Gali Tzarfati ◽  
Matias Costa ◽  
Marga Serafimova ◽  
Akiva Korn ◽  
...  
Keyword(s):  
Risk Factors ◽  
Strong Predictor ◽  
Performance Status ◽  
Neurological Deficits ◽  
Functional Improvement ◽  
Motor Deficits ◽  
Low Grade ◽  
Neurocognitive Functions ◽  
Ischemic Complications ◽  
And Performance

OBJECTIVEIschemic complications are a common cause of neurological deficits following low-grade glioma (LGG) surgeries. In this study, the authors evaluated the incidence, risk factors, and long-term implications of intraoperative ischemic events.METHODSThe authors retrospectively evaluated patients who had undergone resection of an LGG between 2013 and 2017. Analysis included pre- and postoperative demographic, clinical, radiological, and anesthetic data, as well as intraoperative neurophysiology data, overall survival, and functional and neurocognitive outcomes.RESULTSAmong the 82 patients included in the study, postoperative diffusion-weighted imaging showed evidence of acute ischemic strokes in 19 patients (23%), 13 of whom (68%) developed new neurological deficits. Infarcts were more common in recurrent and insular surgeries (p < 0.05). Survival was similar between the patients with and without infarcts. Immediately after surgery, 27% of the patients without infarcts and 58% of those with infarcts experienced motor deficits (p = 0.024), decreasing to 16% (p = 0.082) and 37% (p = 0.024), respectively, at 1 year. Neurocognitive functions before and 3 months after surgery were generally stable for the two groups, with the exception of a decline in verbal rhyming ability among patients with infarcts. Confusion during awake craniotomy was a strong predictor of the occurrence of an ischemic stroke. Mean arterial pressure at the beginning of surgery was significantly lower in the infarct group.CONCLUSIONSRecurrent surgeries and insular tumor locations are risk factors for intraoperative strokes. Although they do not affect survival, these strokes negatively affect patient activity and performance status, mainly during the first 3 postoperative months, with gradual functional improvement over 1 year. Several intraoperative parameters may suggest the impending development of an infarct.

Relationship between Conditioning Intensity and Comorbidity in Patients (Pts) with Acute Myeloid Leukemia (AML) or Myelodysplasia (MDS) Receiving Allogeneic Hematopoietic Cell Transplantation (HCT).

Blood ◽  
2005 ◽  
Vol 106 (11) ◽  
pp. 705-705 ◽  
Author(s):  
Mohamed Sorror ◽  
Barry Storer ◽  
Brenda M. Sandmaier ◽  
Michael Maris ◽  
Frederic Baron ◽  
...  
Keyword(s):  
High Risk ◽  
Hematopoietic Cell Transplantation ◽  
Proportional Hazards ◽  
Disease Risk ◽  
Refractory Anemia ◽  
Unrelated Donor ◽  
Stem Cell Source ◽  
Hazard Ratios ◽  
High Risk Disease ◽  
Total Body

