ALBERT

Description: Abstract 151 In 2005, the NIH Consensus Conference proposed measures to improve the documentation of clinically meaningful changes in chronic GVHD (cGVHD) for clinical trials. We evaluated the NIH recommended measures and the Vienna Skin Scale (VSS) for their correlation with provider and patient perceptions of skin changes and with survival. Methods: Patients ≥ age 2 with cGVHD ≤ 3 years after allogeneic hematopoietic cell transplantation requiring systemic treatment were eligible. The NIH response tool scores 8 body regions according percentage of body surface area (BSA) involved with erythematous rash, moveable sclerosis, and non-moveable sclerosis. The VSS scores 10 body regions with percentage involvement of pigmentary changes, rash, and sclerosis. Regional scores are summed for a Vienna Skin Total (VST) score of 0–50. The categorical NIH skin score grades subjects from 0–3 based on extent of skin involvement, sclerotic features, and symptoms. Also collected were the Hopkins skin sclerosis score (0–4), Hopkins fascia score (0–3), and two patient-reported measures: skin itching (0–10) and the Lee Symptom Score skin subscale (0–100). At follow-up visits every six months, patients and providers rated separately their perception of change in skin involvement on an 8-point scale, which was analyzed as improved, stable, or worse. Multivariable linear models were used to test the strength of association between changes in measures of skin severity and clinician and patient assessments of change in skin involvement, adjusting for other significant clinical variables. Overall survival (OS) and non-relapse mortality (NRM) were analyzed using Cox regression models, adjusting for other significant variables. Results: Nine sites in the Chronic GVHD Consortium had enrolled 458 participants as of December, 2010. At enrollment, 200 (44%) patients had no skin involvement and one was missing skin assessments. The remaining 257 patients had erythema (n=196, 43%), moveable sclerosis (n=85, 19%), and non-moveable sclerosis (n= 43, 9%). Per NIH overall scoring criteria, 148 (32%) subjects had severe and 262 (57%) had moderate chronic GVHD at study entry. At a total of 538 follow-up visits with skin involvement or following a visit with skin involvement, change in cGVHD skin symptom was rated by the providers as improved in 45%, stable in 46%, or worse in 9%, and by patients as 58%, 35%, 7% respectively. Change in the categorical NIH skin score assessed by clinicians and the skin subscale of the Lee Symptom Score assessed by patient were best correlated with clinician and patient perception of change (Table and Figure). With a median survivor follow-up of 18.3 months, baseline NIH skin score of 3 was associated with worse OS (HR 2.6, 95% CI 1.3–5.0, p =.004) and NRM (HR 3.7, 1.8–7.7, p 〈 0.001) compared to no skin involvement. In addition, worsening in NIH skin score at 6 months was associated with lower OS (HR 5.3, 1.2–25.5, p =.03) and higher NRM (HR 7.0, 1.4–40.4, p =.02) compared to stable skin among patients with cutaneous involvement at baseline. Change of NIH skin score at 12 months was not associated with OS or NRM. Conclusions: The strong correlation between change in NIH skin score 0–3 with provider- and patient-reported cutaneous changes in both directions and its predictive value for OS at 6 months supports use of this single item scale as a composite measure to evaluate skin involvement in clinical trials.Figure.Correlation between change in the categorical NIH skin score and the Lee Symptom Skin Score with clinician and patient perception of change.Figure. Correlation between change in the categorical NIH skin score and the Lee Symptom Skin Score with clinician and patient perception of change.Table.Multivariable linear mixed models to predict clinician or patient reported change in skin involvementMeasure of skin severityContrast in clinician or patient perception of changeClinicianPatientp-valuep-valueNIH erythemaImproved vs Stable

Description: Abstract 348 We previously reported results of 3 sequential trials of GVHD prophylaxis with mycophenolate mofetil (MMF) BID/TID and cyclosporine (CSP) BID with various taper schedules in patients (pts) with advanced hematologic malignancies given unrelated G-CSF-mobilized peripheral blood stem cell (PBSC) grafts after fludarabine 90 mg/m2 and 2 Gray total body irradiation. Cumulative incidences of grades II-IV acute GVHD in the 3 trials were 52, 53 and 77%, respectively. The goal of the current protocol was to evaluate, in a phase II randomized 3-arm study, which drug combination or schedule was most promising in preventing acute GVHD. Tacrolimus (Tac) was used in place of CSP and each of the 