Myeloablative Allogeneic Hematopoietic Cell Transplantation Research Articles

The graft-versus-leukemia effect using matched unrelated donors is not superior to HLA-identical siblings for hematopoietic stem cell transplantation

AbstractDo some patients benefit from an unrelated donor (URD) transplant because of a stronger graft-versus-leukemia (GVL) effect? We analyzed 4099 patients with acute myeloid leukemia (AML), acute lymphoblastic leukemia (ALL), and chronic myeloid leukemia (CML) undergoing a myeloablative allogeneic hematopoietic cell transplantation (HCT) from an URD (8/8 human leukocyte antigen [HLA]–matched, n = 941) or HLA-identical sibling donor (n = 3158) between 1995 and 2004 reported to the CIBMTR. In the Cox regression model, acute and chronic GVHD were added as time-dependent variables. In multivariate analysis, URD transplant recipients had a higher risk for transplantation-related mortality (TRM; relative risk [RR], 2.76; P < .001) and relapse (RR, 1.50; P < .002) in patients with AML, but not ALL or CML. Chronic GVHD was associated with a lower relapse risk in all diagnoses. Leukemia-free survival (LFS) was decreased in patients with AML without acute GVHD receiving a URD transplant (RR, 2.02; P < .001) but was comparable to those receiving HLA-identical sibling transplants in patients with ALL and CML. In patients without GVHD, multivariate analysis showed similar risk of relapse but decreased LFS for URD transplants for all 3 diagnoses. In conclusion, risk of relapse was the same (ALL, CML) or worse (AML) in URD transplant recipients compared with HLA-identical sibling transplant recipients, suggesting a similar GVL effect.

Mesenchymal Stem Cell Infusion As Prevention For Graft Rejection And Graft-Versus-Host Disease After Allogeneic Hematopoietic Cell Transplantation With Nonmyeloablative Conditioning From HLA-Mismatched Donors: A Pilot Study

Background: Allogeneic hematopoietic cell transplantation (HCT) following nonmyeloablative conditioning has been an effective treatment for many pts with hematological malignancies who have a HLA-matched related or unrelated donor. However, results of nonmyeloablative HCT in pts with HLA-mismatched donors have been disappointing due to high incidence of graft rejection and severe acute GVHD. Recent studies have suggested that infusion of mesynchymal stem cells (MSC) the day of HCT might promote engraftment and prevent acute GVHD after myeloablative allogeneic HCT.

Assessment of the Hematopoietic Cell Transplantation Comorbidity Index in Non-Hodgkin Lymphoma Patients Receiving Reduced-Intensity Allogeneic Hematopoietic Stem Cell Transplantation

The hematopoietic cell transplantation comorbidity index (HCT-CI), a weighted index of 17 pretransplantation comorbidities, has been validated in nonmyeloablative and myeloablative allogeneic hematopoietic stem cell transplantation (HSCT) studies, but it has not been specifically tested in patients with non-Hodgkin lymphoma (NHL) receiving reduced-intensity conditioning (RIC). We performed a retrospective analysis to assess the impact of the HCT-CI on outcomes of NHL patients treated with HSCT relative to treatment-related mortality (TRM), disease-related mortality (DRM), with a specific emphasis on overall survival (OS). Individual pretransplantation and disease-related factors also were analyzed with HCT-CI relative to their impact on OS. All patients were uniformly treated with an identical pretransplantation induction regimen and an identical RIC regimen (cyclophosphamide [Cy]/fludarabine [Flu]), and received T cell–replete allografts from HLA-matched siblings. The analysis included 63 NHL patients with a median HCT-CI score of 2 (range, 0 to 11). The HCT-CI (0 to 2 comorbidities vs 3+ comorbidities) demonstrated a potential association with TRM, but not with DRM, at 100 days (4.5% vs 26.3%) and at 1 year (13.6% vs 36.8%) posttransplantation. The factor most strongly associated with OS was response to pretransplantation chemotherapy ( P = .0001), based on a composite measure. In a Cox model, pretransplantation chemotherapy response remained the most important factor ( P < .0001) relative to OS, and there was a trend ( P = .056) toward HCT-CI adding predictive value for OS. Although HCT-CI may be useful for predicting TRM, our data further underscore the importance of response to chemotherapy before transplantation as a predictor of overall transplantation outcome in NHL patients being considered for RIC allogeneic HSCT.

Unrelated Donor Reduced-Intensity Allogeneic Hematopoietic Stem Cell Transplantation for Relapsed and Refractory Hodgkin Lymphoma

Myeloablative allogeneic hematopoietic cell transplantation (HCT) may cure patients with relapsed or refractory Hodgkin lymphoma (HL), but is associated with a high treatment-related mortality (TRM). Reduced-intensity and nonmyeloablative (RIC/NST) conditioning regimens aim to lower TRM. We analyzed the outcomes of 143 patients undergoing unrelated donor RIC/NST HCT for relapsed and refractory HL between 1999 and 2004 reported to the Center for International Blood and Marrow Transplant Research (CIBMTR). Patients were heavily pretreated, including autologous HCT in 89%. With a median follow-up of 25 months, the probability of TRM at day 100 and 2 years was 15% (95% confidence interval [CI] 10%-21%) and 33% (95% CI 25%-41%), respectively. The probabilities of progression free survival (PFS) and overall survival (OS) were 30% and 56% at 1 year and 20% and 37% at 2 years. The presence of extranodal disease and the Karnofsky Performance Scale (KPS) <90 were significant risk factors for TRM, PFS, and OS, whereas chemosensitivity at transplantation was not. Dose intensity of the conditioning regimen (RIC versus NST) did not impact outcomes. Unrelated donor HCT with RIC/NST can salvage some patients with relapsed/refractory HL, but relapse remains a common reason for treatment failure. Clinical studies should be aimed at reducing the incidence of acute graft-versus-host disease (GVHD) and relapse.

