Abstract There is limited information on the outcome when organs other than heart or kidneys are involved by immunoglobulin light-chain amyloidosis (AL). We report the outcome of 53 patients with AL ...with gastrointestinal (GI), peripheral nerve (PN), liver, lung, or soft-tissue involvement, who underwent high-dose chemotherapy and autologous hematopoietic stem cell transplantation (auto-HCT) at our institution between 1997 and 2013. The median age at auto-HCT was 56 years (range, 35 to 74). One, 2, 3, or 4 organs were involved in 43%, 22%, 28%, and 4% of patients, respectively. Concurrent cardiac, renal, or both were involved in 24 (45%) patients. Forty-six patients received induction therapy before auto-HCT. The 100-day and 1-year treatment-related mortality (TRM) were 3.8% (n = 2) and 7.5% (n = 4), respectively. Forty-one (80%) patients achieved a hematologic response. Organ response at 1 year after auto-HCT was seen in 23 (57%) of the 40 evaluable patients. With a median follow-up of 24 months, the median progression-free survival and overall survival (OS) were 36 and 73 months, respectively. Auto-HCT was associated with a low TRM, durable organ responses, and a median OS of > 6 years in selected patients with AL and GI, PN, liver, lung, or soft-tissue involvement.
Background: Chromosomal abnormalities detected by conventional cytogenetic analysis are known to adversely impact the outcome in myeloma patients. Abnormalities of chromosome 1, 13, 14 and 17 are ...commonly described. Deletions of the short arm of chromosome 1 presumably result in a loss of tumor suppressor genes, including p73, a member of the p53 family. We report the outcome of 83 myeloma patients with clonal cytogenetic abnormalities who underwent high-dose therapy and single autologous stem cell transplantation at our institution.
Methods: We identified 83 patients (median age: 56 years) with clonal cytogenetic abnormalities detected at diagnosis by conventional chromosomal analysis. Patients underwent high-dose therapy and a single autologous transplant between April 2000 and May 2005. All 83 patients received high-dose melphalan, either alone (73) or as a combination of topotecan, melphalan and cyclophosphamide (TMC =10). Sixty-four patients were transplanted for the consolidation of first remission or for primary refractory disease, while 19 patients were transplanted for relapsed disease. The most common chromosomal abnormalities observed were hyperdiploidy (21%), del 1p (19%), 14q32 abnormalities (14%) and del 13q (10%).
Results: Median follow up among surviving patients was 25.5 months. Median interval from diagnosis to autotransplant was 7.7 months (range 2.5–52). Median progression-free survival (PFS) for the entire group was 19 months and the median overall survival (OS) was 52 months. On univariate analysis, both PFS and OS were significantly shorter in patients with del 1p (p= 0.001 and <0.0001, respectively), and those transplanted with relapsed disease (p= 0.03 and 0.04). Median PFS and OS for patient with del 1p were 12 and 22 months (vs. 26 moths and not reached for others), respectively. Thirty-two patients whose cytogenetic abnormalities resolved prior to autotransplant had a trend towards longer OS than the patients with persistent abnormalities (p = 0.08). Age, disease stage, β2m, serum albumin level, serum creatinine, and isolated abnormalities of chromosome 13q, 17 and 14 q32 did not emerge as significant predictors of outcome in this set of patients.
Conclusion: Del 1p is associated with a significantly shorter remission and survival in patients undergoing high-dose therapy and a single autologous transplant. Patients with this abnormality are candidates for novel therapeutic approaches including newer antimyeloma drugs and nonablative allogeneic transplantation.
Post transplant cyclophosphamide (PTCy), tacrolimus, and MMF GvHD prophylaxis makes transplantation from haploidentical donors feasible without T cell depletion. In matched donor transplant ...recipients, cumulative incidences of grades II-IV acute, grades III-IV acute, and chronic GVHD were 51%, 15%, and 14%, respectively when single agent PTCy was used (Kanakry et al JCO 2014 32:3497-3505). However; as a single agent it was inferior to tacrolimus and methotrexate in another study (Alousi etal BBMT 2015, 906-912). We therefore hypothesized that addition of tacrolimus to PTCy may be needed to prevent severe acute GVHD and improve transplant outcomes.