Abstract We developed a new HCT-specific comorbidity index (HCT-CI) as a sensitive tool to capture pretransplant comorbidties among pts given allogeneic HCT (Sorror et al, online, 2005; DOI 10.1182/blood-2005-05-2004). In the current report, we used the HCT-CI to explore differences in the tolerability of nonablative compared to ablative HCT in MDS or AML pts with pretransplant comorbidities. Consecutive pts (n=88) receiving nonablative conditioning with 2 Gy total body irradiation (TBI) alone (6%) or with 90 mg/kg of fludarabine (94%) were compared to concurrent pts (n=361) conditioned with cyclophosphamide plus busulfan (70%) or 12–14 Gy TBI (30%). All pts were classified into low (AML-first complete remission or MDS-refractory anemia) and high-risk disease (all others). Overall, 76% of nonablative pts had AML compared to 66% of ablative pts. At HCT, nonablative pts differed substantially from ablative pts with respect to age (median 60 vs 46 years), use of unrelated donor grafts (57% vs 42%), use of marrow grafts (5% vs 20%), and HCT-CI scores of ≥2 (75% vs 45%). Smaller differences existed for high-risk disease (64% vs 58%) and pt cytomegalovirus positive sero-status (59% vs 55%). Proportional hazards models were used to estimate the hazard ratio (HR) for non-relapse mortality (NRM) and survival for pts receiving nonablative compared to ablative conditioning regimens; these models were adjusted for stem cell source, pt age, donor type, pt cytomegalovirus sero-status, diagnoses (MDS vs AML), and HCT-CI scores (Table). Adjusted HRs were not statistically significantly different, except among pts with high-risk disease and HCT-CI scores of ≥2 where nonablative pts had lower HR for NRM (0.34, P=0.005) and worse survival (0.51, P=0.006, Fig.1). These results suggest that pts with high-risk MDS or AML and HCT-CI scores of ≥2 might have less NRM and better survival with nonablative than with ablative HCT. Prospective randomized trials are warranted to confirm this retrospective observation. Additional data are needed for AML and MDS pts with low comorbidities or low disease risk in order to clarify the usefulness of nonmyeloablative conditioning. Table: Adjusted hazard ratios for pts receiving nonablative relative to ablative conditioning Nonablative/ablative NRM Survival Number HR* (95% CI) P HR* (95% CI) P *HR &lt;1 indicates more favorable outcome for pts receiving nonablative conditioning Low-risk disease HCT-CI scores 0–1 7/86 0.0 (undefined) 0.33 0.8 (0.1–6.3) 0.83 HCT-CI scores ≥2 25/64 1.97 (0.7–5.9) 0.23 1.86 (0.8–4.1) 0.13 High-risk disease HCT-CI scores 0-1 15/112 0.60 (0.1–2.7) 0.51 0.96 (0.5–2.0) 0.92 HCT-CI scores ≥2 41/99 0.34 (0.2–0.7) 0.005 0.51 (0.3–0.8) 0.006 Figure Figure

Impact of the Intensity of Conditioning Therapy On the Outcomes of Patients Aged 40 to 60 Years with Acute Myeloid Leukemia/Myelodysplastic Syndrome Undergoing Allogeneic Hematopoietic Cell Transplantation.

Blood ◽  
2009 ◽  
Vol 114 (22) ◽  
pp. 1202-1202
Author(s):  
Murtadha K. Al-Khabori ◽  
Mohamed El-Emary ◽  
Gordon Guyatt ◽  
Ahmed Galal ◽  
John Kuruvilla ◽  
...  
Keyword(s):  
Hematopoietic Cell Transplantation ◽  
Disease Risk ◽  
Performance Status ◽  
Chronic Gvhd ◽  
Free Survival ◽  
Co Morbidity ◽  
High Risk Disease ◽  
Conditioning Regimens ◽  
Conditioning Therapy ◽  
Morbidity Index

Abstract Abstract 1202 Poster Board I-224 Introduction: The eligibility of patients to undergo allogeneic hematopoietic cell transplantation (AHCT) is limited by age, co-morbid conditions and performance status. Utilizing reduced and minimal intensity conditioning regimens, older and less fit patients could benefit from this modality with the graft versus leukemia effect. Methods: We performed a retrospective analysis of adults aged 40-60 years with acute myeloid leukemia (AML) or myelodysplastic syndrome (MDS) undergoing AHCT at our center from January 2002 to June 2008. The objective of the study is to compare the overall (OS), relapse free (RFS), acute GvHD free and chronic GvHD free survival between the different conditioning regimens. The regimens are classified according to the definition of CIBMTR as conventional intensity (CIC) or reduced intensity (RIC). High risk disease is defined as patients meeting one of the following criteria: AML with poor risk cytogenetics, secondary AML with preceding hematologic disorder, AML in second complete remission or AML/MDS with preceding malignancy. Results: There are 106 patients eligible for the study (CIC 67, RIC 39); 56 patients with de novo AML, 22 with MDS and 28 with secondary AML. High risk disease comprised 64% of our study population. The baseline characteristics between the two groups including performance status (Karnofsky Performance Score; CIC 81%, RIC 83%, p=0.08) are not different except for age (mean in years; CIC 50.2, RIC 52.9, p=0.03), graft versus host disease (GvHD) prophylaxis (cyclosporine/alemtuzumab; CIC 16%, RIC 57%, p<0.001), donor type (unrelated donor; CIC 30%, RIC 54%, p=0.04) and Seattle co-morbidity index score (score of ≥3; CIC 12%, RIC 31%, p=0.03). The median follow up duration for all patients was 1.93 years. There is no statistically significant difference in the OS between the two groups (median OS in years; CIC 1.93, RIC 2.59, Log-rank p=0.62). Furthermore, RFS between the two groups were similar (median RFS was not reached in either groups, Log-rank p=0.86). Using Cox-model adjusting for important prognostic factors at baseline (age, disease risk, donor type, performance status, Co-morbidity index score and type of conditioning regimen), only performance status and disease risk are significant for both OS (HR 0.906 [p=0.01] and 2.13 [p=0.04] respectively) and RFS (HR 0.854 [p=0.04] and 6.931 [p=0.007] respectively). The acute GvHD and chronic GvHD free survival curves are not significantly different in the two groups (Log-rank p values are 0.66 and 0.16 respectively). Conclusion: Despite inferior baseline characteristics in the patients receiving RIC, the outcomes were similar. Disease biology rather than intensity of the conditioning therapy is the determinant of overall survival and relapse risk after AHCT in patients aged 40-60 years with AML/MDS. Prospective randomized studies are needed to determine the superiority of RIC in patients who are deemed suitable to undergo CIC. Disclosures: No relevant conflicts of interest to declare.