Positive impact of maintaining minimal caloric intake above 1.0 × basal energy expenditure on the nutritional status of patients undergoing allogeneic hematopoietic stem cell transplantation

American Journal of HematologyVolume 84, Issue 1 p. 63-64 Correspondence and Letters to the EditorFree Access Positive impact of maintaining minimal caloric intake above 1.0 × basal energy expenditure on the nutritional status of patients undergoing allogeneic hematopoietic stem cell transplantation Shigeo Fuji, Shigeo Fuji Department of Hematology and Stem Cell Transplantation, National Cancer Center Hospital, Tokyo, JapanSearch for more papers by this authorSung-Won Kim, Sung-Won Kim Department of Hematology and Stem Cell Transplantation, National Cancer Center Hospital, Tokyo, JapanSearch for more papers by this authorTakahiro Fukuda, Takahiro Fukuda Department of Hematology and Stem Cell Transplantation, National Cancer Center Hospital, Tokyo, JapanSearch for more papers by this authorShigemi Kamiya, Shigemi Kamiya Division of Nutritional Management, National Cancer Center Hospital, Tokyo, JapanSearch for more papers by this authorSetsuko Kuwahara, Setsuko Kuwahara Division of Nutritional Management, National Cancer Center Hospital, Tokyo, JapanSearch for more papers by this authorYoichi Takaue, Yoichi Takaue Department of Hematology and Stem Cell Transplantation, National Cancer Center Hospital, Tokyo, JapanSearch for more papers by this author Shigeo Fuji, Shigeo Fuji Department of Hematology and Stem Cell Transplantation, National Cancer Center Hospital, Tokyo, JapanSearch for more papers by this authorSung-Won Kim, Sung-Won Kim Department of Hematology and Stem Cell Transplantation, National Cancer Center Hospital, Tokyo, JapanSearch for more papers by this authorTakahiro Fukuda, Takahiro Fukuda Department of Hematology and Stem Cell Transplantation, National Cancer Center Hospital, Tokyo, JapanSearch for more papers by this authorShigemi Kamiya, Shigemi Kamiya Division of Nutritional Management, National Cancer Center Hospital, Tokyo, JapanSearch for more papers by this authorSetsuko Kuwahara, Setsuko Kuwahara Division of Nutritional Management, National Cancer Center Hospital, Tokyo, JapanSearch for more papers by this authorYoichi Takaue, Yoichi Takaue Department of Hematology and Stem Cell Transplantation, National Cancer Center Hospital, Tokyo, JapanSearch for more papers by this author First published: 08 October 2008 https://doi.org/10.1002/ajh.21307Citations: 12AboutPDF ToolsRequest permissionExport citationAdd to favoritesTrack citation ShareShare Give accessShare full text accessShare full-text accessPlease review our Terms and Conditions of Use and check box below to share full-text version of article.I have read and accept the Wiley Online Library Terms and Conditions of UseShareable LinkUse the link below to share a full-text version of this article with your friends and colleagues. Learn more.Copy URL No abstract is available for this article. References 1 Sheean PM,Freels SA,Helton WS, et al. Adverse clinical consequences of hyperglycemia from total parenteral nutrition exposure during hematopoietic stem cell transplantation. Biol Blood Marrow Transplant 2006; 12: 656– 664. 2 Sheean PM,Braunschweig C,Rich E. The incidence of hyperglycemia in hematopoietic stem cell transplant recipients receiving total parenteral nutrition: A pilot study. J Am Diet Assoc 2004; 104: 1352– 1360. 3 Fuji S,Kim SW,Mori S, et al. Hyperglycemia during the neutropenic period is associated with a poor outcome in patients undergoing myeloablative allogeneic hematopoietic stem cell transplantation. Transplantation 2007; 84: 814– 820. 4 Kubrak C,Jensen L. Malnutrition in acute care patients: A narrative review. Int J Nurs Stud 2007; 44: 1036– 1054. 5 Muscaritoli M,Conversano L,Cangiano C, et al. Biochemical indices may not accurately reflect changes in nutritional status after allogeneic bone marrow transplantation. Nutrition 1995; 11: 433– 436. Citing Literature Volume84, Issue1January 2009Pages 63-64 ReferencesRelatedInformation

Obesity Does Not Preclude Safe and Effective Myeloablative Hematopoietic Cell Transplantation (HCT) for Acute Myeloid Leukemia (AML) in Adults

