Ernesto Ayala

5-Azacitidine for myelodysplasia before allogeneic hematopoietic cell transplantation

Relapse remains a leading cause for treatment failure after hematopoietic cell transplantation (HCT) in patients with intermediate- or high-risk myelodysplastic syndrome (MDS). To discern the impact of 5-azacitine treatment pretransplant on the risk for relapse after HCT, we analyzed the post transplant outcomes of all 54 consecutive patients with MDS or chronic myelomonocytic leukemia who received HCT from HLA-compatible donors according to pretransplant 5-azacitidine exposure. Thirty patients received a median of four (1–7) cycles of 5-azacitidine, and 24 patients did not receive 5-azacitidine before HCT. The 1-year estimates of overall survival, relapse-free survival and cumulative incidence of relapse were 47, 41 and 20%, for 5-azacitidine patients and 60, 51 and 32%, respectively, for non-5-azacytidine patients. These observations suggest that outcomes are similar in both groups with a trend toward decreased early relapse in patients receiving 5-azacitidine. 5-Azacitidine may be of value in stabilizing the disease, thereby allowing time for patients to reach transplant and does not appear to affect transplant outcomes.

Phase III Randomized Study of Rituximab/Carmustine, Etoposide, Cytarabine, and Melphalan (BEAM) Compared With Iodine-131 Tositumomab/BEAM With Autologous Hematopoietic Cell Transplantation for Relapsed Diffuse Large B-Cell Lymphoma: Results From the BMT CTN 0401 Trial

PURPOSE This clinical trial evaluated standard-dose radioimmunotherapy with a chemotherapy-based transplantation regimen followed by autologous hematopoietic cell transplantation versus rituximab with the same regimen in patients with relapsed diffuse large B-cell lymphoma (DLBCL). PATIENTS AND METHODS Patients with chemotherapy-sensitive persistent or relapsed DLBCL were randomly assigned to receive iodine-131 tositumomab (dosimetric dose of 5 mCi on day -19 and therapeutic dose of 0.75 Gy on day -12), carmustine 300 mg/m(2) (day -6), etoposide 100 mg/m(2) twice daily (days -5 to -2), cytarabine 100 mg/m(2) twice daily (days -5 to -2), and melphalan 140 mg/m(2) (day -1; B-BEAM) or rituximab 375 mg/m(2) on days -19 and -12 and the same chemotherapy regimen (R-BEAM). RESULTS Two hundred twenty-four patients were enrolled, with 113 patients randomly assigned to R-BEAM and 111 patients assigned to B-BEAM. Two-year progression-free survival (PFS) rates, the primary end point, were 48.6% (95% CI, 38.6% to 57.8%) for R-BEAM and 47.9% (95% CI, 38.2% to 57%; P = .94) for B-BEAM, and the 2-year overall survival (OS) rates were 65.6% (95% CI, 55.3% to 74.1%) for R-BEAM and 61% (95% CI, 50.9% to 69.9%; P = .38) for B-BEAM. The 100-day treatment-related mortality rates were 4.1% (95% CI, 0.2% to 8.0%) for R-BEAM and 4.9% (95% CI, 0.8% to 9.0%; P = .97) for B-BEAM. The maximum mucositis score was higher in the B-BEAM arm (0.72) compared with the R-BEAM arm (0.31; P < .001). CONCLUSION The B-BEAM and R-BEAM regimens produced similar 2-year PFS and OS rates for patients with chemotherapy-sensitive relapsed DLBCL. No differences in toxicities other than mucositis were noted.

Two cases of progressive multifocal leukoencephalopathy after allogeneic hematopoietic cell transplantation and a review of the literature

Progressive multifocal leukoencephalopathy (PML) is a rare subacute demyelinating disorder of the central nervous system (CNS) caused by the DNA JC human polyomavirus. In immunocompromised hosts, PML is caused by reactivation of a latent infection rather than de novo primary exposure. PML in the setting of hematopoietic cell transplantation (HCT) is exceedingly rare. PML should be considered in the differential diagnosis of HCT recipients, autologous or allogeneic, presenting with worsening of neurological symptoms, especially associated with post-transplant neurodegenerative findings. Although DNA polymerase chain reaction (PCR) of the cerebrospinal fluid (CSF) has emerged as a promising tool for detecting JC virus, a negative result does not rule out PML. Brain biopsy remains the most reliable and accurate method for diagnosing JC virus-associated PML. Presently, there is no universally effective antiviral therapy against JC virus and outcome is fatal in the majority of cases. We hereby describe two cases of PML developing after allogeneic HCT and provide a comprehensive review of the literature.