Hematopoietic cell transplantation in older patients with hematologic malignancies: replacing high-dose cytotoxic therapy with graft-versus-tumor effects

Blood ◽  
2001 ◽  
Vol 97 (11) ◽  
pp. 3390-3400 ◽  
Author(s):  
Peter A. McSweeney ◽  
Dietger Niederwieser ◽  
Judith A. Shizuru ◽  
Brenda M. Sandmaier ◽  
Arthur J. Molina ◽  
...  
Keyword(s):  
Cell Transplantation ◽  
Graft Rejection ◽  
Hematopoietic Cell Transplantation ◽  
Hematologic Malignancies ◽  
Outpatient Setting ◽  
Hematopoietic Cell ◽  
Mixed Chimerism ◽  
High Dose ◽  
Antitumor Effects ◽  
Total Body

Toxicities have limited the use of allogeneic hematopoietic cell transplantation (HCT) to younger, medically fit patients. In a canine HCT model, a combination of postgrafting mycophenolate mofetil (MMF) and cyclosporine (CSP) allowed stable allogeneic engraftment after minimally toxic conditioning with low-dose (200 cGy) total-body irradiation (TBI). These findings, together with the known antitumor effects of donor leukocyte infusions (DLIs), led to the design of this trial. Forty-five patients (median age 56 years) with hematologic malignancies, HLA-identical sibling donors, and relative contraindications to conventional HCT were treated. Immunosuppression involved TBI of 200 cGy before and CSP/MMF after HCT. DLIs were given after HCT for persistent malignancy, mixed chimerism, or both. Regimen toxicities and myelosuppression were mild, allowing 53% of eligible patients to have entirely outpatient transplantations. Nonfatal graft rejection occurred in 20% of patients. Grades II to III acute graft-versus-host disease (GVHD) occurred in 47% of patients with sustained engraftment. With median follow-up of 417 days, survival was 66.7%, nonrelapse mortality 6.7%, and relapse mortality 26.7%. Fifty-three percent of patients with sustained engraftment were in complete remission, including 8 with molecular remissions. This novel allografting approach, based on the use of postgrafting immunosuppression to control graft rejection and GVHD, has dramatically reduced the acute toxicities of allografting. HCT with the induction of potent graft-versus-tumor effects can be performed in previously ineligible patients, largely in an outpatient setting. Future protocol modifications should reduce rejection and GVHD, thereby facilitating studies of allogeneic immunotherapy for a variety of malignancies.

Anti-CD45 Radioimmunotherapy Facilitates Donor Engraftment and Prolongs Survival in the Absence of TBI Prior to Haploidentical Bone Marrow Transplantation in a Disseminated Murine Leukemia Model

Blood ◽  
2012 ◽  
Vol 120 (21) ◽  
pp. 4101-4101
Author(s):  
Johnnie J. Orozco ◽  
Aimee Kenoyer ◽  
Ethan R. Balkin ◽  
Donald K. Hamlin ◽  
D Scott Wilbur ◽  
...  
Keyword(s):  
Hematopoietic Cell Transplantation ◽  
Conflicts Of Interest ◽  
Conditioning Regimen ◽  
Flow Cytometric Analysis ◽  
Hematologic Malignancies ◽  
Leukemic Cells ◽  
Mixed Chimerism ◽  
Cd8 Cells ◽  
Flow Cytometric ◽  
Total Body