INTRODUCTION: Obesity is increasingly common in the US and is frequently associated with co-morbid medical conditions that may increase the risk of HCT, often the optimal treatment for AML. HCT risk and outcomes for AML on the basis of body mass index (BMI) have not been well-characterized. Using data from the Center for International Blood and Marrow Transplant Research (CIBMTR), we have previously shown no significant difference in outcomes for autologous HCT for lymphoma among normal weight, overweight, and obese patients (pts) but worse outcomes for underweight pts (Navarro et al, BBMT 2006, 12(5): 541–51). Here, we compare outcomes by weight groups for AML patients who underwent autologous, related, or unrelated HCT.METHODS: Our final population included patients age ≥ 18 who underwent myeloablative unpurged autologous or allogeneic HCT for AML in 1st or 2nd complete remission, primary induction failure, or 1st relapse reported to the CIBMTR from 1995 to 2004. Cord blood HCTs were excluded. Four weight groups were defined based on BMI (BMI=weight (kg)/ height (m2)): underweight <18; normal=18–25; overweight >25–30; and obese >30. Treatment-related mortality (TRM), relapse, leukemia-free survival (LFS), and overall survival (OS) were compared using multivariable proportional hazards regression analysis accounting for patient, disease and HCT-related variables.RESULTS: We included 373 autologous, 2041 related, and 1801 unrelated transplant recipients. Patient-, disease-, and transplant characteristics were well-matched across weight groups and transplant types. Multivariable analysis examining risks (95% confidence intervals) relative to the normal weight group are:HCT TypeNormalUnderweightOverweightObeseAutologousn=164n=5n=112n=81Death–NSNSTreatment failure–NSNSRelapse–NSNSTRM–NSNSRelated Allogeneicn=1161n=31n=543n=268Death1.86 (1.24–2.78)NS1.23 (1.04–1.47)Treatment failure2.08 (1.37–3.15)NS1.19 (1.00–1.42)Relapse2.02 (1.18–3.47)NSNSTRM2.22 (1.17–4.22)NS1.32 (1.02–1.70)Unrelated Allogeneicn=846n=31n=523n=368DeathNSNSNSTreatment failureNSNSNSRelapseNS0.82 (0.68–0.99)0.76 (0.60–0.96)TRMNSNSNS– =not done due to insufficient number of pts; NS=not significant; treatment failure = death or recurrence of disease.CONCLUSIONS: There were no significant differences in risk of TRM, LFS, relapse or OS for normal weight, overweight or obese patient groups who received autologous HCT. Obese recipients of related HCT for AML had increased risk of death, treatment failure, and TRM, though the magnitude was small, an effect was not seen in the unrelated HCT group. Underweight patients who received a related, but not unrelated HCT, fared substantially worse than normal weight patients for all outcomes. It may be that the higher risk of the unrelated HCT procedure masks important but less obvious risks associated with being underweight whereas in the related donor HCT setting, such risks become manifest. Small numbers of patients limit the ability to better characterize this finding in underweight patients. Disproportionately, fewer transplants have been reported in underweight patients which suggest they experience disease and patient-related factors that preclude transplantation. No differences were observed for incidence of acute or chronic GVHD for any weight group. Overweight and obesity should not be a barrier to HCT; however, caution should be exercised in selecting underweight patients for HCT.

Non-Myeloablative Allogeneic Hematopoietic Stem Cell Transplantation (NMHCT) for Patients Relapsing after Autologous Stem Cell Transplantation (autoHCT) for B Cell Non-Hodgkin Lymphoma (NHL)

The prognosis of patients (pts) with NHL who relapse after autoHCT is poor. Myeloablative allogeneic hematopoietic stem cell transplantation has been utilized in these pts since the allograft is tumor free and may induce a graft-versus-tumor effect. Unfortunately, this approach results in prolonged survival for only a minority of pts. NMHCT is increasingly utilized in this setting since it affords the potential benefits of myeloablative transplantation and may reduce morbidity and treatment-related mortality (TRM). Reports using this approach show conflicting results but are limited by small numbers of pts. The purpose of this study was to determine the outcome of pts with NHL who underwent NMHCT after autoHCT failure including TRM, progression/relapse rate, overall survival (OS) and progression free survival (PFS). The study included 267 pts who underwent NMHCT for relapsed B cell NHL after autoHCT failure, from 1997 to 2006 and reported to the Center for International Blood and Marrow Transplant Research. Patients younger than 21, pts who underwent planned second transplants and recipients of cord blood transplants were excluded. The median age at NMHCT was 52 yrs (range 23–70); 64% were male and 61% had a Karnofsky Performance Score (KPS) of ≥ 90%. Fifty six percent of pts had diffuse large cell lymphoma, immunoblastic or follicular large cell lymphoma; 17% had follicular small or mixed NHL and 27% had mantle cell lymphoma. The time interval from 1st to 2nd transplant was < 1 year in 21% of pts, 1 to 2 years in 30% and > 2 years in 49% of pts. At the time of NMHCT, 63% had chemosensitive NHL, 31% resistant NHL and 6% were untreated after autoHCT. Multiple conditioning regimens were used including most frequently melphalan (25%) busulfan (21%) and fludarabine ± cyclophosphamide (26%). A fourth of the pts received 200 cGy of total body irradiation (TBI) as part of the conditioning regimen. The graft source was peripheral blood in 78% and 90% used unrelated donors. Median follow up of survivors was 37 months. TRM at 3 years was 42%. The cumulative incidence of disease progression at 3 years was 36%. The three-year probabilities of OS (figure 1) and PFS were 33% and 22%, respectively. The incidence of grade II-IV acute graft-versus-host disease (AGVHD) at 100 days was 39% and the incidence of chronic GVHD at 3 years was 41%. The most frequent causes of death were progression of NHL (29%), infection (19%), multiorgan failure (19%) and GVHD (14%). Factors associated with a lower risk of NHL progression or death include KPS ≥ 90%, interval between transplants >24 months, TBI as part of the conditioning regimen and complete remission at the time of NMHCT (figure 2). AGVHD decreased the risk of relapse (RR = 0.59, p=0.036) [Display omitted] [Display omitted]

Comparison of Outcomes of HLA-Matched Related, Unrelated, or HLA-Haploidentical Related Hematopoietic Cell Transplantation following Nonmyeloablative Conditioning for Relapsed or Refractory Hodgkin Lymphoma