Autologous or Reduced-Intensity Conditioning Allogeneic Hematopoietic Cell Transplantation for Chemotherapy-Sensitive Mantle-Cell Lymphoma: Analysis of Transplantation Timing and Modality

PURPOSE To examine the outcomes of patients with chemotherapy-sensitive mantle-cell lymphoma (MCL) following a first hematopoietic stem-cell transplantation (HCT), comparing outcomes with autologous (auto) versus reduced-intensity conditioning allogeneic (RIC allo) HCT and with transplantation applied at different times in the disease course. PATIENTS AND METHODS In all, 519 patients who received transplantations between 1996 and 2007 and were reported to the Center for International Blood and Marrow Transplant Research were analyzed. The early transplantation cohort was defined as those patients in first partial or complete remission with no more than two lines of chemotherapy. The late transplantation cohort was defined as all the remaining patients. RESULTS Auto-HCT and RIC allo-HCT resulted in similar overall survival from transplantation for both the early (at 5 years: 61% auto-HCT v 62% RIC allo-HCT; P = .951) and late cohorts (at 5 years: 44% auto-HCT v 31% RIC allo-HCT; P = .202). In both early and late transplantation cohorts, progression/relapse was lower and nonrelapse mortality was higher in the allo-HCT group. Overall survival and progression-free survival were highest in patients who underwent auto-HCT in first complete response. Multivariate analysis of survival from diagnosis identified a survival benefit favoring early HCT for both auto-HCT and RIC allo-HCT. CONCLUSION For patients with chemotherapy-sensitive MCL, the optimal timing for HCT is early in the disease course. Outcomes are particularly favorable for patients undergoing auto-HCT in first complete remission. For those unable to achieve complete remission after two lines of chemotherapy or those with relapsed disease, either auto-HCT or RIC allo-HCT may be effective, although the chance for long-term remission and survival is lower.

A Randomized Phase II Trial Comparing Tacrolimus and Mycophenolate Mofetil to Tacrolimus and Methotrexate for Acute Graft-versus-Host Disease Prophylaxis

Tacrolimus (Tac) plus methotrexate (MTX) is a standard regimen for graft-versus-host disease (GVHD) prophylaxis. Mycophenolate mofetil (MMF) is sometimes used instead of MTX to minimize toxicity, despite the lack of controlled studies demonstrating efficacy. We conducted a single-center, randomized phase II trial comparing Tac + MMF to Tac + MTX. Intent-to-treat analyses included 42 patients randomized to Tac + MMF and 47 to Tac + MTX. Patient characteristics were not different between the study arms. Patients in the Tac + MMF arm were less likely to experience severe mucositis, require narcotic analgesia and parenteral nutrition, and had earlier hospital discharge. The Tac + MMF arm had the same time to neutrophil recovery, but earlier platelet recovery. The cumulative incidence of grade II-IV acute GVHD (aGVHD) at 100 days was similar (P = .8), but grade III-IV aGVHD was higher in the Tac + MMF arm (19% versus 4%; P = .03); this was predominantly seen in unrelated donor transplants (26% versus 4%; P = .04), and less in related donor transplants (11% versus 4%; P = n.s.). Moderate or severe chronic GVHD was similar (P = .71). There were no significant differences between the arms in relapse, nonrelapse mortality, or overall and relapse-free survivals. MMF was associated with less early toxicity than MTX but was not as effective in preventing severe aGVHD, especially in unrelated donor transplants.

Valganciclovir is safe and effective as pre-emptive therapy for CMV infection in allogeneic hematopoietic stem cell transplantation

Despite significant advances in prevention and therapy, cytomegalovirus (CMV) infection continues to be an important cause of morbidity and mortality in the hematopoietic stem cell transplant (HSCT) recipient. The standard drug for pre-emptive therapy is intravenous ganciclovir (GCV). Valganciclovir (VGC), the oral pro-drug of GCV, has excellent bioavailability and is ideal for oral therapy. Since March 2002, VGC was adopted in our center for outpatient pre-emptive therapy in all patients undergoing allogeneic HSCT. Fifty-two allogeneic HSCT recipients were followed weekly via Digene hybrid capture assay®. Patients with a positive assay were treated with VGC 900 mg p.o. b.i.d. × 14 days followed by 900 mg p.o. QD until at least 7 days after a negative test. Eighteen patients (14 sib, four MUD) had 30 episodes of CMV DNA detection treated with oral VGC. Median duration of therapy was 21 days (range 10–21 days). The rate of response was 93% (28/30) as confirmed by a negative assay within 14 days. No significant toxicity was encountered. Two patients failed oral VGC. One case of CMV enteritis was diagnosed in a patient with acute GVHD. Pre-emptive therapy of CMV infection with oral VGC is safe and effective in allogeneic HSCT recipients.

Human immunodeficiency virus (HIV)-negative plasmablastic lymphoma: A single institutional experience and literature review

Plasmablastic lymphoma (PBL) is a rare aggressive B-cell lymphoproliferative disorder. HIV-negative PBL has not been extensively reported. Nine HIV-negative PBL patients evaluated at Moffitt Cancer Center were studied. Eight patients had extranodal diseases. All patients were treated with CHOP or hyper-CVAD. Responses were observed in 8 cases (7 complete, 1 partial responses). Four patients underwent consolidation with autologous hematopoietic stem cell transplant (HSCT) in first complete remission (CR1). At median follow-up of 23.9 months, 7 patients were alive and 5 were disease-free. Aggressive induction chemotherapy and consolidation with autologous HSCT in CR1 might be considered for patients with HIV-negative PBL.

