ALBERT

Description: Rituximab, a chimeric CD20 antibody, has been incorporated in various chemotherapy regimen for B-cell lymphoma. It has also been used as maintenance therapy in some of these patients. However, the effects of its long-term use on the immune system has not been previously documented. Here, we present our preliminary analysis of the effect of maintenance rituximab therapy on the B-cell immune repertoire in nine consecutive patients with B-cell lymphoma who were treated with maintenance rituximab after autologous stem cell transplant (ASCT) for high-risk disease. Nine patients (seven men and two women) with high-risk B-cell lymphoma were treated. Their diagnosis were: advanced mantle cell lymphoma in first CR (6), Stage IV DLCL in CR1 (1) and high grade NHL in CR2 (2). Median age was 66 years (range 38–72 years). CR was achieved using R-CHOP (8) or R-DHAP (1). Autologous stem cells were harvested during hematopoietic recovery from the last course of chemo-immunotherapy and G-CSF. Within two weeks after stem cell harvest, each patient received intravenous melphalan (200 mg/m2) following by the infusion of at least 2 x 106/kg CD34+ cells. All patients received a rituximab infusion (375 mg/m2) every three months starting D+100 after ASCT for a total of 2 years or until disease relapse. Unlike patients who underwent ASCT without rituximab, in whom B-cell recovery occured between 3–6 months, we observed severe delays in the immunoglobulin recoveries in these patients. At 9 months after transplant, all patients were IgM and IgG deficient, with only 1/9 patient acheived a normal IgA level. Even at 24 months after transplant, all patients were still IgM deficient and only 20% achieved normal IgA and IgG levels. The severity of immuno-deficiencies was next examined. We observed severe immunoglobulin deficiency (defined by 〈 50% normal levels) in IgM in all patients and in IgG and IgA in more than 20% patients at 24 months, suggesting that the immunoglobulin recovery was both delayed and severely affected. The severe immunoglobulin deficiencies may be clinically relevant. One patient developed two episodes (follow-up of 12+ months), one seven episodes (follow-up 28+ months) and another two episodes of chest infection and a vancomycin-sensitive chronic diarrhea (follow-up 18+ months). All three patient had severe and prolonged immunoglobulin deficiencies. With a median follow-up of 27 months (range 12–31 months), all patients have remained lymphoma-free. These preliminary results, therefore, suggest that rituximab administration every three months after autologous transplant for high-risk B-cell NHL delays immunoglobulin recovery and may be associated with increased risks of infection. Although this approach may reduce lymphoma relapse, careful monitoring of the immunoglobulin recovery and interventional as appropriate should be done routinely in these patients.

Description: Conflicting results has been found on how the size of a transplant program affected the clinical outcome of hematopoietic stem cell transplant (HSCT). Some insurance carriers demand their clients to only receive HSCT in large centers, even if the service is available locally and the patients have to travel a long distance away from their home to receive the service at the approved program. Amarillo, Texas is 350 miles from Dallas and 600 miles from Houston. The HSCT program was established in Dec 2001. 18–25 transplants (autologous, allogeneic and umbilical cord blood (UCB) transplants) are performed a year. To determine whether a justification could be made to offer HSCT in a program that is small, new and community-based, we have analyzed the outcome of the adult mismatched umbilical cord blood transplants (UBCT) carried out on an unselected group of patients needing HSCT but without a matched sibling donor in our center in the last five years. Thirteen patients (8 males and 5 females) have undergone unrelated mismatched UBCT. The median age was high at 54 years (range 17 to 78). Four patients received reduced intensity conditioning regimen with Flu/Mel and 9 patients received the myelo-ablative regimen with Bu/Cy. Four patients received two units and nine single unit of umbilical cord blood. The diagnosis were: CML in CP1 (1), CML in blast crisis (2), HD relapsed within three months after autologous transplant (1), SAA (2), refractory CLL (1), ALL with multiple relapses (1), AML in CR3 (1), untreated secondary AML (2), primary refractory AML (1) and secondary AML in CR1 (1). Five patients received UCB units that were 1 antigen mismatch, 4 patients 2 antigen mismatches and 4 patients 3 antigen mismatches. GVHD prophylaxis in all cases consisted of cyclosporine A and methylprednisone. This is a group of mainly very high risk older patients. Not unexpectedly, early mortality rate