3 arms used MMF TID until day 30 and then BID, but the subsequent duration of MMF varied. In Arm1, pts received Tac until day 180 and MMF until day 96. In Arm2, Tac was given until day 150 and MMF until day 180. In Arm3, Tac was given until day 150 and MMF until day 180 with the addition of rapamycin from days -3 through 80. One hundred seventy-five pts ineligible for myeloablative conditioning were enrolled on this multi-institutional study between Jan/05 and Aug/09, and results on the first 159 pts (Arm1 n=56; Arm2 n=51; Arm3 n=52) are reported here with a median follow-up of 18.4 months for surviving pts. The median age of pts was 60 (range 13-75) yrs. Sixty-six (42%) had previous autologous (n=55) or allogeneic (n=11) HCT. All pts were matched for HLA-DRB1 and -DQB1 at the allele level: 16 had single allele mismatches at HLA-A, -B or –C and the remainder (n=143) were fully HLA-matched. Diagnoses included AML (n=72), NHL (n=36), MM (n=19), ALL (n=10), CLL (n=9), MDS (n=8), HL (n=4), and CML (n=1). Randomization was based upon transplant center (FHCRC vs other), number of prior chemotherapy treatments (0-2 vs 3+), and age (

Description: Abstract 2256 Poster Board II-233 Correlation of the NIH and Vienna Skin scores with provider and patient-reported skin changes in chronic graft-versus-host disease (GVHD) In 2007 we began a multi-center, prospective, observational study of patients diagnosed with chronic GVHD (cGVHD) by National Institute of Health (NIH) Consensus Conference criteria. A major objective is to develop sensitive and valid organ-specific criteria for cGVHD activity to document clinically meaningful changes in clinical trials. This preliminary analysis evaluated the NIH skin tool and the Vienna Skin scale (VS) for their ability to quantify the type and extent of skin involvement, and for their correlation with provider and patient perceptions of change in the skin. Methods: Patients ≥ age 2 diagnosed with cGVHD within 3 years after allogeneic hematopoietic cell transplantation requiring systemic treatment were eligible. Providers and patients complete multiple cGVHD assessment tools at study entry and every 3-6 months. The NIH scale grades 8 body regions according to the percent of body surface area (BSA) involvement by 3 manifestations: 1) erythematous rash, 2) moveable sclerosis, and 3) non-moveable sclerosis, with possible values of 0-100% total BSA for each manifestation. The VS scores each of 10 body regions with percentage involvement of 4 types of skin manifestations: 1 = hypo/hyperpigmentation, erythematous rash, 2 = lichenoid plaque, thickening, able to move, 3 = thickened, limited motion, pinchable, 4 = hidebound, unable to move or pinch. For areas scored as 3 or 4, concurrent fraction involved with erythema is also recorded. Regional scores are summed for a Vienna Skin Total (VST) score of 0-50. At follow-up visits patients and providers rated change in skin involvement as improved, stable, or worse. Proportional odds regression was used to predict improved, stable and worse rates using the difference in NIH subscales or VST since the last visit (change scores). Predictive ability for each scale was summarized using the c index of concordance. Results: Of the 229 participants as of 4/30/09, 61% were males, the median age was 52 years (2-79) and median time from transplant to study entry was 393 days (91-1233). Table 1 shows the scores on the two scales for patients with any skin involvement at baseline (n=161, 70%). At 168 follow-up visits with NIH and VS data, skin GVHD was rated by the providers as improved, stable, or worse in 43%, 48%, and 9%, respectively. Both tools appeared to predict subjective change with the c index of concordance of 0.76 for NIH and 0.71 for VS. Compared to providers, patients were more likely to rate the skin as improved (56%), and less likely to report stable (38%) or worse (6%). The same differences (VST, and NIH erythema and non-moveable sclerosis) were still significant predictors of patients' subjective change. Concordance (c index) and parameter estimates (odds ratios) were attenuated compared to models of provider ratings.Results of the 4 models are summarized in Table 2. Conclusions: Skin involvement is frequent in cGVHD. Both NIH and VS scores are associated with provider- and patient-reported changes in skin severity. These results suggest that the NIH and VS tools are quantitative measures that are sensitive to provider and patient-perceived skin changes over time. Data from additional patients with a broader range of skin severity and longer follow up are needed to better define the roles of these scales as endpoints in clinical trials. Disclosures: Jagasia: Genzyme: Research Funding.