Abstract Abstract 4101 Background: Despite the curative promise of hematopoietic cell transplantation (HCT), many patients with hematologic malignancies relapse and others may not proceed to HCT due to the unavailability of a matched donor. Toxicities remain high with HCT, due in part to the administration of non-specific therapies such as total body irradiation (TBI) as part of preparative regimens. We aim to overcome these limitations by replacing TBI with anti-CD45 radioimmunotherapy (RIT) for haploidentical HCT to deliver radiation directly to leukemic cells while sparing normal organs and minimizing non-specific toxicities. Methods: We established an initial TBI HCT regimen in B6SJLF1/J mice (H-2Db haplotype) conditioned with fludarabine (FLU, days -6 to -2), followed by TBI (250, 500, 750 cGy; day -1). The mice then received 15 million donor (CB6F1/J, H-2Dd) BM cells (day 0), followed by cyclophosphamide (CY) for graft-versus-host disease (GvHD) prophylaxis (day +2). Subsequent RIT HCT studies involved B6SJLF1/J mice conditioned with and without fludarabine (FLU) and escalating doses (200–400 μCi) of 90Y-anti-CD45 Ab (30F11) RIT without TBI, followed by infusion of haploidentical BM cells from CB6F1/J mice and a single dose of cyclophosphamide (CY) 2 days after HCT. Chimerism studies were performed using flow cytometric analysis to assay for engraftment of donor CD8+ cells. Therapeutic studies were performed in B6SJLF1/J mice given 105 syngeneic leukemia cells via tail vein (day -5), followed by 200 or 400 μCi 90Y-30F11 (day -3), and 1.5 × 107 BM donor cells (day 0) and two doses of CY (days -2 and +2) without FLU. Results: Using this model we have demonstrated that mixed chimerism was established in mice transplanted with TBI or escalating doses (200–400 μCi) of 90Y-30F11 RIT followed by injection of haploidentical BM donor rescue cells. TBI-based HCT showed that chimerism as determined by flow cytometric analysis for donor CD8+ cells was TBI dose-dependent; mice receiving ≥500 cGy were fully chimeric 4 weeks post-HCT, and persisted ≥12 months. RIT-based HCT also revealed mice with mixed chimerism, with up to 89% of donor CD8+ cells 1 month after HCT. Elimination of FLU from the conditioning regimen did not significantly decrease chimerism, as mice transplanted without FLU showed up to 70% donor CD8+ cells 1 month after HCT. Subsequent RIT experiments in B6SJLF1/J mice harboring AML were treated with escalating doses of 90Y-30F11 prior to HCT without FLU. Mice treated with anti-CD45 RIT using 200 μCi and 400 μCi of 90Y-30F11 had a median overall survival (OS) of 73 (p<0.001) and 107.5 (p=0.0015) days, respectively, compared to untreated leukemic control mice which had a median OS of 34 days after HCT (p values by Log rank (Mantel-Cox) testing)(Figure). Two mice in the 400 μCi-90Y-30F11 group were euthanized on day 3 for excessive weight loss, without gross histology abnormality in kidneys or liver. Conclusion: These studies suggest that anti-CD45 RIT in the absence of TBI and FLU prior to haploidentical HCT can lead to establishment of mixed chimerism. Moreover, this anti-CD45 RIT in combination with haploidentical HCT can lead to improvement in survival for mice with AML. These results suggest that clinical studies with anti-CD45 RIT in lieu of TBI and FLU in a haploidentical HCT regimen should be considered for further investigation. Disclosures: No relevant conflicts of interest to declare.

Charlson Comorbidity Index (CCI) and Hematopoietic Cell Transplantation Specific-Comorbidity Index (HCT-CI) Do Not Predict Transplant Related Mortality (TRM) and Post-Transplant Outcomes In Young Patients Undergoing Reduced Intensity Conditioning (RIC) Umbilical Cord Blood (UCB) Transplantation

Blood ◽  
2013 ◽  
Vol 122 (21) ◽  
pp. 4582-4582
Author(s):  
Oana V. Paun ◽  
Tamila L. Kindwall-Keller ◽  
Hillard M. Lazarus ◽  
Mary J. Laughlin ◽  
Paolo F. Caimi ◽  
...  
Keyword(s):  
High Risk ◽  
Acute Gvhd ◽  
Hematopoietic Cell Transplantation ◽  
Performance Status ◽  
Young Patients ◽  
Hematologic Malignancies ◽  
Post Transplant ◽  
Transplant Outcomes ◽  
Comorbidity Index ◽  
Ecog Ps

