ALBERT

Description: Primary mediastinal B-cell lymphoma (PMBCL) is a relatively rare clinico-pathologic subtype of diffuse large B-cell lymohoma. The optimal management, the prognostic factors and the role of PET/CT scan in this entity remain a matter of debate. While several retrospective studies suggested that dose-dense regimens are more effective than standard CHOP, the impact of adding rituximab (R) on the outcome of patients (pts) with PMBCL has not been fully evaluated. In this retrospective analysis we reviewed the clinical and radiological records of 81 consecutive pts with PMBCL treated in Sheba Medical Center between August 1985 and October 2006. Chemotherapy in the pre-rituximab era (−R cohort) included VACOPB (n=47) or 6 courses of standard CHOP (n=5). Since October 2002, 6 cycles of R were added concurrent with the treatment in another 29 pts (+R cohort): R-VACOPB (n=21) and R-CHOP (n=8). Radiotherapy was not administered following initial chemotherapy to any of the pts. Median age at diagnosis was 31 years (yrs) (range 17–61). Stage I/II and bulky mediastinum (≥ 10 cm in diameter) were present in 88% and 33%, respectively, and extranodal involvement was evident in 44% of all pts. After a median follow-up of 85 months (range 9–240), the overall (OS) and progression-free (PFS) survival at 5 yrs for the entire cohort were 89% and 66%, respectively, with a plateau 1–2 yrs following treatment. PFS at 5 years was significantly better with +R (81%) than with -R cohort (58%, P=0.03). Five-year PFS in pts treated with R-VACOPB, R-CHOP, VACOP-B and CHOP were 84%, 74%, 62%, 20%, respectively (P=0.025). Yet, there was no significant difference in OS between +R and -R cohorts (96% vs. 88% at 5 yrs, p=0.29). Direct survival comparisons demonstrated that 5-yr OS and PFS were significantly better in VACOPB than in CHOP (P=0.04 and 0.05, respectively) and that R-VACOPB was significantly superior to VACOPB in terms of PFS (p=0.05). In contrast, there was no difference in 5-yr PFS between R-VACOPB and R-CHOP (p=0.44). Univariate analysis revealed that aaIPI was not predictive of OS (p=0.51). Age above 31 yrs (p=0.02) and pericardial effusion (p=0.04) were the only predictors of reduced OS. Furthermore, beginning in 2003, 16 consecutive pts in the +R cohort, who were scanned by PET/CT-FDG before starting and after completion of therapy, were also evaluated in the middle (mid-PET) of treatment. The estimated 3-year PFS rate for mid-PET negative pts (n=8) and for mid-PET positive pts (n=8) was 86% and 75%, respectively (P=0.48). In terms of treatment failure, the negative predictive value of mid-PET was 100%, while the positive predictive value was only 25%. In conclusion, our population-based historical comparison demonstrates that the addition of R to anthracycline-based therapy significantly improved PFS in pts with PMBCL. We observed superior PFS with VACOPB compared with CHOP, but this superiority was abrogated by the introduction of R as part of initial therapy. These findings merit further study in randomized prospective studies.

Description: ABVD is widely considered as the gold standard treatment for advanced Hodgkin’s lymphoma (HL), although about 40% of patients relapse or do not respond to initial treatment. Recently, the HD9 trial of the German Hodgkin’s Lymphoma Study Group has shown that escalated (esc) BEACOPP regimen can achieve better disease control than ABVD, but has a high incidence of acute and long-term toxicities including high occurrence of AML/MDS. In an attempt to decrease toxicity while preserving the potential benefit of upfront intensive therapy, we conducted a pilot study, which tested the feasibility, toxicity and efficacy of combined escBEACOPP-ABVD regimen as therapy for newly diagnosed patients with high risk (IPS≥3) stage III–IV HL. Patients initially received 2 cycles of escBEACOPP followed by reevaluation with CT and gallium or PET/CT-FDG scans. When complete response (CR) or partial response (PR) was achieved, patients continued to receive 4 cycles of ABVD, while those failing to achieve a response were withdrawn from the study. Since August 2001, 21 patients entered the study and at the time of present analysis four of them are still receiving therapy. Three (18%) of 17 patients, who completed chemotherapy, received consolidative radiotherapy. Median age at diagnosis was 26 years (range 18–56) and 11 (57%) were males. Stage IV and B symptoms were evidenced in 19 (90%) and 17 (81%), respectively, and 7 (33%) had bulky mediastinal mass. Histology included nodular sclerosis in 18 patients (86%), mixed cellularity in 2 (10%) and lymphocyte predominance in 1 (5%). Following the first 2 cycles of escBEACOPP the overall response rate (CR+PR) was 100%. At the end of all therapy 15 patients (88%) were in CR, one patient in PR and only a single patient had progressive disease. With a median follow-up of 20 months no patient relapsed or died. Toxicity included WHO grade III–IV granulocytopenia in 15 patients (88%) and grade III–IV infection in one patient. Hospitalization for intravenous antibiotics was necessary in 10 patients (59%). Almost all of these events occurred during the first two cycles of escBEACOPP, while acute toxicity during the ABVD phase was mild. In conclusion, the combined escBEACOPP-ABVD regimen is well tolerated and is associated with a high CR rate when used in advanced HL patients with high IPS scores. Further follow-up is obviously required in order to determine long-term survival and late complications of this regimen.

