ALBERT

Description: A 34% response was obtained in 202 evaluable patients in the terminal phase of chronic granulocytic leukemia using combinations of hydroxyurea, 6-mercaptopurine, and corticosteroids. Twelve percent of responses were complete and 22% partial. Overall median survival was 12 wk. A 30 wk median survival for responding patients was statistically superior to the 7-wk survival for nonresponders (p less than 0.001). Response was inversely correlated with toxicity. No responses were obtained in patients sustaining both severe infectious and bleeding complications. No benefit could be demonstrated from the addition of vincristine in induction and daunorubicin for consolidation. Although the response frequency and duration of survival with this combination chemotherapy were generally superior to those previously reported by our group, the terminal phase of chronic granulocytic leukemia still remains a formidable and generally refractory disease.

Description: The ability to modulate granulocyte-macrophage colony-forming unit (CFU- GM) Ia-antigen expression and response to growth inhibition in vitro was investigated in normals and patients with chronic myeloid leukemia (CML). The hyporesponsiveness of CML CFU-GM to inhibition by prostaglandin E and acidic isoferritins in vitro and their associated diminished capacity for Ia-antigen expression could be reversed following suspension culture of bone marrow cells in the presence of prostaglandin E prior to soft agar culture. Suspension preculture with prostaglandin E for 24 hr resulted in the detection of a population of CFU-GM that were equivalent to normal CFU-GM in both response to inhibition by prostaglandin E and acid isoferritins and in their pattern of Ia-antigen expression. Cytogenetic analysis of the progeny of CFU-GM proliferating in cultures established from marrow cells, cultured directly upon isolation or following suspension culture in the absence or presence of prostaglandin E for 24 hr, indicated that the responding cell population belonged to the Ph1-positive leukemic clone. Antigen detection on these CFU-GM resulted both from Ia-antigen reexpression and the induction of noncycling cells into S-phase with coincident expression of Ia-antigens. These studies provide further evidence for a direct regulatory association between Ia-antigen and control of granulocyte-macrophage progenitor cell proliferation, offer a possible explanation for the disordered regulatory responses observed in patients with CML, and indicate that abnormal growth phenotypes can be modulated, at least in vitro.

Description: BACKGROUND: The phase 2 SUMMIT trial of patients (pts) with relapsed and refractory MM showed that btz (VELCADE®) is active, with a response rate of 27% (CR/PR) as a single agent, median TTP of 7 months, and median OS of 17 months. The phase 3 APEX trial in pts with relapsed MM following 1–3 prior therapies showed btz to be superior to high-dose dexamethasone (dex) in terms of response rate, TTP, and OS. Updated APEX data show a CR/PR rate of 43%, median TTP of 6.2 months, and median OS of 29.8 months. This analysis evaluated the relationship between quality of response to btz (CR/nCR versus PR; PR does not include nCR in this analysis) in these trials and clinical benefit, as defined by treatment-free interval and time-to-alternative-therapy (TFI and TTAT; time from last and first dose of btz, respectively, to first dose of alternative antineoplastic therapy), OS, and TTP. METHODS: In SUMMIT, 202 pts received btz 1.3mg/m2 on days 1, 4, 8, and 11 for up to eight 21-day cycles (median # of cycles: 6). Dex 20mg was added on the day of and day after each btz dose in pts with suboptimal responses to btz alone. In one arm of APEX, 333 pts received btz 1.3mg/m2 on days 1, 4, 8, and 11 for eight 3-week cycles and then on days 1, 8, 15, and 22 for three 5-week maintenance cycles (median # of cycles: 6). Responses in both trials were assessed according to EBMT criteria (modified to include nCR, a CR with positive immunofixation test). RESULTS: Data are shown in the Table. Median TFI appeared longer in pts with CR/nCR vs PR (SUMMIT, 9.8 vs 3.1 months; APEX, 17.5 vs 6.7 months). Similarly, TTAT appeared longer in pts with CR/nCR vs PR (SUMMIT, 15.4 vs 8.5; APEX, 21.2 vs 14.0). Median OS in all response groups has not yet been reached after a median follow-up of 22 months. TTP tended to be longer with CR/nCR vs PR in both studies (SUMMIT, 16.4 vs 9.2; APEX, 12.2 vs 8.3). CONCLUSIONS: Increasing quality of response to btz is associated with greater clinical benefit assessed by extended TFI ,TTAT, and TTP. Long un-maintained remissions can be attained with btz by achieving maximum tumor mass reduction (CR/nCR), even in pts with relapsed/refractory MM. Updated APEX data show that despite rapid initial response, many pts showed continued improvement in terms of M-protein reduction, and an increasing proportion of pts achieved CR with continued therapy. These data, together with the findings of this analysis, support maximizing tumor mass reduction to CR/nCR with btz to achieve greater clinical benefit. Clinical benefit of btz by response Kaplan-Meier median (95% CI) CR/nCR PR* *PR does not include nCR in this analysis; †Includes 8 cycles of protocol-specified therapy plus maintenance cycles SUMMIT, n 19 34 TFI, mo 9.8 (2.7,14.3) 3.1 (2.0,8.7) TTAT, mo 15.4 (7.9,17.6) 8.5 (7.3,14.0) TTP, mo 16.4 (10.6,NE) 9.2 (7.2,NE) Median cycles, n 8 8 APEX, n 48 87 TFI, mo 17.5 (6.7,24.1) 6.7(4.4,10.0) TTAT, mo 21.2 (14.0,27.1) 14.0 (12.6,16.1) TTP, mo 12.2 (8.8,NE) 8.3 (7.6,10.3) Median cycles,† n 9 10

