Rituximab In Transplantation Research Articles

Practice changing information in aggressive lymphoma, ASH 2015

Out of the numerous papers dealing with lymphoma at the American Society of Hematology (ASH) 2015 meeting, three could change clinical practice. The DA-EPOCH-R regimen has improved the evidence for efficacy in Burkitt lymphoma. For lymphoproliferative disease after solid organ transplantation rituximab is a reasonable first-line treatment and nonresponders can be salvaged with R‑CHOP. For anaplastic large cell lymphoma the addition of etoposide to the CHOP regimen is an option. However, better regimens with new drugs are eagerly awaited.

In-Vivo Purging with Rituximab (R) Followed By Z/BEAM Vs BEAM/R Autologous Stem Cell Conditioning for Relapsed Diffuse Large B-Cell Lymphoma (DLBCL) Patients (pts): Mature Results from a Combined Analysis of 3 Trials

In-Vivo Purging with Rituximab (R) Followed By Z/BEAM Vs BEAM/R Autologous Stem Cell Conditioning for Relapsed Diffuse Large B-Cell Lymphoma (DLBCL) Patients (pts): Mature Results from a Combined Analysis of 3 Trials

Incidence of Human Leucocyte Antigen Antibodies in Lymphoma Patients Treated with and without Rituximab

Introduction: Platelet support in patients who are pancytopenic after autologous stem-cell transplantation (auSCT) is difficult in the presence of human leukocyte antigen antibodies (HLA-AB) class I. Multiple transfusions and pregnancy are risk factors for development of HLA-AB. In renal transplantation rituximab (R-mab) is used to reduce HLA-AB levels in HLA-incompatible kidney transplantation. We evaluated whether the incidence of HLA-AB was lower in lymphoma patients who were treated with R-mab during salvage therapy prior to auSCT.Methods: Single-centre retrospective evaluation of patients treated with DHAP-VIM-DHAP salvage (with or without R-mab) and BEAM plus auSCT for B-cell non-Hodgkin lymphoma (B-NHL) or Hodgkin’s lymphoma (HL). After becoming available R-mab was given to patients with CD20-positive lymphoma; R-mab was not used before it’s availability and in CD20-negative lymphoma. HLA-AB were measured in case of insufficient platelet yield after transfusion.Results: Between January 1st 1999 and December 31st 2013, 164 patients with a B-NHL or HL underwent auSCT (Table). Age at auSCT was median 52.5 (17.8 – 70.2) years, 73 (45%) patients were female and 89 (54%) were treated with R-mab. Type of lymphoma was diffuse large B-NHL (DLBCL) in 82 (50%) patients, HL in 46 (28%) patients, follicular lymphoma (FL) in 30 (18%) patients and other in 6 (4%) patients. All transfused cellular blood products were leucoreduced.Of R-mab treated patients, 42 (47%) were female versus 31 (41%) non R-mab treated patients, p=0.529 (Table). R-mab treated patients were older at auSCT than non R-mab treated patients: median 57.4 (18.3 – 70.2) years versus 48.1 (17.8 – 64.6) years, p<0.001. Type of lymphoma in R-mab patients was DLBCL in 61 (69%), HL in 2 (2%), FL in 23 (26%) and other in 3 (3%) patients. In non R-mab treated patients type of lymphoma was DLBCL in 21 (28%, p=<0.001), HL in 44 (59%, p=<0.001), FL in 7 (9%, p=0.008) and other in 3 (4%, p=1.000) patients. In R-mab treated patients median 6 (1 – 53) random platelet concentrates (rPC) were transfused versus median 5 (1 – 54) in non R-mab treated patients, p=0.529. HLA-AB were found in none of 89 R-mab treated patients and in 3 of 75 non R-mab treated patients, p=0.094.All 3 patients who developed HLA-AB were female (100%) versus 44% (n=70) of patients without HLA-AB, p=0.086. All 3 women (100%) with HLA-AB have been pregnant versus 51 (73%) women without HLA-AB (p=0.704); in 8 women without HLA-AB their history of pregnancy was unknown. None (0%) of 3 patients with HLA-AB were treated with R-mab versus 89 of 161 (55%) patients without HLA-AB, p=0.094. Age at auSCT was median 44.2 (39.1 – 52.4) years in patients with HLA-AB and median 52.6 (17.8 – 70.2) years in patients without HLA-AB, p=0.246. Number of rPC transfused was median 7 (4 – 14) in patients with HLA-AB and median 6 (1 – 54) in patients without HLA-AB, p=0.666. There was no significant difference seen in type of lymphoma between patients with and without HLA-AB.Conclusion: The incidence of HLA-AB in our cohort of lymphoma patients treated with DHAP-VIM-DHAP salvage with or without rituximab followed by BEAM plus auSCT for B-NHL or HL is very low. A trend was seen towards treatment without R-mab and female gender, not towards a history of pregnancy. TableOverallRituximabNo Rituximabpn16489 (54)75 (46)Female (n)73 (45)42 (47)31 (41)0.529Age auto-Tx (years)52.5 (17.8 – 70.2)57.4 (18.3 – 70.2)48.1 (17.8 – 64.6)< 0.001HLA-antibodies (n)3 (2)03 (4)0.094Transfused rPC (n)6 (1 – 54)6 (1- 53)5 (1 – 54)0.529Type of lymphomaDLBCL (n)82 (50)61 (69)21 (28)< 0.001Hodgkin (n)46 (28)2 (2)44 (59)< 0.001FL (n)30 (18)23 (26)7 (9)0.008Other (n)6 (4)3 (3)3 (4)1.000Denoted as median (range), categorical variables as number (%). DisclosuresNo relevant conflicts of interest to declare.