Description: The expected 5-year freedom from progression of advanced stage Hodgkin’s lymphoma (HL) patients (pts) with IPS≥3, treated with COPP-ABVD, was reported as 55%. While the superiority of escalated (esc) BEACOPP regimen over COPP-ABVD was shown for all risk groups, it was more pronounced in pts with a poor IPS. However, pts receiving escBEACOPP had more acute and long-term toxicities including a higher incidence of MDS/AML. In an attempt to reduce this toxicity, while preserving improved initial tumor control in this high risk group of pts, we conducted a phase II study, which tested the feasibility, toxicity and efficacy of a regimen which utilized the combination of escBEACOPP and ABVD. Newly diagnosed HL pts, with unfavorable stage IIB or stages III–IV with IPS≥3 were initially received two cycles of escBEACOPP followed by reevaluation with FDG- PET/CT scans. When complete or partial response (CR, PR) was achieved, pts then continued to receive four cycles of ABVD, while pts who failed to obtain this response were planned to receive salvage therapy. Since starting in late 2001, 40 eligible pts received this regimen. Median age at diagnosis was 27 years (range 18–56) and 29 (73%) were males. Histology included nodular sclerosis (n=30), mixed cellularity (n=6) and unclassified (n=4). Stage IV, III and IIB were evident in 29 (73%), 8 (20%) and 3 (7%) pts, respectively and extranodal involvement was noted in 28 (70%). Following the first two cycles of escBEACOPP the overall response rate (CR+PR) was 100% and at the end of all therapy 36 (90%) pts were in CR, 2 (5%) in PR and 2 (5%) pts had progressive disease. After a median follow-up of 30 months (range 7–61), 38 pts are alive while two pts died from progressive HL. The estimated 5-year Progression free survival (PFS) and overall survival rates were 78% (95% CI, 64–92%) and 91% (95% CI, 78–100%), respectively. The 5-year cumulative incidence of relapse was 13% (95% CI, 5-33%). These survival rates are higher than those expected for ABVD containing regimens and comparable with the reported estimated long term survival rates achieved with the poor prognostic subgroup of pts, receiving eight cycles of escBEACOPP in the GHLSG HD9 trial. Furthermore, the estimated 5-year PFS rate for early PET negative pts (n=27) and for early PET positive pts (n=11) was 82% (95% CI, 66–98%) and 64% (95%, CI 35–92%), respectively (P=0.14) (in 2 pts early PET results were not conclusive). In terms of treatment failure, the positive predictive value was only 35%, while the negative predictive value was 85%. As expected, the incidence of acute hematologic toxicities was more common in the escBEACOPP than in the ABVD phase. Non hematologic adverse effects included grade III–IV infection (n=1), avascular necrosis of the hip (n=1) and cognitive impairment (n=1). In conclusion, combined escBEACOPP-ABVD therapy is well tolerated and may improve the outcome in pts with advanced HL who have high IPS scores. Larger scale randomized studies, comparing this combination regimen with previously reported dose-intensified chemotherapy regimens, are required in order to verify its true merit in this high risk subgroup of pts.