Description: Lenalidomide or Revlimid® has recently been approved for the treatment of relapsed or refractory MM. It has been demonstrated that Biaxin(Bi) augments tumor mass reduction and improves responses in patients (pts) receiving low-dose thalidomide and/or Dexamethosone (D). The results of a phase II trial exploring the combination of Bi, R & D in newly diagnosed MM are reported here. The planned accrual target was met and additional patients accrued for correlative studies. The BiRD regimen consists of R 25 mg po daily on days 1–21 of a 28-day cycle. D 40 mg once weekly and Bi 500 mg po twice daily. All pts received low dose aspirin (ASA)(81mg) once daily as thrombosis prophylaxis, prophylactic sulfamethoxazole/ trimethoprim, and a proton pump inhibitor. PATIENTS: 58 pts[median follow-up 9 months (range 2–21)] have been accrued. Median age of 62.5 years (range 36–80), hemoglobin of 10.9 g/dL (range 7.2–15.1), platelets of 242 k/uL (range 51–526), B2M of 3mg/L (range 0.8–12.8), CRP of 0.56 mg/dL (range 0.12–14.2), creatinine (Cr) of 1.2 mg/dL (range 0.6–3.1), albumin of 3.55g/dL (range 2.3–4.9), and calcium of 9.3mg/dL (range 6.9–11.2). 50% of the pts are stage IIIa, 7% are stage IIIb, 41.4% are stage Iia. According to ISS classification 28/58 are stage I (48%), 18/58 are stage II (31%) & 12/58 are stage III (20%). RESULTS: This combination yielded a 95% overall response rate (EBMTR) by ITT with 38% of the pts achieving either a CR(16/58) or a nCR(6/58). Of the remaining 36 pts, 92% achieved a PR. Of those PR pts, 11/36 pts had 〉90% reduction in the initial paraprotein, while 12/36 pts had 〉75% decrease. All R dose reductions were due to myelosupression. R dose reduction scheme for myelosupression was defined as follows: Grade≥ 3 Neutropenia: Level −1: 25 mg po daily + G-CSF. Level −2 : 15 mg po daily and Level −3: 10 mg po daily. Thrombocytopenia: Level −2 : 15 mg po daily. Level −3: 10 mg po daily. 18% of the pts required at least one dose reduction. Of these patients, 6% required further dose reductions to level 2, and 2 patients were reduced to level 3. Mean time to R dose reduction level 1 was 65.1 days (range 15 to 142), to level 2 was 113 days (range 35 to 166) and to level 3 was 170 days (range 95 to 244). Baseline Cr level correlated with R dose reductions. Of the 11 patients who were dose-reduced, 1 had a baseline serum Cr level of ≤1.4 mg/dL, while the rest had a baseline serum Cr level 〉1.4 mg/dL (p40 (p=0.0014). Other toxicities included PE (4%), DVT (9%), AMI (2%), and sudden death (2%). Other non-hematological toxicities included myopathy (6%), diverticular abscess (10%), hand tremor, weakness and hyperglycemia. Conclusions: BiRD is highly effective and safe in the initial Rx of MM. Myelosuppression & renal dysfunction potentiated the need for R dose reduction.

Description: Two hundred fifty-two previously untreated evaluable patients with multiple myeloma were entered into a study testing a regimen of three intravenous alkylating agents, melphalan, cyclophosphamide, and carmustine (BCNU), given in combination (BCMP) against a regimen employing oral melphalan (MP). Both regimens included a tapering course of prednisone. Objective responses based on the Myeloma Task Force criteria were significantly more frequent in the group receiving BCMP. Survival for the entire group of BCMP-treated patients was not significantly better than that for MP-treated patients (p = 0.62). However, when the survival of the poor-risk (high tumor cell load) group of patients treated with BCMP was compared with the survival of the poor-risk (high tumor cell load) group of patients treated with MP, an improvement in survival attributable to BCMP therapy was seen (p = 0.049 and 0.02, respectively). In the good-risk (low and intermediate tumor cell load) group, BCMP treatment resulted in a trend toward poorer survival, but this did not achieve statistical significance (p = 0.080 and 0.23, respectively). These results indicate that optimal therapy in myeloma may be dependent on the extent of disease at the time of first treatment. Additional studies to explore the effects of treatment intensity and duration are needed in order to design improved myeloma treatment based on the patient's extent of disease.