Description: Fourteen patients with cytogenetic relapse of chronic myeloid leukemia (CML) after transplantation with unmanipulated bone marrow were treated with α-2a–interferon. There were eight men and six women, median age, 33 years. Twelve patients received marrow from a related allogeneic donor and two received marrow from a syngeneic donor. The median percentage of Ph-positive metaphases at the time of starting interferon was 55% (10% to 87%). Daily interferon was started at a dose of 1 to 3 × 106 U/M2/d, depending on initial blood counts and was adjusted as tolerated to maintain the white blood count in the range of 2,000 to 3,000/μL and the platelet count greater than 60,000/μL. After a stable cytogenetic remission was achieved, the interferon dose was decreased to a maintenance level. Twelve patients achieved a complete cytogenetic remission on at least one occasion. Median time to achieve a complete cytogenetic remission was 7.5 months (range, 1.5 to 12). Eight patients remain in cytogenetic remission for 10+ to 54+ months from the time of first documented remission. After complete cytogenetic remission was established, nine patients were tested for the presence of the mRNA transcript of the bcr/abl fusion gene by polymerase chain reaction (PCR) testing. Four patients were PCR-negative on at least one occasion: two patients were PCR-negative on a single occasion; one patient had serial tests, which were PCR-negative; and one patient had serial PCR-negative peripheral blood tests with a single PCR-positive bone marrow obtained concurrently with a negative peripheral blood test. Median follow-up time for all patients is 44 months (range, 20 to 64). Interferon was generally well tolerated; only one responding patient was unable to continue interferon because of toxicity. Interferon induces durable cytogenetic remissions in a significant proportion (57%) of patients with cytogenetic relapse following bone marrow transplantation (BMT) without causing life-threatening toxicities.

Description: Background. We investigated the impact of graft composition on GVHD in 1520 allogeneic transplant recipients given PBSC. Methods. Graft composition was determined by FACS analyses and expressed as cells/kg of recipient weight. Cell types were defined as follows: CD3+ T cell (CD3+CD56−), CD4+ T cell (CD3+CD4+), CD8+ T cell (CD3+CD8+), natural killer (NK) cell (CD3−CD56+), NK/T cell (CD3+CD56+), B cell (CD20+), monocyte (CD14+), and CD34+ cells (CD34+CD14−). Cell doses were modeled as continuous linear variables or by quartiles. Cox (for chronic) and logistic (for acute) regression models were adjusted for conditioning regimen intensity, pt age, female donor to male recipient vs. other gender combination, and disease risk. Results. The median age among all pts was 52 (45 among myeloablative, 57 among nonmyeloablative); 27% of pts were male transplanted from a female donor; 66% of pts had high-risk disease; 49% were transplanted from an alternative donor (47% unrelated, 2% mismatched sibling); 51% received a nonmyeloablative conditioning. Table 1 shows graft composition and GVHD incidences according to donor type and conditioning intensity. There were no statistically significant associations between cell dose and acute GVHD, although there was a suggestion that the association of NK/T cell was dependent on conditioning. In particular, increasing NK/T cells were associated with an increased probability of grades 2–4 GVHD among myeloablative pts (p=.03) but not among nonmyeloablative pts. There were no statistically significant associations between cell dose and chronic GVHD, but several cell types showed evidence of an interaction between donor and cell dose. In particular, increasing B cells and CD3+, CD4+, and CD8+ T cells were associated with an increased risk of chronic GVHD among pts with an HLA-identical donor (p=.006, p=.0003, p=.0002, p=.02, respectively) while the associations among alternative donors were in the opposite direction and were not statistically significant (p=.68, p=.26, p=.44, and p=.15, respectively). Lack of correlation in the alternative donor group may reflect differences in T-cell