Towards a rational graft-versus-host disease (GVHD) prophylaxis: rituximab should not be forgotten

Towards a rational graft-versus-host disease (GVHD) prophylaxis: rituximab should not be forgotten

Targeted IV busulfan and fludarabine followed by post-allogeneic hematopoietic cell transplantation rituximab demonstrate encouraging activity in CD20+ lymphoid malignancies without increased risk of infectious complications

We examined pharmacokinetic-targeted IV busulfan (75-170mg/m(2), with target AUC of 3500-6000μmolmin) and fludarabine (40mg/m(2))×4days with rituximab (t-IV Bu/Flu+rituximab) 375mg/m(2) on days +1 and +8 followed by allogeneic hematopoietic cell transplantation in 19 patients (median age 56, range 35-68years) with CD20+ lymphoid malignancies. Median time to neutrophil and platelet engraftment was 15 and 12days. The cumulative incidence of grade II-IV acute graft-versus-host disease (GVHD) was 58% (95% confidence interval, CI 39-85%), and chronic GVHD was 50% (95% CI 28-88%). With a median follow up of 7 (range 1-31)months, overall response was observed in 15, and stable or progressive disease in 4. Overall survival at 1year was 67%. Engraftment, chimerism, and infectious complications did not differ significantly from a contemporaneous non-rituximab containing comparator group. The addition of rituximab 375mg/m(2) to t-IV Bu/Flu does not appear to adversely affect engraftment, donor chimerism, or increase the risk of infectious complications.

Targeted Iv Busulfan And Fludarabine Followed By Post-Allogeneic Hematopoietic Cell Transplantation Rituximab Demonstrate Encouraging Activity In High Risk CD20 + Positive Lymphoid Malignancies Without Increased Infectious Complications

Rituximab has activity in lymphoid malignancies and may augment responses after allogeneic hematopoietic cell transplantation (HCT); however prolonged lymphopenia may increase the risk for infectious complications. We examined the safety of Rituximab after reduced toxicity conditioning HCT. Sixteen patients (median age 56, range 35 – 68), (CLL 7, follicular lymphoma 4, mantle cell lymphoma3, and large cell lymphoma 2 with CD20 positive lymphoid malignancies. Twelve had a partial response and 4 complete response to prior conditioning with pharmacokinetic-targeted IV busulfan(130-145mg/m2) and fludarabine (40mg/m2) x 4 days (t-IV Bu/Flu) followed by HCT.

