Improving outcomes after allogeneic hematopoietic cell transplantation for Hodgkin lymphoma in the brentuximab vedotin era.

Allogeneic hematopoietic cell transplantation (alloHCT) remains a valuable treatment alternative for relapsed/refractory (R/R) Hodgkin lymphoma (HL). Data on alloHCT outcomes in the era of new HL therapies are needed. We evaluated 72R/R HL patients who received reduced intensity conditioning alloHCT and compared the time periods 2009-2013 (n=20) with 2000-2008 (n=52). Grafts included HLA-matched sibling (35%), unrelated donor (8%) and umbilical cord blood (56%). In the recent period, patients more often received brentuximab vedotin (BV, 60% vs 2%), had fewer comorbidities (Sorror index 0: 60% vs 12%) and were in complete remission (50% vs 23%). Median follow-up was 4.4 years. Three-year PFS improved for patients treated between 2009 and 2013 (49%, 95% CI 26-68%) as compared with the earlier era (23%, 95% CI 13-35%, P=0.02). Overall survival (OS) at 3 years was 84% (95% CI 57-94%) vs 50% (95% CI 36-62%, P=0.01), reflecting lower non-relapse mortality and relapse rates. In multivariate analysis mortality was higher among those with chemoresistance (HR 3.83, 95% CI 1.38-10.57), while treatment during the recent era was associated with better OS (HR for period 2009-2013: 0.24, 95% CI 0.07-0.79) and PFS (HR 0.46, 95% CI 0.23-0.92). AlloHCT in patients with R/R HL is now a more effective treatment than previously.

A prognostic model predicting autologous transplantation outcomes in children, adolescents and young adults with Hodgkin lymphoma.

Autologous hematopoietic cell transplantation (AutoHCT) is a potentially curative treatment modality for relapsed/refractory Hodgkin lymphoma (HL). However, no large studies have evaluated pretransplant factors predictive of outcomes of AutoHCT in children, adolescents and young adults (CAYA, age <30 years). In a retrospective study, we analyzed 606 CAYA patients (median age 23 years) with relapsed/refractory HL who underwent AutoHCT between 1995 and 2010. The probabilities of PFS at 1, 5 and 10 years were 66% (95% confidence interval (CI): 62-70), 52% (95% CI: 48-57) and 47% (95% CI: 42-51), respectively. Multivariate analysis for PFS demonstrated that at the time of AutoHCT patients with Karnofsky/Lansky score ⩾90, no extranodal involvement and chemosensitive disease had significantly improved PFS. Patients with time from diagnosis to first relapse of <1 year had a significantly inferior PFS. A prognostic model for PFS was developed that stratified patients into low-, intermediate- and high-risk groups, predicting for 5-year PFS probabilities of 72% (95% CI: 64-80), 53% (95% CI: 47-59) and 23% (95% CI: 9-36), respectively. This large study identifies a group of CAYA patients with relapsed/refractory HL who are at high risk of progression after AutoHCT. Such patients should be targeted for novel therapeutic and/or maintenance approaches post-AutoHCT.

Alternative donors extend transplantation for patients with lymphoma who lack an HLA matched donor.

Alternative donor transplantation is increasingly used for high-risk lymphoma patients. We analyzed 1593 transplant recipients (2000-2010) and compared transplant outcomes in recipients of 8/8 allele HLA-A, -B, -C and DRB1 matched unrelated donors (MUDs; n=1176), 7/8 allele HLA mismatched unrelated donors (MMUDs; n=275) and umbilical cord blood donors (1 or 2 units UCB; n=142). Adjusted 3-year non-relapse mortality of MMUD (44%) was higher as compared with MUD (35%; P=0.004), but similar to UCB recipients (37%; P=0.19), although UCB had lower rates of neutrophil and platelet recovery compared with unrelated donor groups. With a median follow-up of 55 months, 3-year adjusted cumulative incidence of relapse was lower after MMUD compared with MUD (25% vs 33%, P=0.003) but similar between UCB and MUD (30% vs 33%; P=0.48). In multivariate analysis, UCB recipients had lower risks of acute and chronic GVHD compared with adult donor groups (UCB vs MUD: hazard ratio (HR)=0.68, P=0.05; HR=0.35; P<0.001). Adjusted 3-year OS was comparable (43% MUD, 37% MMUD and 41% UCB). These data highlight the observation that patients with lymphoma have acceptable survival after alternative donor transplantation. MMUD and UCB can extend the curative potential of allotransplant to patients who lack suitable HLA matched sibling or MUD.

Ph+ ALL patients in first complete remission have similar survival after reduced intensity and myeloablative allogeneic transplantation: impact of tyrosine kinase inhibitor and minimal residual disease.