responses to the greater minor histocompatability divergence, or changes in T-cell functionality associated with the dose of G-CSF (higher in sibling donors) used for mobilization. Increasing CD34+ cells was not statistically associated with chronic GVHD in either myeloablative (negative association, p=.10) or nonmyeloablative (positive association, p=.11) pts. Conclusions. Higher numbers of transplanted T and B cells were associated with an increased risk of extensive chronic GVHD in pts given grafts from HLA-identical siblings. Increasing CD34+ cells were not associated with a statistically significant increase in chronic GVHD. Further analyses looking at other clinical outcomes such as survival are forthcoming. Table 1. Graft composition and GVHD according to conditioning intensity and donor type Nonmyeloablative conditioning and HLA-id sibling Myeloablative conditioning and HLA-id sibling Nonmyeloablative conditioning and alternative donor Myeloablative conditioning and alternative donor Median # of T cell transplanted (× 108/Kg) 3.4 2.5 2.5 2.8 Median # of CD34+ cell transplanted (× 106/Kg) 8.6 7.5 6.9 7.5 Incidence of grade II–IV acute GVHD (%) 47 66 61 81 Incidence of extensive chronic GVHD (%) 40 54 41 49

Description: With increasing success of myeloablative HCT for patients with hematologic disorders, development of pre-pubertal children through puberty, return of gonadal function and the ability to become pregnant are of concern. To determine the impact of the preparative regimen on these issues, long-term follow-up records of more than 2,000 patients have been evaluated. Preparative regimens include cyclophosphamide (CY) 200 mg/kg, busulfan (BU) 16 mg/kg plus 120 or 200 mg/kg CY, or CY 120 mg/kg and 12–15.75 Gy total body irradiation (TBI). Among girls who were pre-pubertal at HCT and are now 〉12 years of age, 24/26 (92%) CY recipients, 11/23 (52%) BUCY recipients, and 46/96 (51%) CY + TBI recipients have developed normally through puberty. Among 148 post-pubertal women transplanted with CY only, 75 (50%) recovered gonadal function at a median of 6 months after HCT and 45 (30%) have become pregnant. This is in contrast to 2 (1%) of the 207 women who received BUCY who have shown gonadal function recovery and 1 has become pregnant. Among the fractionated TBI recipients, 39 (8%) of 460 women who received CY + 12 Gy TBI recovered ovarian function and 17 (3%) have become pregnant whereas among the 366 women who received 14.0–15.75 Gy TBI, 14 (4%) have recovered ovarian function and 4 (1%) have become pregnant. All women who recovered ovarian function after BUCY or TBI regimens were

Description: Low dose methotrexate (MTX) is widely used for treatment of autoimmune diseases because of its anti-inflammatory activity. Encouraged by this practice, we have administered low dose MTX for treatment of refractory chronic GVHD, with the goal of reducing the amount of prednisone needed to control the disease. Fourteen patients with refractory chronic GVHD were treated with MTX at a dose of 7.5 mg/m2 per week for 3–50 weeks. All patients had involvement of the oral cavity and 11 of the 14 (78%) had skin involvement, often with scleroderma or fasciitis. The median duration of chronic GVHD at the start of MTX therapy was 38 (range 1–135) months. In this retrospective review, we found no grade 3–4 toxicities, and none of the patients required blood transfusion or treatment with hematopoietic growth factors. In 10 patients (71%), chronic GVHD could be adequately controlled with prednisone at doses below 1 mg/kg every other day without the addition of other immunosuppressive agents. Four patients decreased the amount of concomitant immunosuppressive treatment, 5 continued with the same regimen, 4 required an increase in immunosuppressive treatment, and one decided to discontinue all treatment. Improvement or resolution was observed most frequently in the gastrointestinal tract (80%) and skin (50%). From this preliminary analysis, MTX appears to be a well tolerated, inexpensive and possibly steroid-sparing immunosuppressive agent that is worthy of further evaluation in prospective trials for treatment of chronic GVHD.