A Randomized, Doubleblind, Placebo-Controlled, Study of Single-Dose Rituximab as Induction in Renal Transplantation

We performed a prospective, double blind, randomized, placebo-controlled multicenter study on the efficacy and safety of rituximab as induction therapy, together with tacrolimus, mycophenolate mofetil, and steroids. The primary endpoint was defined as acute rejection, graft loss, or death during the first 6 months. Secondary endpoints were creatinine clearance, incidence of infections, and incidence of rituximab-related adverse event. We enrolled 140 patients (44 living donor and 96 deceased donor), and of those, 68 rituximab and 68 placebo patients fulfilled the study. In all the patients receiving rituximab, there was a complete depletion of CD19/CD20 cells, whereas there was no change in the number of CD19/CD20 cells in the placebo group. There were 10 treatment failures in the rituximab group versus 14 in the placebo group (P=0.348). There were eight rejection episodes in the rituximab group versus 12 in the placebo group (P=0.317) Creatinine clearance was 66+/-22 mL/min in the study group and 67+/-23 mL/min in the placebo group. There was no difference in the number of bacterial infections, cytomegalovirus infections, and BK virus infections or fungal infections. We performed a placebo-controlled study of rituximab induction in renal transplantation. There was a tendency toward fewer and milder rejections during the first 6 months in the rituximab group. Although induction with one dose of rituximab induced a complete depletion B cells, there was no increase in the incidence of infectious complications or leukopenia and it seems safe, therefore, to conduct further studies on the use of rituximab in transplantation.

Rituximab purging and maintenance combined with auto-SCT: long-term molecular remissions and prolonged hypogammaglobulinemia in relapsed follicular lymphoma

We enrolled 23 patients with relapsed follicular lymphoma (FL) in a prospective single-arm study of auto-SCT combined with in vivo rituximab graft purging and post transplant rituximab maintenance. Minimal residual disease was monitored with quantitative PCR testing. With a median follow-up of 74.2 months, neither median overall survival (OS) nor PFS has been reached. Here, 5-year OS and 5-year PFS are 78% (95% confidence interval (CI) 61-95%) and 59% (95% CI 38-80%), respectively. Time to progression (TTP) with the experimental regimen was significantly improved compared with TTP with the last prior treatment (P<0.001). Durable molecular remissions occurred in 11 of 13 assessable patients. PFS was significantly longer in patients who achieved a molecular remission by 3 months post-auto-SCT (P=0.001). Prolonged hypogammaglobulinemia occurred in most patients; however, no increase in major infections was observed.

Rituximab for Graft-Versus-Host-Disease-Prophylaxis after Allogeneic Stem Cell Transplantation Given as Treatment of High Risk Relapse of Aggressive Lymphoma: Results of a Randomized Phase II Study.

Background: High dose therapy (HDT) followed by autologous stem cell support has poor outcome in patients with primary progressive lymphoma or relapse after primary HDT. Allogeneic SCT may help these patients by exerting an GVL effect. Its use however is hampered by high incidence of severe GVHD and non-relapse mortality in this population. Rituximab has been claimed to reduce the incidene of GVHD without negative impact on the relapse rate.Patients and Methods: We initiated a randomized phase II study using intermediate conditioning (Fludarabine 125 mg/m2, Busulfan 12 mg/kg and cyclophosphamide 120 mg/kg) followed by GVHD prophylaxis with short term mycophenolat mofetil plus tacrolimus. Anti-thymozyte globulin (ATG) was given due to center decision. Patients were randomized to receive two times four doses of rituximab (375 mg/m2) post transplant starting day +21 and day +175 or no additional GVHD prophylaxis. From June 2004 to July 2007 sixty five patients with aggressive NHL were enrolled and 59 were eligible for analysis. Thirty one pts had diffuse large B cell NHL, 3 patients follicular lymphoma grade 3, 7 pts blastic mantle cell lymphoma, 2 pts aggressive marginal zone lymphoma, 2 patients lymphoblastic B cell lymphoma, and 12 T cell lymphoma. 42 (71%) pts received at least one cycle of HDT and autologous SCT prior to alloSCT; 78% had early relapse ( < 12 months) or primary progressive disease, 59% chemo-refractory disease and 48% had progressive disease with high or high intermediate age adjusted IPI immediately prior to conditioning.Results: Allo-PBPC were obtained from HLA-identical siblings in 17 pts, from matched unrelated donors in 32 pts and from one locus mismatched unrelated donors in 10 pts. 33 patients did receive ATG. Median observation time of surviving patients is 1,8 years. 30 pts died, in 19 patients death was attributed to treatment related causes. After one year, estimated overall survival is 49%, progression free survival is 39%, relapse rate is 28 % and incidence of GVHD > grade 1 is 73%. The last documented lymphoma progress occurred at day 288 after alloSCT. There are no significant differences in OS, PFS and GvHD in relationship to the application of Rituximab.Conclusion: Intermediate intensity conditioning followed by allogeneic SCT is a valuable treatment option in patients with high-risk relapse of aggressive NHL. The incidence of GVHD and non-relapse mortality is high. On the background of this very high basic incidence of GVHD, we did not find a significant impact of post transplant rituximab on GVHD, relapse rates or survival, respectively. Therefore, ATG will be added as an obligatory part of the conditioning regimen in the next study phase in additional 30 patients

Vaccine Efficacy Following Autologous Peripheral Blood Stem Cell Transplant for Lymphoma.

