ALBERT

Description: Allogeneic bone marrow transplantation (BMT) from an HLA-identical sibling is a curative form of therapy for patients with acquired severe aplastic anemia. Survival has significantly improved over the past 3 decades. The actuarial risk of rejection has been reduced to about 7%. Improved results with survival in excess of 90% have been reported. Current preparative therapies are associated with early and late sequelae such as acute and chronic graft-versus-host disease (aGvHD or chGvHD, respectively) and secondary tumors. Two patients (6 years and 11 years old) with SAA, who had an HLA-identical sibling donor could not proceed with myeloablative therapy at the time of transplant due to delay in results of chromosome stability and fragility in one patient and abnormal pulmonary function in the second. Both received reduced intensity preparative regimen with Fludarabine (30 mg/m2×4 doses) Cyclophosphamide (5 mg/kg×4 doses) and rabbit ATG (1.5 mg/kg×4 doses) followed by an unmanipulated allogeneic BMT from their HLA-identical sibling donors. Graft versus host disease prophylaxis consisted of Cyclosporine from day -1 and Methotrexate 15 mg/m2 on day +1 and 10 mg/m2 on days +3, +6, +11 after transplant. Myeloid engraftment occurred on day +15 and day +28. The time to a platelet count 〉20,000 unsupported was +11 days and +29 days. No transplant-related toxicities, including mucositis or alopecia, were recorded. There were no signs for aGvHD or chGvHD. The patients continue with full donor chimerism 27 months and 130 days post transplant, respectively. This data suggests that a non-myeloablative, immunosuppressive regimen is sufficient to provide a stable engraftment in the patients with SAA. This approach may be associated with decreased transplant-related short- and long-term toxicities. A larger study is needed to fully evaluate the outcome and the toxicity associated with this conditioning.

Description: Allogeneic bone marrow transplantation is a curative form of therapy for patients (pts) with acquired severe aplastic anemia. Current preparative therapies are associated with early and late sequelae such as organ injury, and secondary tumors. Recent studies showed that BMT following reduced-intensity or NMCR may result in long-term survival for a fraction of pts with hematologic malignancies (Giralt, Biol. Blood Marrow Transplant, 13:884, 2007). However, with the exception of BMT for pts With Fanconi’s anemia, little is known about using NMCR for patients with non-malignant disorders. We report the use of NMCR in patients with SAA. Patients and Methods: Four female pts ages 6–12 years, diagnosed with SAA, had allogeneic BMT from an HLA-identical sibling (SIB) (Pts #1 and #2) or a matched unrelated donor (MUD) (pts #3 and #4). The reasons to offer NMCR were: delay in results of chromosome fragility studies (Pt #1), abnormal pulmonary function (Pt #2), history of recent life threatening infection (Pt #3), and failure to respond to immunosuppressive therapy (Pt #4). The NMCR consisted of fludarabine (FLU) (30 mg/m2 x 4), low dose cyclophosphamide (LDC) (5 mg/kg x 4) and rabbit antithymocyte globulin (rATG) (1.5 mg/kg x 4) in patients with SIB donor and FLU, LDC, at a higher dose of 15 mg/kg x 4), rATG and a single fraction of total body irradiation at 200 cGy in patients with a MUD donor. Supportive care, prophylactic anti-microbial therapy, and treatment for prevention of aGvHD were given according to the institution standard guidelines. Results: The NMCR was well tolerated in all 4 patients. Pts #1 and #2 who had a SIB BMT had no transplant-related toxicities, including mucositis or alopecia. Toxicities in the MUD BMT patients included mild mucositis and partial alpecia in both pts. Pt#3 had reactivation od Enterobacter cloacae sepsis with typhlitis and later CMV viremia. Myeloid and platelet engraftment were uneventful in pts #1, #2, and #4. The recovery of peripheral blood counts was slow in Pt #3 following typhlitis and CMV viremia. Myeloid engraftment occurred on day +19 (range 15–33 days). The median time to a platelet count 〉20,000 unsupported by transfusion was day +33, (range 12–76 days). Periodic engraftmen anlyses using short tandem repeat (STR) by PCRT continue to show full donor chimerism in all 4 pts. There were no signs for acute or chronic graft-vs-host disease (aGvHD or chGvHD, respectively) in pts with SIB BMT. Both patients continue to do well with a fully recovered hematopoietic system 17 months and 42 months post transplant. There were no aGVHD.or chGVHD in Pt#3. Pt #4 had aGVHD of the skin, clinical grade II, which responded well to immunosuppressive therapy. Both MUD BMT pts are well 5 and 3 months post-transplant, respectively, with partial hematopoietic recovery in Pt #3 and normal counts in Pt #4. Conclusion: This data suggests that a non-myeloablative, immunosuppressive regimen is sufficient to provide a stable engraftment in the patients with SAA. This approach may be associated with decreased transplant-related, short- and long-term, toxicities. A larger study is needed to fully evaluate the outcome and the toxicity associated with this conditioning.