was high. Death within 28 days of transplant occurred in 2 patients due to toxicity. Death within 100 days of transplant occurred in 8/13 (61.5%) patients. All the deaths occurred due to either infection or toxicity, except in one patient (age 67 years) who died due to a thrombotic stroke. Death due to disease relapse occurred in another patient 5 months after transplant for CML in blast crisis. Engraftment was documented in 9 patients. Despite the high antigen mismatches and the age of the patients, Grade I – II GVHD occurred in 7 patients and Grade III – IV in only 2 patients. With a maximum follow-up of 49 months, 4/13 (30%) patients are alive disease-free: 49+ months (age 45 years, one DRB1 mismatch), 22+ months (25 years, two antigen mismatches), 15+ months (48 years, three antigen mismatches) and 4+ months (54 years, three antigen mismatches). These results, in a group of very high risk unselected older patients in a community setting, are extremely encouraging and are comparable to those reported on younger groups of patients. Conclusions: Adult mismatched UBCT is feasible in a small program in a community setting; Patients 〉45 years may benefit from UBCT, even in the setting of multiple antigen mismatches; Patient selection should reduce early death and improve survival; Insurance companies should not deny patients to have transplant in their local program based on the size of the program.

Description: Clonotypic B cells are frequently isolated from the peripheral blood of patients with multiple myeloma (MM). These clonotypic B cells may be clonogenic cells of MM. We hypothesized that rituximab may be a useful maintenance therapy in MM after autologous stem cell transplant (ASCT). The rationale was that CD20 antibody would deplete the clonotypic and, hence, clonogenic B cells to reduce the risk of disease relapse. ASC were mobilized with Cytoxan (3g/m2) and G-CSF from patients with MM. Two weeks after ASC collection, high dose IV melphalan (200 mg/m2) was administered followed 24 hours later by the infusion of at least 2x106/kg CD34+ cryopreserved ASC. Rituximab infusion (375 mg/m2) was started on day +30. Each patient received one antibody infusion every 3 months for 2 years or until disease progressed. All patients continued on monthly zoledronate and did not receive any other antimyeloma treatment. A total of 10 patients have been treated. Seven patients who have had post-transplant follow-up periods of 〉12 months were evaluated. The immunoglobulin recovery and incidence of infections in this group of patients were compared to 6 patients with MM who have undergone an ASCT without rituximab maintenance. The total normal IgM level in all 7 patients was severely depressed following rituximab administration. IgG and IgA were variably affected in these patients. The IgM immunosuppression was prolonged and consistent, being seen in all patients, regardless of the disease status after transplantation. In contrast, the control group showed normalization of the total IgM levels by 3 months after transplant. Two patients treated with rituximab received pneumococcal vaccines 12 months after transplant and neither developed any IgG response to the vaccines. The data indicate that rituximab infusion following ASCT for MM severely impaired B-cell immune reconstitution. Six of the 7 patients developed moderate to severe infections during the first 12 months after initiation of rituximab infusion. There were a total of 23 episodes of infections: 21 pneumonia and 2 septicemia (one pneumococcus and one Pseudomonas). A patient died in CR due to pneumonia. In contrast, only one episode of pneumonia was observed in the control group during the same follow-up period. Therefore, the IgM deficiency probably predisposed the patients to infection. Of the 7 patients who have had more than 12 months of follow-up periods, 4 had disease refractory to standard induction chemotherapy. Of all the 10 patients treated, 6 achieved CR (2 were in CR before treatment, 2 achieved CR 3 months and 2 achieved CR 6 months after starting rituximab). All 4 patients with refractory MM (all had a follow-up of more than 12 months) achieved CR, one before and 3 after starting rituximab. One of the refractory patients has since relapsed, one died of pneumonia in CR 12 months and the other 2 have remained in CR 12+ and 18+ months after ASCT. With a follow-up of 29 months after transplant, the progression-free survival was 56.5% and the overall survival 71.4%. Rituximab infusion after ASCT for MM is therefore associated with severe IgM deficiency and an increased risk of infection. Further works are needed to determine the antitumor activities of rituximab in MM in the setting of minimal residual disease, but this should only be carried out with special attention to the prevention of infection.