Despite guidelines from the CDC and EBMT, most centers do not consistently re-immunize adults following an autologous transplant. Over the last decade outbreaks of measles, mumps, and pertussis in the general population highlight the need for effective vaccination in this vulnerable population. We have analyzed the pre and post vaccine titers of 106 adult survivors of an autologous PBSCT for the treatment of Hodgkin's lymphoma (HL, n=58) or Non-Hodgkin's Lymphoma (NHL, n=48) performed at this center. Eighty percent of patients evaluated received a transplant between 1/1/00 and 7/31/05. The median age at PBSCT was 37 years and at vaccination, 41 years. Patients transplanted for HL were significantly younger than those transplanted for NHL (median 31 years vs 49 yrs). Cytoreduction for the majority of patients with HL included BEAM or CBV with or without involved field RT (IFRT), or TLI/IFRT/CBV. Sixty-five percent of patients transplanted for NHL received BEAM and 33 of 48 received post HCT adjuvant Rituximab. Pre-vaccination titers evaluated at a median of 25.2 months after HCT demonstrated that 90% of patients lacked protective titers against pneumococcus. Titers against H flu, tetanus, and polio were negative in 58%, 23%, and 16% of the population, respectively. Sixty-percent of patients transplanted for HL were susceptible to measles, mumps, and rubella when tested >24 months post HCT compared to 30% of those transplanted for NHL (p=0.03).Vaccine ResponsesPPV23InfluenzaH fluMMRTetanusIPV# Vaccinated545332192214% Response13%4%81%32%41%93%As shown in the above table, the response to IPV and H flu were excellent. There was no difference in the response to these vaccines among patients who were transplanted for HL or NHL +/− adjuvant Rituximab. In contrast, response to the 23-valent pure polysaccharide pneumococcal (PPV23) vaccine and the inactivated influenza vaccine were poor. Only 7 of 54 patients who received PPV23 as their initial pneumococcal vaccine seroconverted and no individual (0/17) who received post transplant Rituximab responded to this vaccine. In contrast, 67% of patients who received a series of the protein conjugated pneumococcal vaccine, Prevnar® (PCV7) either as their first pneumococcal vaccine post HCT or after having failed PPV23, responded. Following a single MMR (n=19), Td (n=9) or Tdap (n=13), less than half of the patients developed immunity. This study demonstrates that the majority of adult survivors of an autologous transplant for HL or NHL lack protective immunity against one or more vaccine preventable diseases emphasizing the need for re-immunization of this population. Pre and post vaccine titers should be obtained to document seroconversion as many patients fail to develop protective antibodies after single immunizations. This data also suggests that autologous HCT recipients would benefit by replacement of the pneumococcal vaccine, PPV23 with PCV7, administration of two rather than one MMR vaccines, and that more data is needed to justify the use of Tdap as the initial tetanus vaccine after HCT.

Intermediate Intensity Conditioning Followed by Allogeneic Peripheral Blood Stem Cell Transplantion for Treatment of High Risk Relapse of Aggressive Lymphoma. Interim Analysis of the DSHNHL R3 Study.