We compared the outcome of nonmyeloablative allogeneic hematopoietic cell transplantation (HCT) for patients with relapsed or refractory Hodgkin lymphoma (HL) based on donor cell source. Ninety patients with HL were treated with nonmyeloablative conditioning followed by HCT from HLA-matched related, n=38, unrelated, n=24, or HLA-haploidentical related, n=28 donors. Patients were heavily pretreated with a median of 5 regimens and most patients had failed autologous HCT (92%) and local radiation therapy (83%). With a median follow-up of 25 months, 2-year overall survivals, progression-free survivals (OS)/(PFS), and incidences of relapsed/progressive disease were 53%, 23%, and 56% (HLA-matched related), 58%, 29%, and 63% (unrelated), and 58%, 51%, and 40% (HLA-haploidentical related), respectively. Nonrelapse mortality (NRM) was significantly lower for HLA-haploidentical related (P=.02) recipients compared to HLA-matched related recipients. There were also significantly decreased risks of relapse for HLA-haploidentical related recipients compared to HLA-matched related (P=.01) and unrelated (P=.03) recipients. The incidences of acute grades III-IV and extensive chronic graft-versus-host disease (aGVHD, cGVHD) were 16%/50% (HLA-matched related), 8%/63% (unrelated), and 11%/35% (HLA-haploidentical related). These data suggested that salvage allogeneic HCT using nonmyeloablative conditioning provided antitumor activity in patients with advanced HL; however, disease relapse/progression continued to be major problems. Importantly, alternative donor stem cell sources are a viable option.

Mannose-binding lectin status is associated with risk of major infection following myeloablative sibling allogeneic hematopoietic stem cell transplantation

AbstractMannose-binding lectin (MBL) is a mediator of innate immunity that influences the risk of infection in a range of clinical settings. We previously reported associations between MBL2 genotype and infection in a retrospective study of myeloablative allogeneic hematopoietic stem cell transplantation (allo-HCT). However, other studies have been inconclusive, and the role of MBL in reduced-intensity conditioning (RIC) transplantation is unknown. Here we report a prospective study examining MBL2 genotype, MBL levels, and risk of major infection following HLA-matched sibling myeloablative (n = 83) and RIC (n = 59) HCT. Baseline MBL levels were higher in recipients than donors (P < .001), and recipient MBL levels increased during the peritransplantation period (P = .001), most notably in MBL2 wild-type individuals receiving myeloablative total body irradiation (mTBI). MBL2 coding mutations were associated with major infection in recipients receiving mTBI. The cumulative incidence of major infection in recipient harboring an MBL2 mutation receiving mTBI was 70.6%, compared with 31.1% of those without mutations not receiving mTBI (P = .01). MBL status was not associated with infection in RIC transplants. These results confirm the association of MBL status with risk of infection in myeloablative, TBI-conditioned transplantation. Studies examining the role of MBL replacement therapy to prevent infection in this setting should be considered.

Case of a patient with Philadelphia-chromosome-positive acute lymphoblastic leukemia relapsed after myeloablative allogeneic hematopoietic stem cell transplantation treated successfully with imatinib and sequential donor lymphocyte infusions

A 23-year-old man with Philadelphia-chromosome-positive (Ph(+)) acute lymphoblastic leukemia (ALL) underwent myeloablative allogeneic hematopoietic stem cell transplantation (allo-HSCT) from his HLA-identical brother in first hematological remission following induction chemotherapy which included imatinib. He had no acute graft-versus-host disease (GVHD), and 4.5 months after HSCT, he had a molecular relapse (180,000 copies/mug RNA of minor bcr/abl transcripts (m-bcr/abl) without mutation in 22 sites including the p-loop region). Following discontinuation of cyclosporine A, imatinib (600 mg daily) was restarted and 4 days later donor lymphocyte infusion (DLI) (5 x 10(7)/kg of CD3(+) cells) was given. In 2 weeks, the marrow m-bcr/abl became undetectable. He received two further DLIs and imatinib was continued at a reduced dose of 400 mg a day. At the time of this report, he remains in complete hematological remission more than 33 months after allo-HSCT and persists in the second molecular remission for longer than 24 months. During this clinical course, he became positive for anti-nuclear antibody after second DLI, without any other manifestations of GVHD. The standard treatment for Ph(+) ALL relapsing after allo-HSCT still remains to be established. Imatinib in combination with DLI for early molecular relapse may be a promising option.

Similar Risks for Chronic Kidney Disease in Long-Term Survivors of Myeloablative and Reduced-Intensity Allogeneic Hematopoietic Cell Transplantation

Chronic kidney disease (CKD) in recipients of myeloablative (MA) allogeneic hematopoietic cell transplantation (HCT) has been well characterized. However, the risk of CKD after HCT using reduced-intensity conditioning (RIC) is not well known. We compared the incidence of CKD by conditioning regimen in 221 allogeneic HCT recipients (MA = 117, RIC = 104) who had survived for ≥1 year post-HCT and had no history of CKD pretransplant. CKD was defined as glomerular filtration rate (GFR) <60 mL/min/1.73 m 2 for ≥3 months anytime after 180 days post-HCT. The median follow-up was 28 months (range: 12-75) for MA and 25 months (range: 12-67) for the RIC group. The 3-year cumulative incidence rate of CKD was 28% (95% confidence intervals [CI], 19%-36%) in MA and 29% (95% CI, 20%-38%) in the RIC group ( P = .44). In multivariate analysis, conditioning regimen intensity had no impact on the risk of developing CKD (relative risk [RR] for MA 1.50 [95% CI, 0.78-2.89] versus the RIC regimen). Factors independently associated with an increased risk of CKD were older age at transplant, acute graft-versus-host disease, cyclosporine use for >6 months, and acute kidney injury in the early posttransplant period. CKD is frequent in long-term adult allogeneic HCT survivors, but RIC is associated with similar risks as MA conditioning. Continuous monitoring of renal function is necessary in allogeneic HCT survivors, and studies exploring prevention strategies are needed.