Description: A diagnosis of a cancer sometimes changes the priorities and perspective of an individual. Previous literature suggests that cancer patients were more likely to indicate support for cancer treatment than non-cancer patients, even when the treatment may not be curative and when the odds for cure are low. We have carried out a questionnaire study to evaluate the attitude towards cancer treatment of a convenience sample of individuals attending a community cancer center situated along the “Bible belt” of the USA. A total of 460 individuals were recruited (100 newly diagnosed cancer patients; 100 cancer patients in complete remission; 60 cancer patients with relapsed/refractory disease; 100 non-cancer patients and 100 care-givers of cancer patients). The overall questionnaire return rate was 88% (range 84–91%). We used Chi square tests in two-way tables to test for significance. When asked whether or not the subject will agree to treatment that might be associated with uncomfortable side-effects for a cancer with less than 10% cure rate, 63.1% of cancer patients responded positively when compared to 48.9% of non-cancer patients (p = 0.02). This difference is most notable when relapsed/refractory patients were compared to non-cancer patients (70.6% vs 4.9%) (odd ratio = 0.345) (p = 0.007). These results, therefore, indicate that the positive attitude of most cancer patients to high risk cancer treatment is observed even in a region heavily influenced by religion. Moreover, the preference for treatment is stronger when the patient is faced with a real issue, rather than a hypothetical choice. Therefore, patients should be given an opportunity to revise living wills and other documents after they have been diagnosed with cancer. The study next examined the attitude towards intervention for potentially fatal treatment-related complications. Cancer patients were marginally more likely to agree (69.8%) to intervention of the life-threatening complications than non-cancer patients (60.0%) (p = 0.09) even if their life expectancy from the cancer is only 6 months. However, these differences were no longer apparent if the complication has arisen from a cancer that has a cure rate of 30%. Younger patients were also more likely to agree to intervention of life-threatening complications than older patients whether the intervention was for a cancer with a life-expectancy of only 6 months (p=.002) or 30% cure rates (p=.0002). Our study therefore suggests that most cancer patients, even those in the ‘Bible belt” and especially those with relapsed/refractory disease, expect oncologists to treat their disease and treatment-related complications whether or not the intervention only produces low cure rates or prolongs their life marginally. However, older patients are more likely to decline treatment. We next compared the responses from cancer patient care-givers to cancer patients. There was no significant difference in the attitude towards treatment between cancer care-givers and cancer patients regardless of how the question was posed, suggesting that daily contact with cancer patients may have positively influenced the attitude of individuals to high risk cancer treatment. This result also suggests that, when the patients are seriously ill and unable to make decisions on treatment, the decision by the care-givers probably reflects that of the patients.