High dose therapy (HDT) followed by autologous stem cell support has poor outcome in patients with primary progressive lymphoma or relapse after primary HDT due to high relapse rates and failure free survival below 20%. Allogeneic SCT may help these patients by exerting an GVL effect. Its use however, is followed by high incidence of severe GVHD and treatment related mortality (TRM) in this population. The anti-CD20 monoclonal antibody rituximab has been claimed to solve this problem. We initiated a randomized phase II study using intermediate conditioning (Fludarabine 125 mg/m2, Busulfan 12 mg/kg and cyclophosphamide 120 mg/kg) followed by GVHD prophylaxis with short term mycophenolat mofetil plus tacrolimus. Patients were randomized to receive two times four doses of rituximab (375 mg/m2) post transplant starting day +28 and day +175 or no further GVHD prophylaxis. Here we report the results of a first interim analysis. From January 2005 to August 2007 sixty patients (pts) with aggressive NHL were enrolled. Thirty one pts had diffuse large B cell NHL, 9 patients follicular lymphoma grade 3, 8 pts blastic mantle cell lymphoma, one patient aggressive marginal zone lymphoma and 11 patients peripheral T cell lymphoma. The median number of prior treatment regimens was 3 (range 1 to 6). 43 (72%) pts received at least one cycle of high-dose therapy and autologous SCT prior to alloSCT; 79% had early relapse (< 12 months) or primary progressive disease, 58% chemo-refractory disease and 52% had progressive disease with high or high intermediate age adjusted IPI immediately prior to conditioning. Allo-PBPC were obtained from HLA-identical siblings in 16 pts, from fully matched unrelated donors in 32 pts and from 1 locus mismatched unrelated donors in 12 pts. Engraftment of leukocytes was rapid (median 10 days, range 8–27) and all patients achieved complete (> 95%) donor type chimerism after alloSCT. Median observation time is 8 months (range 1–35 months). 32 pts died, in 20 patients death was attributed to treatment related causes. After one year, estimated overall survival is 47%, failure free survival is 43%, TRM is 37%, relapse rate is 33% and incidence of GVHD > grade 1 is 57%. With an observation time precluding final analysis, there are no significant differences between patients randomized to receive rituximab post transplant and those who were not. There was a trend to lower relapse rates in patients with GVHD > grade 1 (25% vs 44%, p=0.14). Intermediate intensity conditioning followed by allogeneic SCT is a valuable treatment option in patients with high-risk relapse of aggressive NHL. The basic incidence of GVHD and TRM is high. Due to the short observation time, a definitive conclusion regarding the impact of post transplant Rituximab cannot be drawn. The study will be continued.

Response to Immunizations Following Allogeneic HCT with Adjuvant Rituximab Therapy.

Use of anti-CD20 monoclonal antibody after allogeneic HCT for the treatment EBV lymphoma or viremia, autoimmune cytopenias, and the prevention or treatment of recurrent NHL has become more frequent. There is limited data on the effect of this therapy on specific antibody production following allogeneic HCT. We therefore examined the response to standard childhood immunizations of 30 patients, including 20 adults (>18 years of age) who received rituximab following a T cell depleted (n=26) or unmodified (n=4) HCT at our institution. T cell function was assessed in vitro by proliferative response to PHA and B cell reconstitution was confirmed by recovery of CD19+ and CD20+ circulating lymphocytes. Patients received a median (range) of 4 (1–12) doses of rituximab, with 15 patients receiving 4–6 doses. The median age of the patient population was 28.5 years with a range of 0.8–63.0 years. Children (median age: 8.5 yrs) received a transplant from an unrelated (n=7), HLA mismatched related (n=2), or HLA matched related (n=1) donor and adults (median age: 42.5 yrs), received a transplant from an unrelated (n=7), HLA mismatched related (n=2), or HLA-matched related (n=11) donor. Patients were vaccinated when their PHA response was at least 75% of the lower limit of normal and CD20+ cells were >100/ul. Vaccination was initiated at a median of 270 and 525 days following the last dose of rituximab in children and adults, respectively. A two to 3-fold rise in titers following a series of 3 tetanus and IPV vaccinations occurred in 19 of 21 and 19 of 19 evaluable patients, respectively. Although 8 of 9 children responded to the H flu conjugate vaccine, only 5 of 13 adults mounted an adequate response. Eighteen patients received the recombinant Hepatitis B vaccine. Nine responded following the initial series (5/7 children, 4/11 adults). Two of three patients who failed initial Hepatitis B vaccination, responded to a second series (1 child, 1 adult). Response to pneumococcal vaccination was the least consistent. None of 11 adults who received the unconjugated 23-valent pneumococcal vaccine developed an adequate response. In view of this observation, children given rituximab were immunized with the conjugated pneumococcal vaccine. Four of eight children responded to the initial series, and two additional children responded following a second series. These preliminary data suggest that both adult and pediatric patients given rituximab following an allogeneic HCT can mount successful antibody responses to standard T-helper cell dependent vaccines. However, B cell responses to T cell independent vaccines may be particularly impaired. Larger prospective trials, stratified by age, comparing vaccine responses in patients following allogeneic transplant in the presence or absence of post transplant rituximab therapy are warranted.