Similar and Promising Outcomes in Lymphoma Patients Treated with Myeloablative or Nonmyeloablative Conditioning and Allogeneic Hematopoietic Cell Transplantation

We compared the outcomes of 141 consecutive patients who received allogeneic transplantation with either myeloablative (MA) or nonmyeloablative/reduced intensity (NMA) conditioning for non-Hodgkin and Hodgkin lymphoma at the University of Minnesota. All patients were transplanted between 1997 and 2004. NMA transplant recipients were older and received umbilical cord blood grafts more frequently (MA: 6 [9%]; NMA: 33 [43%], P < .001). NMA patients had more advanced disease and 30 (39%) patients had undergone prior autologous transplantation. The 4-year overall survival (OS) (MA: 46% versus NMA: 49%; p = .34) and the 3-year progression-free survival (PFS) (MA: 44% versus NMA: 31%; P = 0.82) were similar after MA or NMA conditioning. However, MA conditioning resulted in significantly higher 1-year treatment-related mortality (TRM) (MA: 43% versus NMA: 17%; P < .01) but a lower risk of relapse at 3 years (MA: 11% versus NMA: 36%; P < .01). We conclude that similar transplant outcomes are achieved after allogeneic hematopoietic stem cell transplantation using MA conditioning in younger patients and NMA conditioning in older patients or those with prior autologous transplantation not eligible for MA conditioning. Modifications to refine patient assignment to the preferred conditioning intensity and reduce relapse risks with NMA approaches are needed.

Predictive factors for outcomes after reduced intensity conditioning hematopoietic stem cell transplantation for hematological malignancies: a 10-year retrospective analysis from the Société Française de Greffe de Moelle et de Thérapie Cellulaire

This retrospective study analyzed the impact of demographic and transplantation variables on outcomes of 1108 patients who have undergone allogeneic hematopoietic stem cell transplantation after reduced intensity conditioning (RIC HSCT) for hematological malignancies and were reported to the Société Française de Greffe de Moelle et de Thérapie Cellulaire registry between November 1994 and December 2004. Only 442 patients (40%) were in complete remission (CR) at time of transplantation. Peripheral blood stem cells were used in the majority of patients (n = 878; 79%), 255 patients received fludarabine and low-dose total body irradiation, while 465 patients (42%) fludarabine and busulfan with rabbit anti-thymocyte globulins (ATG). The impact of demographic and transplant variables was studied on overall (OS) and event-free survival (EFS) in univariate and multivariate analysis. With a median follow-up of 21 months, 3-year probability of OS and EFS was 42% and 30%, respectively, and treatment-related mortality was 15% at 2 years. The multivariate analysis showed a significant negative impact on OS and EFS of the absence of CR status before transplantation; conditioning regimen, including >10 mg/kg ATG; and minor ABO incompatibility. In conclusion, this study highlights the major impact on RIC HSCT outcome of disease status before transplantation, ATG dose and ABO incompatibility.

Sexual function changes during the 5 years after high-dose treatment and hematopoietic cell transplantation for malignancy, with case-matched controls at 5 years

AbstractThis prospective study evaluated sexual function through 5 years after myeloablative allogeneic hematopoietic cell transplantation (HCT) for cancer to determine sexual function recovery and residual problems. Adults completed measures before HCT (N = 161), with survivors followed at 6 months and at 1, 2, 3, and 5 years. At 5 years case-matched controls also completed assessments. Analyses indicated that men and women differed in rates of being sexually active across time (P < .001) and in overall sexual function (P < .001). Both sexes declined in sexual activity rates and sexual function from before HCT to 6 months afterward (P ≤ .05). Activity rates recovered for men by 1 year (74%) and for women by 2 years (55%). Men improved from their 6-month nadir in sexual function by 2 years (P = .02), whereas women did not improve by 5 years (P = .17). Both male and female survivors were below controls in rates of sexual activity and sexual function at 5 years. Most women reported sexual problems (80% of survivors vs 61% of controls, P = .11); in contrast for men 46% of survivors versus 21% of controls (P = .05) reported problems. Thus, despite some recovery, sexual dysfunction remained a major problem for men and women after HCT. Aggressive efforts are needed to treat these deficits.

141: Similar Risks for Hypothyroidism in Myeloablative and Reduced-Intensity Allogeneic Hematopoietic Cell Transplant Survivors