All patients with AML undergoing first allogeneic transplant from matched sibling or at least 9/10 matched unrelated donor between 1/1/2011 to 4/30/2018 were eligible for this retrospective study if they received a melphalan or timed sequential busulfan (course AUC 20,000 umol/min) based conditioning regimen. GVHD prophylaxis consisted of tacrolimus and methotrexate 5mg/m2 on day 1, 3, 6, and 11 in the Tac/MTX cohort (n=140); and cyclophosphamide 50mg/kg given on days 3 and 4 and tacrolimus in the PTCy cohort (n=76).
Patient characteristics were similar in both cohorts except that patients in PTCy cohort were younger with a median age of 59 years versus 63.5 years (P<0.001) and more likely to be in CR-57% v/s 41% (P=0.03).
Outcomes and results of univariate analysis are summarized in Table1.
Tacrolimus and PostCy based GVHD prophylaxis reduces severe GVHD and improves survival.
The cell of origin (COO) classification has been shown to predict survival outcomes in de-novo diffuse large B-cell lymphoma (DLBCL), however, it is unclear if this holds true following high-dose ...chemotherapy and autologous stem cell transplantation (auto-SCT) in relapsed DLBCL patients. The current analysis aims to compare survival outcomes based on COO classification in relapsed DLBCL patients who received auto-HCT.
This retrospective study includes relapsed/refractory DLBCL patients, aged 18 and above, who received auto-HCT with standard of care conditioning from January 2007 to December 2016 at our institution. Hans algorithm using CD10, BCL6 and MUM1 markers was performed to classify patients as per COO into the GCB and non-GCB types. Kaplan Meier method was used to estimate progression free survival (PFS) and overall survival (OS).
A total of 122 DLBCL (71 GCB, 51 non-GCB) patients were analyzed. Detailed patient characteristics are provided in Table 1. Except for GCB cohort being older (64 vs. 58 years, p<0.004), there were no significant differences in patient characteristics between the two groups. Over a median follow-up of 42 months (3-104), the total number of relapses in GCB and non-GCB group were 29.5% (21/71) and 31.3% (16/51), respectively. 2-yr PFS for GCB and non-GCB group was similar at 70.9% and 66.6%, respectively (HR=0.9, p=0.7, 95% CI 0.5-1.5). On univariate analysis, age>70 (HR=2.9, p=0.03) and IPI score 0 (HR=0.3, p=0.005) were significant variables in predicting PFS. After adjusting for these variables, no significant differences were seen in PFS between two groups. The median OS has not yet been reached in both groups therefore a difference in OS cannot be analyzed.
Our results suggest that cell of origin is not prognostic for patients with relapsed/refractory DLBCL treated with high dose chemotherapy followed by auto-SCT.
The abnormal expression of P53 is prognostically important in patients (pts) with CLL treated with conventional chemotherapy. In order to determine its significance upon survival in CLL pts ...undergoing NST, we analyzed outcome of P53 expression in conjunction with clinical and laboratory parameters in 86 pts transplanted at the MD Anderson Cancer Center between 02/96 and 01/06. Pts were eligible if they had failed conventional chemotherapy and had an HLA-identical or one-antigen mismatched donor.
<<Patient Characteristics>> Median age (range) was 58 (36–73), the majority (81.4%) were males and the median Hematopoietic Stem Cell Transplantation (HSCT) Co-morbidity score was 3 (range 0–8). Pts were heavily pretreated with advanced disease at time of transplant: 66% had 3 or more lines of chemotherapy regimens, 41 (48%) had failed alemtuzumab, 55/65 (85%) had Binet stage B/C, 19(22%) had experienced transformation to Richter's, 31 (36%) had progressive disease, and 22 (33%) were gallium/PET positive. Twenty-eight of 39 pts (72%) tested had unmutated IgVH. Immunoglobulin (Ig) G, A and M were below normal in 68%, 78% and 50%, respectively. CD4 and CD8 levels were <100 in 26% and 32% of pts, respectively. Median time (range) from diagnosis to NST was 62.3 (6.5–306.6) months. Donors were matched siblings in 43 pts (50%), matched unrelated in 35 pts (40.7%), mismatched unrelated in 2 pts (2.3%), mismatched related in 4 pts (4.7%) and 2 pts (2.3%) from other family members. The source of graft was peripheral blood in 71% of pts, with a median dose of 4.8x106/Kg CD34+ cells infused. Median donor age was 49 (14–77.6) years. Pts and donors were sex-, or ABO-mismatched in 50.7% and 36% of cases, respectively. The conditioning regimens consisted of fludarabine(F), cyclophosphamide(C), rituximab (R) in 40 pts (47%), FCR/Zevalin in 12 pts (14%), FCR/Alemtuzumab (30 mg total) in 26 pts (30%), and 8 pts (9%) received FR/Melphalan.