Description: The reported incidence of t-MDS/t-AML following traditional ASCT for lymphoma ranges between 0–12%. Previously identified risk factors include older age, prior alkylator therapy and use of radiation either prior to ASCT or as part of the preparative regimen. It is unclear whether novel conditioning regimens for ASCT that utilize targeted RIT with the potential to deliver higher radiation doses to the marrow are associated with a higher risk of t-MDS/t-AML. We identified a case-series of 83 pts who underwent RIT based ASCT between 06/00 and 01/06 to evaluate the incidence of t-MDS/t-AML; Forty-one pts received standard dose 90Y ibritumomab tiuxetan (0.4mci/kg: median dose 32.9 mci (range 20–40)) in combination with high dose BEAM (BCNU 450mg/m2, etoposide 800mg/m2, cytarabine 800mg/m2, melphalan 140mg/m2) and 42 pts received high dose 90Y based on dosimetry (median 70.8 mci range 36–105) in combination with etoposide 60mg/kg plus cyclophosphamide 100mg/kg. Pts were followed prospectively post ASCT with serial bone marrow biopsies approximately annually. The median age at ASCT was 54 years (range 19–78). Disease histology included diffuse large cell n=40, follicular NHL n=17, mantle cell n=21, transformed n=4, SLL n=1. Disease status at ASCT was 1st CR n=17, 1stPR n=14, induction failure n=14, 1st relapse or greater n=38. With a median follow-up of 39 months (range, 1.4–83), three patients (3.61%) have developed t-MDS/t-AML. The three pts also had associated complex chromosomal abnormalities including de1(13q), del(5q), del (20q). The median time to t-MDS/t-AML was 2.63 years (range, 1.51 – 8.41) post NHL diagnosis and 1.99 years (range, 0.56 – 5.10) post ASCT. The cumulative incidences of t-MDS/t-AML at 1 and 2 years were 1.20% (95%CI, 0.17– 8.1%) and 2.60% (95%CI 0.64–9.9%). None of the potential risk factors including age(〉50 at ASCT) (p=0.33), prior radiotherapy (p=0.99), number of prior regimens (p=0.5) and 90Y dose (p=0.99) were statistically significant by univariate analysis. As 82/83 pts had received prior alkylator therapy this was not analyzed as a separate risk factor. Two year overall survival for the entire cohort is 90% (95%CI 83–95). Although the follow up is relatively short, the incidence of t-MDS/t-AML is consistent with our previous institutional experience in ASCT patients who received non-RIT based conditioning (Krishnan et al. Blood 2000) and with the 2.5% incidence of t-MDS/t-AML observed in pts receiving 90Y in registration and compassionate use trials (Czuczman et al JCO 2007 in press). In conclusion RIT based conditioning does not appear to confer an increased risk of t-MDS/t-AML above what has been previously reported with traditional ASCT preparative regimens. Incidence of t-MDS/t-AML Incidence of t-MDS/t-AML

Description: Current CGVHD prognostic and staging systems are still undergoing development and have identified plt count; CGVHD types progressive(P), quiescent(Q), de novo(DN); KPS, and GI involvement as significant risk factors affecting outcome. A simple reproducible staging system such as used for AGVHD to apply in clinical trials is still lacking. We evaluated whether the PSE dose required to control CGVHD at 3 months from diagnosis would have a prognostic effect on survival and in and of itself serve as a criteria for secondary intervention or investigational therapy. We hypothesized that by 3 months from start of treatment patients would be on the lowest dose dictated by medical necessity rather than by physician driven dose preference. A retrospective analysis of charts from 109 patients diagnosed with CGVHD between 6/2000 and 6/2003 was done. Data collected included age, donor type(mud/sib), plt count, CGVHD type(P/Q/DN), KPS, GI involvement. Outcome analysis included survival and cause of death. PSE dose was calculated in mg/kg at 3 months from first diagnosis of CGVHD. With a median follow up of 47.2 months(range 6.6–67.2) relapse censored survival of patients on a 3 month PSE dose of more than .3 mg/kg was 53% compared to all lower doses 86%(P.03). In a univariate analysis only PSE dose (P .05) and KPS (P