Description: A 34% response was obtained in 202 evaluable patients in the terminal phase of chronic granulocytic leukemia using combinations of hydroxyurea, 6-mercaptopurine, and corticosteroids. Twelve percent of responses were complete and 22% partial. Overall median survival was 12 wk. A 30 wk median survival for responding patients was statistically superior to the 7-wk survival for nonresponders (p less than 0.001). Response was inversely correlated with toxicity. No responses were obtained in patients sustaining both severe infectious and bleeding complications. No benefit could be demonstrated from the addition of vincristine in induction and daunorubicin for consolidation. Although the response frequency and duration of survival with this combination chemotherapy were generally superior to those previously reported by our group, the terminal phase of chronic granulocytic leukemia still remains a formidable and generally refractory disease.

Description: Eighty-three patients with circulating anticoagulants were studied at The New York Hospital. The lupus-type anticoagulant, an inhibitor of the prothrombin activator complex, was demonstrated in 58 patients. The inhibitor was identified using the blood and tissue thromboplastin inhibition tests. Inhibition by the lupus anticoagulant was augmented in 67% of these patients by a cofactor present in normal plasma. The lupus inhibitor was detected primarily because of an unsuspected abnormal coagulation test. One-half of the patients with the lupus-type anticoagulant did not have systemic lupus erythematosus.

Description: Eighty-three patients with circulating anticoagulants were studied at The New York Hospital. The lupus-type anticoagulant, an inhibitor of the prothrombin activator complex, was demonstrated in 58 patients. The inhibitor was identified using the blood and tissue thromboplastin inhibition tests. Inhibition by the lupus anticoagulant was augmented in 67% of these patients by a cofactor present in normal plasma. The lupus inhibitor was detected primarily because of an unsuspected abnormal coagulation test. One-half of the patients with the lupus-type anticoagulant did not have systemic lupus erythematosus.

Description: Two hundred fifty-two previously untreated evaluable patients with multiple myeloma were entered into a study testing a regimen of three intravenous alkylating agents, melphalan, cyclophosphamide, and carmustine (BCNU), given in combination (BCMP) against a regimen employing oral melphalan (MP). Both regimens included a tapering course of prednisone. Objective responses based on the Myeloma Task Force criteria were significantly more frequent in the group receiving BCMP. Survival for the entire group of BCMP-treated patients was not significantly better than that for MP-treated patients (p = 0.62). However, when the survival of the poor-risk (high tumor cell load) group of patients treated with BCMP was compared with the survival of the poor-risk (high tumor cell load) group of patients treated with MP, an improvement in survival attributable to BCMP therapy was seen (p = 0.049 and 0.02, respectively). In the good-risk (low and intermediate tumor cell load) group, BCMP treatment resulted in a trend toward poorer survival, but this did not achieve statistical significance (p = 0.080 and 0.23, respectively). These results indicate that optimal therapy in myeloma may be dependent on the extent of disease at the time of first treatment. Additional studies to explore the effects of treatment intensity and duration are needed in order to design improved myeloma treatment based on the patient's extent of disease.

Description: The ability to modulate granulocyte-macrophage colony-forming unit (CFU- GM) Ia-antigen expression and response to growth inhibition in vitro was investigated in normals and patients with chronic myeloid leukemia (CML). The hyporesponsiveness of CML CFU-GM to inhibition by prostaglandin E and acidic isoferritins in vitro and their associated diminished capacity for Ia-antigen expression could be reversed following suspension culture of bone marrow cells in the presence of prostaglandin E prior to soft agar culture. Suspension preculture with prostaglandin E for 24 hr resulted in the detection of a population of CFU-GM that were equivalent to normal CFU-GM in both response to inhibition by prostaglandin E and acid isoferritins and in their pattern of Ia-antigen expression. Cytogenetic analysis of the progeny of CFU-GM proliferating in cultures established from marrow cells, cultured directly upon isolation or following suspension culture in the absence or presence of prostaglandin E for 24 hr, indicated that the responding cell population belonged to the Ph1-positive leukemic clone. Antigen detection on these CFU-GM resulted both from Ia-antigen reexpression and the induction of noncycling cells into S-phase with coincident expression of Ia-antigens. These studies provide further evidence for a direct regulatory association between Ia-antigen and control of granulocyte-macrophage progenitor cell proliferation, offer a possible explanation for the disordered regulatory responses observed in patients with CML, and indicate that abnormal growth phenotypes can be modulated, at least in vitro.