Sirolimus for treatment of steroid-refractory acute graft-versus-host disease

Acute GVHD (aGVHD) is a major cause of morbidity and mortality in hematopoietic allograft recipients. The best therapy for patients failing to respond, or not tolerating, systemic glucocorticoids remains undefined. We evaluated the efficacy of sirolimus in 34 patients, median age of 49 (23–67) years, with steroid-refractory (n=31) or steroid-intolerant (n=3) aGVHD. aGVHD was diagnosed at a median of 34 (7–1042) days post allografting, and confirmed by biopsy in all cases. Initial aGVHD treatment consisted of prednisone up to 2 mg/kg. Sirolimus was initiated at a median of 9 (1–255) days after glucocorticoid initiation. A sirolimus loading dose was administered to 19 (56%) of 34 patients, median 6 (3–8) mg, followed by maintenance of 1–2 mg/day to target therapeutic trough levels between 4 and 12 ng/ml. Overall response rate was 76%. Fifteen (44%) of 34 patients achieved CR, defined as complete resolution of aGVHD sustained for at least 1 month, after sirolimus initiation without additional immunosuppressive agents. CR was achieved in 11 (42%) of 31 steroid-refractory and 2 (67%) of 3 steroid-intolerant patients. Median OS after initiation of sirolimus was 5.6 months, and 1-year OS was 44% (95% CI: 27–60%). Sirolimus is effective in controlling steroid-refractory aGVHD.

Race/ethnicity affects the probability of finding an HLA-A, -B, -C and -DRB1 allele-matched unrelated donor and likelihood of subsequent transplant utilization

Factors relevant to finding a suitable unrelated donor and barriers to effective transplant utilization are incompletely understood. Among a consecutive series of unrelated searches (n=531), an 8/8 HLA-A, -B, -C and -DRB1-matched unrelated donor was available for 289 (54%) patients, 7/8 for 159 (30%) and no donor for 83 (16%). Patients of Caucasian race (P<0.0001) were more likely to find a donor. Younger age (P=0.01), Caucasian race (P=0.03), lower CIBMTR (Center for International Blood and Marrow Transplantation Research) risk (P=0.005), and 8/8 HLA matching (P=0.005) were associated with higher odds of reaching hematopoietic cell transplantation (HCT). In a univariate analysis of OS, finding a donor was associated with hazard ratio (HR) of 0.85 (95% CI 0.63–1.2), P=0.31. Karnofsky performance status (KPS) accounted for interaction between having a donor and survival. Patients with KPS 90–100 and a donor had significantly reduced hazard for death (HR 0.59, 95% CI 0.38–0.90, P=0.02). These data provide estimates of the probability to find an unrelated donor in the era of high-resolution HLA typing, and identify potentially modifiable barriers to reaching HCT. Further efforts are needed to enhance effective donor identification and transplant utilization, particularly in non-Caucasian ethnic groups.

Early Failure of Frontline Rituximab-Containing Chemo-immunotherapy in Diffuse Large B Cell Lymphoma Does Not Predict Futility of Autologous Hematopoietic Cell Transplantation

The poor prognosis for patients with diffuse large B cell lymphoma (DLBCL) who relapse within 1 year of initial diagnosis after first-line rituximab-based chemo-immunotherapy has created controversy about the role of autologous transplantation (HCT) in this setting. We compared autologous HCT outcomes for chemosensitive DLBCL patients between 2000 and 2011 in 2 cohorts based on time to relapse from diagnosis. The early rituximab failure (ERF) cohort consisted of patients with primary refractory disease or those with first relapse within 1 year of initial diagnosis. The ERF cohort was compared with those relapsing >1 year after initial diagnosis (late rituximab failure [LRF] cohort). ERF and LRF cohorts included 300 and 216 patients, respectively. Nonrelapse mortality (NRM), progression/relapse, progression-free survival (PFS), and overall survival (OS) of ERF versus LRF cohorts at 3 years were 9% (95% confidence interval [CI], 6% to 13%) versus 9% (95% CI, 5% to 13%), 47% (95% CI, 41% to 52%) versus 39% (95% CI, 33% to 46%), 44% (95% CI, 38% to 50%) versus 52% (95% CI, 45% to 59%), and 50% (95% CI, 44% to 56%) versus 67% (95% CI, 60% to 74%), respectively. On multivariate analysis, ERF was not associated with higher NRM (relative risk [RR], 1.31; P = .34). The ERF cohort had a higher risk of treatment failure (progression/relapse or death) (RR, 2.08; P < .001) and overall mortality (RR, 3.75; P <.001) within the first 9 months after autologous HCT. Beyond this period, PFS and OS were not significantly different between the ERF and LRF cohorts. Autologous HCT provides durable disease control to a sizeable subset of DLBCL despite ERF (3-year PFS, 44%) and remains the standard-of-care in chemosensitive DLBCL regardless of the timing of disease relapse.