Description: Conventional chemotherapy is non-curative for mantle cell lymphoma (MCL). Although the addition of Rituxan has improved the outcome of these patients, many patients still relapsed and died of their disease. High dose chemotherapy followed by autologous stem cell transplant (ASCT) has been investigated but produced conflicting results, ranging from no demonstrable benefit to a 2-year event-free survival (EFS) of 77%. A recent randomized study compared ASCT with interferon-a maintenance and showed benefits in both the EFS and overall survival for patients in the ASCT study arm. The conflicting results are probably related to the use of different chemotherapeutic agents as conditioning regimens for the transplant and also to different post-transplant therapy. In this study, we have chosen to induce patients with advanced MCL with R-CHOP and consolidate these patients with high dose single agent melphalan, a cytotoxic that has not been previously tested as a single agent in MCL. Since most patients relapsed within the first two years after transplant, low dose maintenance Rituxan therapy is given three-monthly during the first 2 years after ASCT. Following consent from the patients, 8 consecutive patients with advanced Stage III or IV MCL were treated. There were 5 male and 3 female, with a median age of 642 years (range 46–72 years). One patient had Stage III and the other 7 Stage IV diseases. All eight patients received remission + 2 courses of R-CHOP as induction chemotherapy. Autologous stem cells were harvested upon recovery from the last course of R-CHOP and ASCT carried out within 6 weeks from the last course of R-CHOP. High dose intravenous melphalan (200 mg/m2) was administered followed, 24 hours afterward, by the infusion of a minimum of 2 × 106/kg of CD34+ autologous stem cells. Rituxan maintenance therapy was initiated at a dose of 375 mg/m2 given as a single infusion once every three months starting Day +100. As of August 2006, with a median follow-up of 45.5 months from diagnosis (range 10–57 months) and 39 months from ASCT (range 4–52 months), seven patients are alive lymphoma-free, as defined by clinical and PET-CT examination. One patient died in CR of a myocardial infarction. Adverse effects were as expected from the high dose melphalan, except that delayed immunoglobulin reconstitution, as reported previously, was observed in all eight patients. Four of these hypogammaglobulinemic patients had recurrent infections (three with recurrent respiratory tract infection and one with a chronic diarrhea that was Vancomycin sensitive) and two required monthly intravenous immunoglobulin replacement. The result presented here is, therefore, extremely encouraging for a group of patients who normally have a very poor clinical outcome and warrants confirmation in larger multicenter study.

Description: Although autologous stem cell transplant (ASCT) may benefit patients with relapsed or high risk non-Hodgkin’s lymphoma (NHL), many patients still relapse and die of their disease. Most relapses occur during the first three years after transplant. In an attempt to reduce disease relapses, we have applied a maintenance regimen to patients after ASCT for B-cell NHL. In this regimen, all patients received low dose rituximab infusion (375 mg/m2 for one day only) every three months starting D+100 for a total of 2 years or until disease relapse. We reasoned that rituxan infusion given for only one day every three months may be sufficient to prevent disease relapse during this post-transplant period when any residual tumor bulk is likely low. Fifteen patients (eight men, seven women) with high-risk B-cell lymphoma have been treated. Their diagnoses: advanced mantle cell lymphoma in first complete remission (CR1) (8), refractory advanced marginal zone lymphoma (2), refractory follicular large cell lymphoma (1), high risk T-cell rich B-cell NHL in CR1 (1), Stage IV diffuse large cell lymphoma in CR1 (1) and relapsed B-cell NHL in CR2 (2). The median age was 59 years (range 38–72 years). CR was achieved using R-CHOP (10) or R-DHAP/R-ICE (5) and autologous hematopoietic stem cells were harvested during hematopoietic recovery from the last course of chemo-immunotherapy. With a median follow-up of 46 months (range 12–66) for the group and 47 months (range 16–66) for patients with advanced mantle cell lymphoma, the projected 5.5 years relapse-free survival for the group is 100% and the overall survival 80%. Two patients with mantle cell lymphoma died, one due to metastatic breast cancer and another a stroke at 40 and 41 months respectively. Unlike patients who underwent ASCT without rituximab, in whom B-cell recovery occurred between 3–6 months, we observed severe delays in the immunoglobulin recoveries in these patients (Figure 1). With a median immunoglobulin follow-up of 28 months (range 6–64), none of the fifteen patients showed normalization of total IgG. Two patients achieved a normalized total IgA and two a normalized total IgM. This hypogammaglobulinemia persists beyond the rituxan maintenance period. The median time to attainment of 75% normal level of immunoglobulin is 36 months for IgG, 48 months for IgA and not reached for IgM. The severe immunoglobulin deficiencies may be clinically relevant. Six of fifteen patients developed recurrent upper respiratory tract infection. No fatal infection was observed among any of the patients. Our results, therefore, suggest that low dose rituximab administration every three months after ASCT for high-risk B-cell lymphoma may prevent lymphoma relapse. However, this is associated with severe and prolonged delays in immunoglobulin recovery beyond the rituxan maintenance period. Careful monitoring of the immunoglobulin recovery and intervention as appropriate should be done routinely in these patients. Figure Figure