Upto 15% of adult myeloablative (MA) allogeneic hematopoietic cell transplant (HCT) survivors can develop hypothyroidism. HCT using reduced-intensity conditioning (RIC) is associated with lower morbidity and mortality, but the risk of hypothyroidism after RIC HCT is not known. We conducted a retrospective cohort study to compare the incidence of hypothyroidism after MA and RIC HCT. Adult allogeneic HCT recipients were eligible if (1) they had received an allogeneic HCT using a total body irradiation (TBI) based MA or RIC regimen between 2000 and 2005, (2) survived for ≥1 year post-HCT, and (3) had no history of hypothyroidism pre-HCT. TBI dose in MA and RIC regimens was 1320 cGy (165 cGy twice daily × 4 days) and 200 cGy (single fraction), respectively. Hypothyroidism was classified as subclinical (elevated thyroid stimulating hormone [TSH] and normal free thyroxine [FT4]) or overt (elevated TSH and low FT4). All patients had thyroid studies performed at least annually after HCT; if clinically indicated, more frequent assessments were conducted at the discretion of the treating physician. Study eligibility criteria were met by 181 patients (MA = 84, RIC = 97); median follow-up was 28 (range, 12–75) months for MA and 25 (range, 12–67) months for RIC group. MA recipients were younger (median age 37 vs. 54 years, P < 0.01), the two groups were otherwise comparable with respect to gender, race, HCT co-morbidity index scores, disease status, donor source and incidences of acute and chronic GVHD. Eleven patients developed hypothyroidism (subclinical - 9, overt - 2). The 3-year cumulative incidence of hypothyroidism was 8% (95% confidence intervals [CI], 1–14%) in MA and 5% (95% CI, 0–11%) in RIC groups (p = 0.41). In multivariate analyses that included age, gender, race, conditioning regimen intensity, HCT co-morbidity index scores, disease status, donor source, and acute and chronic GVHD, similar risks for developing hypothyroidism were observed between the two types of conditioning regimens (relative risk for MA 1.6 [95% CI, 0.4–5.8] vs. RIC). Female gender was the only factor predictive for hypothyroidism (relative risk 4.5 [95% CI, 1.1–18.0] vs. males). In conclusion, hypothyroidism is relatively infrequent in adult allogeneic HCT survivors. At least in the first few years post-HCT, RIC is associated with similar risks for hypothyroidism as MA conditioning.

Risk Factors for Acute Graft-Versus-Host Disease (GvHD) after Related Donor HLA-Matched Myeloablative Allogeneic Hematopoietic Stem Cell Transplantation (HSCT) for Adult Leukemia: Identification of Modifiable and Non-Modifiable Factors. A CIBMTR Study.

Allogeneic HSCT is a curative therapy for leukemia and other hematologic malignancies and disorders. Acute Graft-versus-Host Disease (aGvHD) is a significant cause of morbidity and mortality that limits the success of HSCT. No large analysis of this complication has been recently performed. Risk factors for aGvHD after HLA-matched sibling myeloablative unmanipulated HSCT were analyzed in 1960 adult (≥18 yrs) patients treated for AML (n=761), ALL (n=303), or CML (n=896) and reported to the CIBMTR registry from 1995–2002 by 226 centers worldwide. All patients received cyclosporine+methotrexate (CSA+MTX) alone (85%) or CSA+MTX+other agents (15%) for aGvHD prophylaxis. 635 (32%) patients developed grade II-IV aGvHD before day +100 post–HSCT. Outcome was measured as time from HSCT to onset of aGvHD Grade II-IV with death as a competing risk. Statistically significant risk factors for aGvHD in the univariate analysis were: Age ≥ 40 vs < 40 at HSCT, RR (95% CI, P) =1.35 (1.16–1.58, P=0.0001); Race, White/Black vs. Asian/Hispanic, RR=1.65 (1.31–2.08, P<0.0001); Recipient Gender, Female vs Male RR=0.83 (0.71–0.98, P=0.025); Stem Cell Source, Peripheral Blood (PB) vs. Bone Marrow (BM), RR=0.76 (0.65–0.89, P=0.0008); Disease, CML vs. AML, RR=1.26 (1.06–1.5, P=0.008), and ALL vs AML, RR=1.12 (0.88–1.42, P=0.37); Disease Status at HSCT, Not in Remission vs. Remission, RR=1.29 (1.03–1.62, P=0.029); Conditioning Regimen, CyTBI vs. BuCy, RR=1.39 (1.18–1.62, P<0.0001); KPS at HSCT, ≤ 80 vs > 80, RR=1.34 (1.12–1.60, P=0.0016); and Donor ever Pregnant, Yes vs No/Male, RR=1.21 (1.10–1.43, P=0.034). Other factors not significant in the univariate analysis were year of HSCT (1995–1998 vs. 1999–2002), recipient/donor sex-matching, time from diagnosis to HSCT, recipient/donor CMV status, donor gender, ABO compatibility, and planned G-CSF use post-HSCT. Multivariate analysis of time to onset of aGvHD Grade II-IV was performed by using a Cox proportional hazards model with backwards step-wise selection and P > 0.05 to remove each clinical factor from the model. Significant independent predictors of aGvHD Grade II-IV risk were: Conditioning Regimen, CyTBI vs BuCy, RR (95% CI, P) RR=1.4, (1.2–1.7, P<0.0001); PB vs BM in Patients 18–39 yrs at HSCT, RR=1.4 (1.1–1.8, P=0.0023); Disease, CML vs. AML/ALL, RR=1.3 (1.1–1.6, P=0.0003); Race, White/Black vs. Asian/Hispanic, RR=1.5 (1.2–1.9, P=0.0003); KPS, ≤ 80 vs > 80, RR=1.3 (1.05–1.5, P=0.014) and recipient/donor CMV status, at least one + vs −/ −, RR=0.8 (0.7–0.99, P=0.04). For pts ≥ 40 yrs at BMT, PB was not an independent risk factor for aGvHD Grade II-IV. There are modifiable risk factors for aGvHD Grade II-IV which include conditioning regimen, stem cell source (in younger patients) and CMV negative donors for CMV negative recipients. There are non-modifiable risk factors such as recipient age, race and gender and underlying diagnosis. Identifying patients at high risk for aGvHD Grade II-IV may allow for individualized risk modification and result in altering treatment strategies.