Description: The impact of the use of autologous BMT (ABMT) as an up-front therapy on the natural history of multiple myeloma (MM) is limited, mainly due to the course of disease at progression after ABMT. Conventional salvage at that stage was reported to offer overall survival of only 14–17 months. The benefit of thalidomide and reduced intensity allogeneic stem cell transplantation (RIC SCT), which were introduced at that stage, is limited by the duration of response and toxicity. It was shown, however, that the aggressiveness of relapse clearly predicts for outcome in this set-up. Methods. Patients (pt’s) with progression after ABMT were treated according to a strategy based on the nature of relapse, with thalidomide (Thal) and reduced intensity conditioning allogeneic stem cell transplantation (RIC SCT) as following: all progressing patients had Thal ± Dexa for induction of response, but only at a clinical indication for therapy. DTPACE combination was given to those who failed to respond to Thal. Pt’s with aggressive progression were offered a RIC SCT at response, while patients with an indolent progression were offered a RIC SCT only at escape from response to Thal or if being resistant to Thal+Dexa. Re-induction therapy was delivered prior to transplant. The post transplant therapy included DLI and/or Thal according to the findings in minimal residual disease (MRD) studies and base line chromosomal studies. Results. Seventy five pts (age 36–66, median 58 y) with indolent (n= 46, 61%) or aggressive (n=29, 39%) progression, were treated according to this strategy. The overall response rate (= or 〉PR) to Thal ± Dexa was 58.6%. Thirty six pt’s (48%) subsequently underwent RIC SCT (27 related, 9 unrelated donor) and 10 pts with an indication but no matched donor had a 2nd ABMT. Treatment related mortality was 9.3% (7 pt, all after RIC SCT, giving transplant related mortality rate of 16.6% for RIC SCT in this setting). RIC SCT reversed resistant to Thal in 7 pt. The median overall survival (OS) from progression of the entire group is 39 months with a projected 3-years survival rate of 52% (follow-up 19m-74m, median= 34m). The nature of relapse was found to be a strong independent favorable prognostic factor with a median post relapse OS of 〉62m (not yet reached) vers. 24m, for pt’s with indolent compared with aggressive relapse (p=0.00002). In 24 patients (32%), the duration of response exceeded the first progression free period (from ABMT until progression). The median OS from ABMT of this group of patients is 85m, compared with a median OS rate of 56m from ABMT in a comparable historical group of 62 patients from our center that relapsed after ABMT prior to the introduction of the Thal /RIC SCT strategy. Conclusion. The therapy with Thal and RIC SCT with a strategy based on the nature of disease progression after ABMT can improve post relapse and overall survival of MM patients. This may significantly add to the contribution of ABMT to the outcome of therapy in MM.

Description: Loss of fertility is a major concern in young women undergoing high dose chemotherapy (HDT). Although it is generally accepted that therapy of the myeloabelative range is related with a high rate of fertility loss, we observed during the last years eight spontaneous pregnancies with normal deliveries in young women after bone marrow transplantation. Seven patients (pt’s) were with lymphoma and MM and were conditioned with BEAM regimen (n=6) and melphalan 200mg/sm (n=1) prior to an autologous SCT, while one patient had a secondary AML and underwent BEAM primed autologous SCT and Busulfex/FA primed allogeneic BMT. The median age at transplant of this group was 28y and median time from transplant to pregnancy was 25 months. More than 100 women of 18–40y.o were transplanted in our center during this period; however, obviously the fertility rate cannot be calculated as it is related with additional parameters including survival, post transplant complications and mainly patient’s preferences. Naturally we observed during the same period many young patients with ovarian failure post transplant, as well as one successful pregnancy from a cryopreserved embryo. Methods. We Therefore initiated in October 2000 a fertility preservation program in which all women of 18 – 40y.o were offered a pretransplant IVF with embryo preservation, and/or ovarian tissue cryopreservation (OTC), according to their clinical status. 651 pt’s were transplanted in our center in the last 44 months, of which 81 were women of 18–41y.o that were all enrolled in this program. Results. Seven pt’s of this group (8.6%) underwent IVF. The major causes of denying IVF were the need to delay BMT for more than clinically accepted, prolonged preexisting ovarian failure, lack of a suitable partner and patient’s preference. Seventeen pt’s (21%) underwent OTC. The major causes of denying OTC were patient’s preference (mainly due to no evidence of success with this method) and thrombocytopenia/neutropenia. During this period: One patient of this group was fertilized with her cryopreserved embryos 32 months after transplant and is at her 16 week of pregnancy. One patient underwent a successful transplantation of her cryopreserved ovarian tissue 2.5 years after HDC while in a documented ovarian failure, and gave birth to a healthy baby on June 2005. The OTC of this patient was performed after cis-platinum containing salvage therapy for relapsing NHL, prior to BEAM primed SCT, and immediately after a failure of hormonal stimulation for IVF. One patient underwent a cryopreserved ovarian tissue transplantation on July 2005 Conclusions: 1. Spontanous pregnancy after HDT, mainly at the younger age, is not a rare phenomenon. 2. Most young patients prior to HDT are not eligible for IVF. 3. Pretransplant ovarian tissue cryopreservation is a feasible tool in this set-up. The first success with this method is promising.