<<P 53 Analysis>> P53 has been commonly tested by FISH methodology. In this report, 37 pts were tested by FISH. As an alternative, immunohistochemistry (IHC) assessing the expression of P53 in the absence of P21 has been suggested as a surrogate for mutated P53 status. IHC was therefore performed using antibodies to P53 (clone DO7; DAKO, Carpinteria, CA), and P21 (clone SX118:BD Pharmingen, San Diego, CA) on paraffin-embedded bone marrow biopsies in 46 pts. Samples were reviewed for expression of P53 and P21 proteins by T.D. and C.B-R., who were blinded as to outcome. Samples were considered positive for P53 mutation only if 20% or more of the malignant cells expressed P53 protein, with less than 5% expressing P21 protein.
< > Thirteen of 46 pts (28%) were tested positive for P53+/P21− by IHC, and 10 of 37 (27%) were FISH+. Twenty-one pts were tested by both IHC and FISH: results were concordant in 16 pts (76%); 3 pts were FISH+/IHC−; 2 pts were FISH−/IHC+.
<<Clinical outcome>> With a median follow-up time for surviving pts of 37 (range, 12–131) months, the estimated three-year survival of all 86 pts was 53%. Univariate Cox proportional hazards regression for OS that considered P53 results as well all other clinical variables described above showed that IgG level below normal range at transplantation (P=0.001), CD4 <100 (P=0.005), acute grade III–IV GVHD (P=0.004), # prior chemotherapy regimens >=3 (P=0.023), Richter's transformation (P=0.038), and % lymphocytes in marrow (P=0.039) were significantly associated with time to death. A multivariate analysis that included all the covariates with P values <0.05 was conducted. This analysis showed the IgG level to be the only significant factor (P=0.033) while CD4 level approached significance (P=0.05). Neither P53 mutation {either by IHC (P= 0.51), or FISH (P=0.95)} nor the HSCT Comorbidity score (P= 0.22) were found to be predictors of survival.
< > NST may overcome the negative predictor significance of P53 mutation. Considering the poor outcome with conventional chemotherapy, these pts may be considered for NST early in the course of their disease, before experiencing further depletion of their immune system as reflected by IgG and CD4 levels.
BACKGROUND: Many recent advances have occurred in the field of MDS including hypomethylating agents, lenalidomide, and WHO classification. Likewise the field of HCT has also undergone major new ...developments including non ablative conditioning, better supportive care, better HLA typing, selection of unrelated donors and development of reduced toxicity ablative regimens like Busulfan and Fludarabine. The role of HCT therefore needs to be redefined in light of these developments. The purpose of this study is to report our recent results.
PATIENTS AND METHODS: 89 consecutive patients with MDS as defined by WHO criteria treated at our institution between Jan 2002 and April 2008 are included in this report. There were 60 males and 29 female with a median age of 54 (23–67). There were 5(6%) patients with RA, 1(1%) RARS, 9(10%) RCMD, 22(25%) RAEB 1, 17(19%) RAEB 2, and 35(39%) therapy related MDS(t MDS). Their IPSS scores were 25(28%) patients with Intermediate 1, 49(55%) Intermediate 2, 15(17%) high. Their WPSS categories were 5(6%) patients Low, 9(10%) Intermediate, 49(55%) high, and 26(29%) very high. 51(57%) patients had a matched related donor and 38(43%) had an unrelated donor. Conditioning regimen were Flu/Bu in 56(63%) patients, Bu/Cy 1(1%), Flu/Mel 32(36%). According to HCT-CI index, the comorbidity scores were 0 in 16(18%) patients, 1 or 2 in 19(21%) and greater then 2 in 54(61%). Median time from diagnosis to transplant was 8 months (range 1–51 months).