TRM, drug toxicities, life-threatening infections, poor quality of life, and graft versus host disease (GVHD) are significant risks of hematopoietic cell transplantation (HCT). In addition to the risks of HCT, existence of pre-transplant comorbidities can have significant impact on transplant outcomes. A comparison of CCI and the HCT-CI revealed that HCT-CI was prognostic and better at predicting TRM and overall survival (OS). However, the HCT-CI and CCI results have been inconsistent in predicting the TRM and OS in validation studies. In subgroup analyses of a large retrospective trial, HCT-CI did not predict TRM or OS for UCB recipients. Patient heterogeneity in age, disease, disease-risk, comorbidities, and conditioning regimens may have limited validation in these UCB recipients. The design of this research was to explore whether or not the HCT-CI and/or CCI can accurately predict post-transplant outcomes in young patients with high risk hematologic malignancies undergoing uniform RIC UCB transplantation. A retrospective chart review was performed on 52 consecutive young (age < 55) UCB transplant recipients receiving the RIC regimen fludarabine, cyclophosphamide, ATG, and 200 cGy TBI. All patients had received cyclosporine and mycophenolate mofetil for GVHD prophylaxis. Information on pre-transplant comorbidities was obtained from the CIBMTR pre-TED form for each patient and retrospective chart reviews. Demographic information, ECOG performance status (PS), identification of comorbidities, and post-transplant outcomes were obtained. Between 2005 and 2011, 52 patients age 19 – 54 (median 38) years, 30 males (58%) and 22 females (42%), underwent RIC UCB transplantation with the above regimen. Most patients had advanced stage or high risk hematologic malignancies; 28 patients had MDS/AML (54%), 8 patients had ALL (15%), while 16 patients had other hematologic malignancies. 39 patients had a PS = 0, while 13 had a PS = 1. Half of the patients were in CR > 2, with the same number receiving more than 2 prior therapies. 8 patients had received a prior autologous HCT, 8 a prior allo-HCT, and one patient had failed a previous UCD transplantation. 11 patients did not achieve engraftment. Median time to neutrophil engraftment was 26 days (95% CI: 24 – 28 d) and median time to platelets engraftment was 38 days (95% CI: 31 – 45 d). No patient developed grade 4 acute GVHD. Grade 3 acute GVHD was seen in 12 / 52 patients (23%). Chronic GVHD was seen in likewise seen in 12 patients (23%). To date 16 patients (30%) have relapsed. OS was 42% and PS was 37% at one year. Median PFS and median OS were 5 months and 7 months, respectively (PFS 95% CI: 1 – 11 months, OS 95% CI: 1 – 13 months). Neither CCI, nor HCT-CI were significant predictors of OS and PFS, however the ECOG PS was significantly associated with an improved OS and PFS (Table).OSPFSN1 yr2 yrs4 yrsp1 yr2 yrs4 yrspECOG PS03946%36%21%0.02644%36%21%0.0311331%0015%00CCI≤ 23944%26%10%0.2238%26%10%0.2> 21338%31%31%38%31%31%HCT-CI02236%31%5%0.3632%32%5%0.3211443%14%14%29%14%14%≥21643%31%31%44%31%31%TRM occurred in 18 patients (35%). Neither comorbidity indices, nor the performance status were correlated to TRM (p > 0.05). For ECOG PS, OR 1.6 p = 0.49, CI 0.42 - 5.93; CCI OR = 2.4, p = 0.09, CI 0.86 - 6.59, HCT-CI OR = 0.6, p = 0.46, CI 0.19 - 2.08. In a previous presentation our group concluded that CCI performs better than HCT-CI in elderly patients undergoing UCB transplant. When tested in a population younger than 55 years old though, we were unable to validate the generally accepted prognostic indices. It is unclear whether this is due to a selection bias: it appears most of the patients were essentially health from a non-hematological stand-point, and as such the “classic” cardiac or pulmonary risk factors were underrepresented. The excess TRM is likely due to the severity of their underlying disease, and the majority were in CR ≥ 2 and had received multiple previous courses of antineoplastic chemotherapy. As umbilical cord transplants become more utilized, a new prognostic index needs to be developed, more fitting to the patients < 55 years old. Disclosures: No relevant conflicts of interest to declare.

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