Description: Background: ASCT is an effective treatment for patients with high risk NHL. However, relapse rates remain high. Attempts at further dose intensification are limited by regimen-related toxicity especially in older patients. Zevalin as a single agent has showed activity in aggressive Non-Hodgkin’s Lymphoma (NHL). We therefore, devised a novel conditioning regimen (Z-BEAM) combining standard dose Zevalin (0.4mci/kg) with high dose BEAM (BCNU 150mg/m2 day-7,-6, cytarabine 800mg/m2 and etoposide 800mg/m2 day-5 to day-2, and melphalan 140mg/m2 day-1). Herein, we provide an update on the study and also retrospectively compare this new conditioning regimen with conventional high dose BEAM in older patients (age 〉=50). Between 1995 and 2005, 65 patients (BEAM n=32, Z-BEAM n=33) underwent ASCT utilizing these regimens. Patient selection was similar for Z-BEAM and BEAM. Patients received BEAM prior to the opening of the Z-BEAM protocol and similiarly after the Z-BEAM protocol completed accrual. The groups were well matched for most demographics and disease status. Median age: Z-BEAM - 62 yrs (range 50–78), BEAM - 64 yrs (range 50–77); 1st CR/PR pts comprised 45% in the Z-BEAM arm and 34% in the BEAM, 〉 =1st Relapse 42% vs 50% and induction failure 12% vs 15%. (p=0.7). Median number of prior regimens was 3 in the Z-BEAM group vs 2 in the BEAM arm.(p=0.08) 54 % had bulky disease at diagnosis in the Z-BEAM group vs 41% in the BEAM group (p=0.30). Results: Two-year OS was 78% for all pts (95%CI, 67–86). Two-year OS/PFS in the Z-BEAM group was 88%(95% CI, 70–95)/72 %(95% CI, 57–83) respectively vs 65% (95%CI, 48–77)/ 67%( 95CI, 50–79) in the BEAM group (Figure1). Analysis by histology showed that in patients with diffuse large B-cell lymphoma (DLBCL), there was a significant difference in OS/PFS of Z-BEAM vs BEAM, 95% vs 48% at 2 yrs (p=.009)/ 88% vs 48% ( p=0.015). The OS/PFS difference of Z-BEAM vs BEAM in patients with mantle cell lymphoma did not reach significance. The toxicity profile and transplant related mortality was similar in both regimens. Conclusions: Our study suggests that the addition of Zevalin to the BEAM conditioning regimen is feasible and well tolerated in older patients. The favorable outcome of patients treated with Z-BEAM compared with BEAM alone, especially in patients with DLBCL, suggests that prospective study in a randomized trial is warranted. Overall Survival 
 ZBEAM versus BEAM Overall Survival 
 ZBEAM versus BEAM

Description: Background: High dose chemotherapy with autologous hematopoietic stem cell rescue has become one of the standard treatment options for many hematopoietic malignancies. Mobilization by granulocyte colony-stimulating factor (GCSF) with or without chemo priming and followed by peripheral blood stem cell (PBSC) collection is the preferred method to obtain progenitor cells. Successful mobilization and collection of stem cells is dependent upon a number of clinical factors including previous chemotherapy history and disease stage. One question concerns whether efficacy of mobilization and collection, as measured by the number of days or number of collections to reach a defined CD34 cell target dose, is an independent prognostic factor for autologous stem cell transplantation outcome. Method: A total of 358 patients transplanted from January 2003 to December 2004 (201 males and 157 females, ages from 2.7 to 77.3 years old with median of 53 years of age) underwent autologous PBSC collection after mobilization with GCSF at 10 mcg/kg to 16mcg/kg with or without chemo priming. PBSC collections are typically initiated on day 5 post GCSF injection, or day 10 after chemo priming and GCSF injection without information about their absolute peripheral CD34 cell count. This retrospective study included patients with the following diagnoses: 45 (13%) acute Myelogenous leukemia (AML), 124 (35%) non-Hodgkin’s lymphoma (NHL) 33 (9%) Hodgkin’s disease (HD), 123 (34%) multiple myeloma (MM), and 33 (9%) solid tumors. All patients underwent 4 hours of daily PBSC collection with an average processed volume of 12 to 15 liters at average flow rate of 40ml to 60ml/minute (by Cobe Spectra, Gambro BCT, Denver, CO) until a minimum CD34 count of 2×106/kg of body weight with a target of CD34 cell count of 5×106/kg is reached. The mean number of collections to reach this minimum CD34 cell dose was 2.7 (median 1, range 1 to 14). Collected cells were cryopreserved and stored at −140°C in the vapor phase of a liquid nitrogen freezer prior to their transplantation. Patients received a median CD34 cell dose of 6.4×106/kg with range 2.0 to 67.6×106/kg for their transplants. Correlations were performed between PBSC mobilization/collection efficacy and transplantation outcomes. Results: Both greater CD34 cell dose used in the transplant (r= −0.24, p

Description: The treatment of HIV-associated lymphoma has changed since the widespread use of highly active antiretroviral therapy. HIV-infected individuals can tolerate more intensive chemotherapy, as they have better hematologic reserves and fewer infections. This has led to higher response rates in patients with HIV-associated Hodgkin disease (HD) or non-Hodgkin lymphoma (NHL) treated with chemotherapy in conjunction with antiretroviral therapy. However, for patients with refractory or relapsed disease, salvage chemotherapy still offers little chance of long-term survival. In the non-HIV setting, patients with relapsed Hodgkin disease (HD) or non-Hodgkin lymphoma (NHL) have a better chance of long-term remission with high-dose chemotherapy with autologous stem cell rescue (ASCT) compared with conventional salvage chemotherapy. In a prior report we demonstrated that this approach is well tolerated in patients with underlying immunodeficiency from HIV infection. Furthermore, similar engraftment to the non-HIV setting and low infectious risks have been observed. Herein, we expand upon this early experience with the largest single institution series of 20 patients. With long-term follow-up we demonstrate that ASCT can lead to an 85% progression-free survival, which suggests that this approach may be potentially curative in select patients with relapsed HIV-associated HD or NHL.