RESULTS: With a median follow up of 28 (3–73) months, 2 year overall(OS) and disease free survival were 54%(95% CI; 42%–66%) and 52%(95% CI; 40%–64%) respectively. Cumulative incidence of non relapse mortality at 2 years was 23% (95% CI; 16%–35%). Cumulative incidence of relapse mortality at 2 years was 23% (95% CI; 15%–34%). As per WHO grouping, OS was 63%, 60%, 46% and 48% in patients with Low blast count (RA, RARS, RAMD), RAEB1, RAEB2 and t MDS( p=0.46) respectively. WPSS score was significantly(P=0.01) predictive of overall survival (see fig): 27% surviving in very high risk group, 61% in high risk group and 78% in Low and intermediate risk group. Likewise cytogenetic risk group and IPSS were significantly predictive of survival. Donor type or graft source did not predict outcome. Five patients developed primary(3) or secondary(2) graft failure. Median time to neutrophil engraftment was 13 days (8–26 days) and to platelet engraftment was 16 days (9–89 days).
CONCLUSION: These results in patients with comorbidities and with a median age of 54 years are promising. Cytogenetics and prognostic scores based on cytogenetics predict outcome after HCT.
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The doping and temperature dependences of the Hall coefficient, R(H), and ab-plane resistivity in the normal state down to 350 mK is reported for oriented films of the electron-doped high-T(c) ...superconductor Pr(2-x)Ce(x)CuO(4-delta). The doping dependences of beta (rho=rho(0)+ATbeta) and R(H) (at 350 mK) suggest a quantum phase transition at a critical doping near x=0.165.
Background: Impact of obesity on transplant outcome is unknown. We hypothesized that obesity increases allogeneic transplant related morbidity/mortality. We therefore performed a case control study ...of obese patients with AML and MDS undergoing allogeneic transplant (AlloSCT) at our institution.
Patients and Methods: Sixty one patients with AML or MDS and a Body Mass Index (BMI) greater than 35 were transplanted from 1987 and 2006. 61 control patients were identified with BMI less than 30. The patients had similar characteristics. Controls were matched for age (within 5 years), disease status (relapse or remission), donor type (sib or MUD) and conditioning regimen.
Results: The median weight of obese patients was 109.5 Kg (range 78–151.3 Kg). Obese and controls had similar distribution of age (median age 47 years and 46 years respectively). Likewise gender, disease status, and cytogenetic risk groups were similar in the two groups. The majority (62%) of patients in both groups had IV Busulfan based conditioning therapy, while 11% had a TBI based regimen and 26% in both groups had reduced intensity conditioning with Fludarabine and Melphalan. Donor was a matched sib in 65% of cases and 66% of controls. The median time between transplant day and discharge was 23 days (range 14–98days) in both groups. Only significant difference between the two groups was the presence of comorbidites in obese patients. 75% of cases had a comorbidty score of 3 or more compared to 38% of controls (p<0.001) as defined by HCT index. Outcomes were similar in both groups. Two year non relapse mortality was 27% (95% CI: 18%-42%) in obese patients and 27% (95% CI: 17%- 41%) in control patients. Grade 3–4 toxicities occurred in 55% of cases compared to 42% of controls (p=0.2). Three-year disease free survival was 44% (95% CI: 31%- 57%) and 42% (95% CI: 29%- 55%) respectively in cases and controls. Median overall survival was 18 months for obese patients and 26 months for controls; 3-year overall survival was not significantly different in the two groups: 45% (95% CI: 31%- 58%) and 45% (95% CI: 31%- 58%) respectively for cases and controls.
Conclusion: Despite the higher prevalence of comorbidities in obese patients, obesity did not impair outcome in patients with AML/MDS undergoing AlloSCT. Hence, obesity should not be considered a contraindication to AlloSCT.
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