Similar Risks for Late-Onset Chronic Kidney Disease in Myeloablative and Reduced-Intensity Allogeneic Hematopoietic Cell Transplant Survivors.

Chronic kidney disease (CKD) has been reported in nearly 20% of recipients of myeloablative (MA) allogeneic hematopoietic cell transplantation (HCT). HCT using reduced-intensity (RIC) conditioning is associated with lower morbidity and mortality, but the risk of CKD after RIC HCT is not well known. We conducted a retrospective cohort study to compare the incidence of CKD after MA and RIC HCT. Adult allogeneic HCT recipients were eligible if (1) they received an allogeneic HCT between 2000 and 2005, (2) survived for ≥ 1 year post-HCT, and (3) had no history of CKD pre-transplant. The dose of total body irradiation in MA and RIC regimens was 1320 cGy (165 cGy twice daily × 4 days) and 200 cGy (single fraction), respectively, and was given without kidney shielding. CKD was defined as glomerular filtration rate (GFR) < 60 ml/min/1.73m2 for ≥ 3 months (National Kidney Foundation definition) anytime after 180 days post-HCT. GFR was estimated using the Modification of Diet in Renal Disease equation [GFR = 186 × (SCr)−1.154 × (Age)−0.203 × (0.742 if female) × (1.210 if African American)]. Study eligibility criteria were met by 221 patients (MA=104, RIC=117); median follow-up was 28 (range, 12–75) months for MA and 25 (range, 12–67) months for RIC group. At the time of transplant, MA recipients were younger (median age 38 vs. 54 years, P<0.01), less likely to have HTN (7% vs. 22%, P<0.01) and more likely to have a body mass index of <30 (87% vs. 72%, P=0.01). The two groups were comparable with respect to prevalence of diabetes mellitus, smoking, HCT co-morbidity index scores, incidence of acute renal failure (ARF) within the first 180 days, and duration of cyclosporine (CSA) use. A total of 60 (MA=30, RIC=30) patients developed CKD, resulting in a 3-year cumulative incidence rate of 29% (95% confidence intervals, 20–37%) in MA and 27% (18–35%) in the RIC group (p=0.44). In multivariate analysis, conditioning regimen intensity had no impact on risk of developing CKD (relative risk [RR] for MA 1.60 [0.86–2.97] vs. RIC regimen). Factors independently associated with an increased risk of CKD were age at HCT (RR 1.05 [1.02–1.08] for each year increase), acute graft-versus-host disease (RR 2.16 [1.19–3.93]) and CSA use for >6 months (RR 3.48 [2.33–2.56]). ARF within the first 180 days also predicted the risk for CKD. Compared to severe ARF [lowest GFR ≤ 30], RR of CKD was 0.40 [0.23–0.69] for moderate ARF [lowest GFR 31–59] and 0 for no ARF [lowest GFR ≥ 60]. In conclusion, CKD is frequent in long term adult allogeneic HCT survivors. RIC is associated with similar risks of CKD as MA conditioning. Older age, ARF, acute graft-versus-host disease and prolonged CSA exposure increases the risk of CKD. Continuous monitoring of renal function is necessary in allogeneic HCT survivors and studies exploring prevention strategies are needed.

A Large Cohort Analysis of CMV Viral Load and Ganciclovir-Related Neutropenia in Nonmyeloablative (NM-HCT) and Myeloablative (M-HCT) Allogeneic Hematopoietic Cell Transplant Recipients.

Background. The “true” nonmyeloablative allogeneic stem cell transplantation (NM-HCT) allows initial establishment of mixed T-cell chimerism for up to 6 months. The prolonged presence of host memory immune response after NM-HCT may play a role in protection against CMV infection especially early after NM-HCT. Furthermore, we previously reported that the incidence and poor outcome of ganciclovir-related neutropenia (GCV-N) is strongly associated with myelotoxic conditioning. Therefore, non-myeloablative HCT may also contribute to a lower risk of GCV-N. In this to date largest cohort we examined the risk of CMV infection and GCV-N after NM conditioning.Methods. We retrospectively analyzed 537 NM-HCT recipients (median age 54.2 yrs) and 2489 M-HCT recipients (median age 39.8 yrs) transplanted between 1/1995 and 12/2005. The conditionings for NM-HCT mostly consisted of 2 Gy TBI with/without fludarabine. Post-grafting immunosuppression consisted of most commonly mycophenolate mofetil and cyclosporine (CSP) for NM-HCT recipients and methotrexate/CSP for M-HCT recipients. CMV surveillance was performed weekly by antigenemia (AG) or plasma PCR testing. GCV/VGCV was given for CMV AG/PCR positivity. We evaluated1.any AG/DNA detection by day 100,2.AG >10/200,000 PBL or PCR> 1000 copies/ml (high-grade CMV AG/DNA) by day 100 and3.GCV-N defined as non-relapse-related neutropenia (ANC<500 μL) after AG/PCR positivity with ANC>1000 μL at time of viremia using multivariable Cox regression.In addition, post-engraftment neutropenia, defined as ANC<500 μL occurring after day 28 post HCT among relapse-free patients.Results. There was no significant difference in the incidence of CMV AG/DNA at any level between NM-HCT and M-HCT (39% vs.37%, HR 1.1, P=0.42). However, there was less high-grade CMV infection in NM-HCT compared to M-HCT patients (9% vs. 14%, adj. HR 0.6, P < 0.01). Risk factors for high-grade CMV infection other than M-HCT were advanced recipient age, CMV serostatus, transplantation year and acute GVHD. The incidence of GCV-N was similar between NM-HCT and M-HCT recipients (28% vs. 20%, adj. HR 1.3, P=0.27). Risk factors for GCV-N were advanced recipient age and acute GVHD. On the other hand, the incidence of post-engraftment neutropenia was higher in NM-HCT (29% vs. 13%, adj. HR 2.1, P<0.0001). Other risk factors for post-engraftment neutropenia included advanced recipient or donor age, cord blood, HLA mismatched/unrelated donor, female donor to male recipient, acute GVHD, recipient CMV seropositivity and CMV infection.Conclusion. Our results suggest that the risk of CMV reactivation is not affected by NM conditioning but that progression to higher levels of viral load is reduced. This may be due to residual host memory immunity after NM-HCT. Despite less toxic conditioning, the incidence of GCV-N in NM-HCT was similar to that in M-HCT. Notably, the incidence of post-engraftment neutropenia was more frequent in NM-HCT compared to M-HCT recipients. This may be due to higher recipient and/or donor age, lower capacity to metabolize drugs, or the use of myelotoxic co-medication such as MMF or TMP-SMX.