Description: Abstract 345 Background: In 2005, an NIH consensus development conference proposed new categories for manifestations of acute and chronic GVHD after allogeneic hematopoietic cell transplantation (HCT). A question not addressed by this NIH consensus development project was whether acute and chronic GVHD result from different pathogenic pathways or from a single pathogenic pathway. Purpose: To explore this question, we analyzed risk factors for grade 2-4 acute GVHD and for chronic GVHD according to NIH consensus criteria after allogeneic hematopoietic cell transplantation (HCT). Identification of different risk factors would support the hypothesis that acute and chronic GVHD result from different pathogenic pathways. Patients and Methods: The study cohort included 2941 recipients of a first related or unrelated allogeneic HCT with bone marrow or growth factor-mobilized blood cells after a myeloablative conditioning regimen for treatment of hematological malignancies between 07/01/1992 and 2005 in Seattle. Endpoints were grade 2-4 acute GVHD that was diagnosed at any time before or after day 100 and chronic GVHD that was diagnosed according to NIH criteria and required systemic treatment. Risks factors considered in multivariate Cox regression analyses were patient and donor age per decade, donor types, stem cell source, recipient/donor gender combination, use of rabbit antithymocyte globulin (ATG) in the conditioning regimen, prior infection of patient or donor with cytomegalovirus, chronic myeloid leukemia (CML) and myeloid malignancy. The multivariate models were also adjusted for year of transplant. The analysis was carried out as of 07/23/2009. Results: The median age of the study cohort was 40 (0.6-71) years. Of the 2941 patients, 1927 (66%) received bone marrow, 1284 (44%) had HLA-matched related donors, 957 (33%) had HLA-matched unrelated donors, and 700 (24%) had HLA-mismatched related or unrelated donors. The cumulative incidence of grade 2-4 acute GVHD was 80% at 6 months, and the cumulative incidence of NIH chronic GVHD at 2 years was 34%. 461 (16%) patients did not develop either grade 2-4 acute GVHD or NIH chronic GVHD. 922 patients (31.3%) had both grade 2-4 acute GVHD and NIH chronic GVHD. Among these 922 patients, 840 (91%) had acute GVHD before NIH chronic GVHD, 77 (8%) developed acute and NIH chronic GVHD at the same time, and 5 (0.5%) had acute GVHD after NIH chronic GVHD. The median time from HCT to onset of grade 2-4 acute GVHD was 20 days (3-711) days and the median time from HCT to onset of NIH chronic GVHD was 162 (66-2805) days. The two diseases had closely similar profiles of risk factors. In multivariate models, most factors showed concordant association with an increased (unrelated, HLA-mismatched donors, male recipients with female donors, mobilized blood cell graft, donor age) or decreased (ATG and CML) risk of acute GVHD and NIH chronic GVHD (figure), although the use of mobilized blood cells had a stronger association with chronic GVHD than with acute GVHD. Only one risk factor showed discordant association with grade 2-4 acute GVHD and NIH chronic GVHD. Older patient age was associated with a slightly increased risk of NIH chronic GVHD (HR 1.12 per decade; 95% CI 1.06-1.18; p 〈 0.0001) but with a slightly lower risk of acute GVHD (HR 0.96 per decade; 95% CI 0.93-0.99, p = 0.02). Conclusion: The close similarity of risk factor profiles for acute and chronic GVHD can not rule out the hypothesis that these diseases result from different pathogenic pathways. Disclosures: No relevant conflicts of interest to declare.