The efficacy of reduced intensity conditioning (RIC) allogeneic hematopoietic cell transplantation (HCT) for Philadelphia chromosome positive (Ph+) acute lymphoblastic leukemia (ALL) is uncertain. We analyzed 197 adults with Ph+ ALL in first complete remission; 67 patients receiving RIC were matched with 130 receiving myeloablative conditioning (MAC) for age, donor type and HCT year. Over 75% received pre-HCT tyrosine kinase inhibitors (TKIs), mostly imatinib; 39% (RIC) and 49% (MAC) were minimal residual disease (MRD)(neg) pre-HCT. At a median 4.5 years follow-up, 1-year transplant-related mortality (TRM) was lower in RIC (13%) than MAC (36%; P=0.001) while the 3-year relapse rate was 49% in RIC and 28% in MAC (P=0.058). Overall survival (OS) was similar (RIC 39% (95% confidence interval (CI) 27-52) vs 35% (95% CI 27-44); P=0.62). Patients MRD(pos) pre-HCT had higher risk of relapse with RIC vs MAC (hazard ratio (HR) 1.97; P=0.026). However, patients receiving pre-HCT TKI in combination with MRD negativity pre-RIC HCT had superior OS (55%) compared with a similar MRD population after MAC (33%; P=0.0042). In multivariate analysis, RIC lowered TRM (HR 0.6; P=0.057), but absence of pre-HCT TKI (HR 1.88; P=0.018), RIC (HR 1.891; P=0.054) and pre-HCT MRD(pos) (HR 1.6; P=0.070) increased relapse risk. RIC is a valid alternative strategy for Ph+ ALL patients ineligible for MAC and MRD(neg) status is preferred pre-HCT.

Hematopoietic cell transplantation for Waldenström macroglobulinemia.

Waldenström macroglobulinemia (WM) is a distinct indolent B-cell lymphoproliferative malignancy characterized by IgM paraproteinemia. Although the disease is sensitive to chemo-immunotherapy, it remains incurable and affected patients have a median survival of 5-10 years. Risk stratification in newly diagnosed patients should start with a prognostic evaluation based on the International Prognostic Scoring System for WM (IPSSWM) to identify those patients in whom particularly poor survival with chemotherapy is expected and in whom alternative treatment strategies, such as hematopoietic cell transplantation (HCT), should be considered. High-dose chemotherapy followed by autologous HCT (auto-HCT) results in disease-free survival of 45-65% at 5 years, but is unlikely to be curative. Chemosensitive disease at the time of auto-HCT is the most important prognostic factor for response rate and overall survival. Allogeneic donor HCT may offer a unique immune-mediated GVL effect with a plateau in relapse rates and potential for extended disease-free survival. The risk of allogeneic HCT complications is justified in HCT-eligible patients whose expected survival is <5 years. Here, we present the advances in non-transplant strategies and the therapeutic role of transplant, and suggest a treatment algorithm for selecting a HCT strategy while adhering to current evidence supporting autologous and allogeneic donor HCT for WM.

Fewer infections and lower infection-related mortality following non-myeloablative versus myeloablative conditioning for allotransplantation of patients with lymphoma.

Non-myeloablative (NMA) allogeneic donor SCT for patients with relapsed lymphoma is associated with lower treatment-related mortality (TRM). However, the impact of conditioning intensity on post transplant infections remains unclear. We evaluated infections in 141 consecutive patients with lymphoma who were allografted using NMA (n=76) or myeloablative (MA; n=65) conditioning regimens. Using infection incidence density per 1000 patient days, we accounted for all infectious episodes during the first post transplant year. Before neutrophil engraftment, the NMA cohort had a 53% lower rate of bacterial infection (relative risk=0.47; P=0.06), whereas after engraftment the density of bacterial infections was similar in the two groups. In the first month, both invasive fungal infections and viral infections were twofold less frequent (P=0.22; P=0.06) in NMA patients. Late viral and fungal infections as well as CMV reactivation were infrequent after either conditioning intensity. The 1-year infection-related mortality was significantly lower after NMA conditioning (NMA 9% (3-16%) vs MA 22% (11-40%); P=0.03). NMA allogeneic transplantation for lymphoma patients results in substantially fewer early infections and lower infection-related deaths, although the similar frequency of later infections suggests that immune reconstitution is delayed with either conditioning intensity.

Unrelated donor allogeneic transplantation for adult acute lymphoblastic leukemia: a review.

Acute lymphoblastic leukemia is highly sensitive to induction chemotherapy; however, long-term survival in adults has been less than 35%, primarily as a result of high relapse rate. Treatment for relapsed disease is even less successful. The optimal post-remission therapy in the first complete remission offers the best opportunity for leukemia-free survival. Allogeneic donor stem cell transplantation can offer a unique anti-leukemia effect and a potential for extended survival. We will discuss advances in unrelated donor (URD) stem cells transplantation, improvements in transplantation process and supportive care along with growing experience with umbilical cord blood (UCB) allografts.

Vancomycin plus imipenem ceftazidime or ciprofloxacin in second line therapy in patients with febrile neutropenia not responding to first line therapy.

137 patients with febrile neutropenia after cytotoxic therapy not responding to ceftazidime plus or ceftriaxone plus netilmicin in received additionally to the previous combination either vancomycin alone or combined with another anti-gram-negative compound: imipenem in those treated prophylactically with ofloxacin and ciprofloxacin in those without prophylaxis. The addition of vancomycin to the previously ineffective combination of a third generation cephalosporin plus aminoglycoside, and replacement of ceftriaxone plus netilmicin with ceftazidime plus amikacin plus vancomycin or with ceftazidime plus vancomycin seems to be less effective (71.8-75 vs. 87.5-90.9%, p < 0.02) and more toxic (20.5-7.2 vs. 0-5%, p < 0.0005) than vancomycin in combination with a different anti-gram-negative compound as previously used: imipenem or ciprofloxacin.