Superior Long Term Progression Free Survival of Myeloablative Allogeneic Hematopoietic Stem Cell Transplantation for Multiple Myeloma Compared to Autologous Hematopoietic Stem Cell Transplantation after Identical Conditioning Regimen.

Allogeneic hematopoietic stem cell transplantation (HSCT) is a treatment option with curative potential that exploits graft versus myeloma effect (GVM). However, myeloablative allogeneic HSCT has been associated with high transplant-related mortality and its impact on risk of relapse has been questioned. The differences in conditioning regimens, GVHD prophylaxis and short follow up have limited our ability to assess the impact of GVM when comparing allogeneic and autologous HSCT.Method: We evaluated the long term outcomes of 74 consecutive patients under the age of 60 who underwent autologous (n=46) or related allogeneic HSCT (n=28) between 3/1994 and 12/2000 following a single myeloablative conditioning regimen of TBI (3 Gy daily on days -10 to -8), oral Busulfan 2.4 mg/kg per day (day -7 to -4) and Cyclophosphamide 60 mg/kg IV daily (day-3 and -2). GVHD prophylaxis was tacrolimus or cyclosporine with or without methotrexate.Results: There were no significant differences observed between groups in regard to gender, immunoglobulin subtype, stage, and time to HSCT and disease status at HSCT. However, there were younger patients with advanced disease in the allogeneic group (Table 1). With median follow up of 10 years as of 12/2006, the allogeneic group had superior progression free survival than autologous group (37% v 9%; P = 0.04). After HSCT, 12 of 22 and 9 of 39 evaluable patients improved to complete remission in the allogeneic and autologous group, respectively (55% v 23%; P=0.02). Overall survival favored the allogeneic group but was not statistically significant (46% v 23%; P=0.56). The cumulative incidence of relapse was 18% in the allogeneic group and 74% in the autologous group (P=0.0001). The cumulative incidence of non-relapse mortality (NRM) was 32% in allogeneic group and 11% in autologous group (P=0.001). The cumulative incidence of acute GVHD (grade II-IV) was 46% and the cumulative incidence of chronic GVHD was 73%.Conclusion: The superior long term progression free survival and lower relapse rate in the allogeneic group suggests strongly GVM effect. However, the NRM in the allogeneic group partially offset the overall survival benefit. The higher than expected OS rate for both allogeneic and autologous group may be related to a beneficial effect of myeloablative conditioning. Future strategies with reduced toxicity myeloablative conditioning regimens and improved GVHD prophylaxis may reduce NRM while harnessing GVM effect.Selected CharacteristicsCharacteristicsAutologousAllogeneicPMedian age at HSCT; y (range)53 (38–59)47 (30–56)0.01Disease status at HSCT, n0.12CR11 (24%)2 (7%)PR32 (70%)22 (79%)Stable or progressive3 (6%)4 (14%)Disease Status after HSCT, n0.79CR20 (44%)14 (50%)PR13 (28%)8 (29%)Stable or progressive6 (13%)0 (0%)Non-evaluable7 (15%)6 (21%)HSCT; hematopoietic stem cell transplantation, CR; complete remission, PR; Partial remission [Display omitted]

Successful treatment of hepatic veno-occlusive disease after myeloablative allogeneic hematopoietic stem cell transplantation by early administration of a short course of methylprednisolone

Hepatic veno-occlusive disease (VOD) is one of the most common and important regimen-related toxicities observed after hematopoietic stem cell transplantation (HSCT). There are no universally accepted preventative or therapeutic approaches for VOD. We prospectively evaluated the safety and efficacy of a short course of methylprednisolone (MP) in 48 patients undergoing allogeneic HSCT who were diagnosed with hepatic VOD. MP was administered at a dose of 0.5 mg/kg i.v. every 12 h for a total of 14 doses, and then discontinued without taper. Thirty (63%) patients responded with a reduction in total serum bilirubin of 50% or more after 10 days of treatment. In univariate analysis, non-responders had a higher total bilirubin at the start of MP therapy, more weight gain, evidence of fungal infection and platelet refractoriness. High SGPT and early engraftment were significant factors among responders. Twenty-five of the 30 responders survived up to day +100, whereas all but three non-responders died within 100 days post-HSCT, for a probability of survival of 58% among responders and 10% for non-responders. Prospective comparative studies are needed to confirm the observed encouraging outcome of MP therapy for VOD.