Description: Fourteen patients with cytogenetic relapse of chronic myeloid leukemia (CML) after transplantation with unmanipulated bone marrow were treated with α-2a–interferon. There were eight men and six women, median age, 33 years. Twelve patients received marrow from a related allogeneic donor and two received marrow from a syngeneic donor. The median percentage of Ph-positive metaphases at the time of starting interferon was 55% (10% to 87%). Daily interferon was started at a dose of 1 to 3 × 106 U/M2/d, depending on initial blood counts and was adjusted as tolerated to maintain the white blood count in the range of 2,000 to 3,000/μL and the platelet count greater than 60,000/μL. After a stable cytogenetic remission was achieved, the interferon dose was decreased to a maintenance level. Twelve patients achieved a complete cytogenetic remission on at least one occasion. Median time to achieve a complete cytogenetic remission was 7.5 months (range, 1.5 to 12). Eight patients remain in cytogenetic remission for 10+ to 54+ months from the time of first documented remission. After complete cytogenetic remission was established, nine patients were tested for the presence of the mRNA transcript of the bcr/abl fusion gene by polymerase chain reaction (PCR) testing. Four patients were PCR-negative on at least one occasion: two patients were PCR-negative on a single occasion; one patient had serial tests, which were PCR-negative; and one patient had serial PCR-negative peripheral blood tests with a single PCR-positive bone marrow obtained concurrently with a negative peripheral blood test. Median follow-up time for all patients is 44 months (range, 20 to 64). Interferon was generally well tolerated; only one responding patient was unable to continue interferon because of toxicity. Interferon induces durable cytogenetic remissions in a significant proportion (57%) of patients with cytogenetic relapse following bone marrow transplantation (BMT) without causing life-threatening toxicities.

Description: Non-myeloablative conditioning regimens and the progress made in conventional transplantation have broadened the age restrictions for recipients of hematopoietic stem cell transplantation (HCT). The increasing age of the patient has naturally increased the age of the donor population. As aging is a risk factor for malignancies, and there is a variable period of time in which malignancies are asymptomatic, the odds of transferring malignant or pre-malignant clones in the process of HCT might increase. We uncovered 8 cases of clonal abnormalities with immunophenotypic or molecular aberrations, characteristic of specific hematologic malignancies found in HCT recipients arising from donor hematologic cells over a decade (1990–2001). The median age for the donors in our series is 44.5 years (range: 36–70 years). In 5 out of the 8 cases, the clone with malignant characteristics was detected both in donor and recipient, and in 3 cases only in the recipient (in 2 cases the donor was not tested). In 3 of the 8 HCT recipients, leukemia of donor origin prompted therapeutic intervention (a second transplant in two cases), while the others have remained under observation, as the aberrant cell clones of donor origin have not resulted in overt hematologic malignancies. In 4 cases, the abnormal clones were B cell in lineage, and have not yet evolved into disease, neither in the patients nor in 2 of the 4 donors studied. In case number 4 the donor developed CLL two years after the HCT, and the aberrant clone was detected with IgH VDJ specific PCR from an aliquot of the donor marrow preserved from the marrow harvest. In cases 5, 6, and 7, the time from the transplant to the detection of the clonal abnormality spanned more than one year. The donor of case 5 was tested and did not present the abnormality detected in his recipient (no information was obtained from donors in cases 6 and 7). In cases 4 and 8, the second malignancies were first detected in the donor. While the recipient in our fourth case has not developed any disease signs or symptoms, the recipient in our eighth case did develop clinical disease shortly after the transplant. The selection bias in discovering these cases makes it difficult to estimate a true prevalence of donor-derived malignancies in our transplant population. However, we speculate that the broadening of age limits for transplantation, with the associated increase of the donor age, has set the stage for the increased appearance of age-related donor malignancies. Increased sensitivity techniques to detect aberrant populations, such as flow cytometry, should perhaps be considered for routine pre-transplant screening of older donors. Donor Tumor Cases Pt. Patient Disease Lab Abnormality / Days post-transplant Clinical disease? / Last follow up Donor age Detected in donor? /Disease in donor? Donor last follow up ND=not done, NFU=no follow up 1 MF MCL/55d No/3.5 m 56 Yes/No 2m 2 MDS CLL/28d No/24 m 70 Yes/No NFU 3 CLL MZL/294d No/55 m 57 Yes/Yes 55m 4 AML CLL/10y No/120 m 45 Yes/Yes 120m 5 Renall Cell Carcinoma AML/15m Yes/21 m 42 No/No 21m 6 CML MDS/4y No/96 m 44 ND/NFU NFU 7 CML MDS/4y Yes/114m 44 ND/NFU NFU 8 ALL ALL/130d Yes/6m 36 Yes/Yes 65m