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These suggested practice guidelines are based on extensive evaluation of the reviewed risk-based data and indicate useful current approaches for managing patients with MDS. Four drugs have recently been approved by the FDA for treating specific subtypes of MDS: lenalidomide for MDS patients with del(5q) cytogenetic abnormalities; azacytidine and decitabine for treating patients with higher-risk or nonresponsive MDS; and deferasirox for iron chelation of iron overloaded patients with MDS. However, because a substantial proportion of patient subsets with MDS lack effective treatment for their cytopenias or for altering disease natural history, clinical trials with these and other novel therapeutic agents along with supportive care remain the hallmark of management for this disease. The role of thrombopoietic cytokines for management of thrombocytopenia in MDS needs further evaluation. In addition, further determination of the effects of these therapeutic interventions on the patient's quality of life is important.(116,119,120,128,129) Progress toward improving management of MDS has occurred over the past few years, and more advances are anticipated using these guidelines as a framework for coordination of comparative clinical trials.

Background Although secondary acute leukemias and myelodysplasia are the known complications of adjuvant chemotherapy for breast cancer, the treatment outcome of these secondary malignancies is presently unclear. We examined the clinical and pathological features as well as the treatment results of a series of patients with acute leukemia/myelodysplasia arising after adjuvant chemotherapy for breast cancer. Patients and methods Patients referred to our institution during a 5-year period for treatment of acute leukemia/myelodysplasia and who had received adjuvant chemotherapy for breast cancer are included. Leukemia-free survival for the whole group and for patients who underwent hematopoietic stem cell transplantation (HSCT) was estimated. Results Fifteen women (14 with acute leukemia and one with myelodysplasia) were identified. Seven of 15 patients had received an anthracycline, cyclophosphamide and a taxane. Ten patients developed acute leukemia/myelodysplasia with a latency period of 2 years or less from initiation of chemotherapy. Although mixed-lineage leukemia (MLL) rearrangement was the commonest chromosomal abnormality (8 of 15 patients), various other chromosomal abnormalities were also detected. Twelve of 15 patients underwent HSCT (11 allogeneic and one autologous). Eleven of these 12 patients who underwent HSCT were in remission at a median follow-up of 20.4 months (range 4.4–53.3 months). Conclusion Durable remissions can be achieved in patients who develop acute leukemia/myelodysplasia secondary to adjuvant chemotherapy for breast cancer and are able to undergo allogeneic HSCT. Our results indicate that HSCT should be an early consideration in the management of such patients who are suitable candidates for the procedure.

In an attempt to decrease toxicity in high-risk patients undergoing unrelated donor hematopoietic stem cell transplantation (URD HSCT), we tested a combination of cyclosporine (CSP) and mycophenolate mofetil (MMF) as graft-versus-host disease (GVHD) prophylaxis with the reduced-intensity conditioning regimen fludarabine/melphalan (Flu/Mel). A total of 22 adult patients with advanced myeloid (n=15) and lymphoid (n=7) malignancies were treated. All patients received Flu 25 mg/m2 for 5 days and Mel 140 mg/m2, with CSP 3 mg/kg daily and MMF 15 mg/kg three times a day. The median age was 49 years (range 18-66). Durable engraftment was seen in all but one patient with myelofibrosis. The 1-year nonrelapse mortality was 32%, 27% from GVHD. The cumulative incidence of acute GVHD grade 2-4 and 3-4 was 63 and 41%, respectively. With a median follow-up of 18 months, the disease-free survival (DFS) and overall survival (OS) are 55 and 59%, respectively. For patients with AML and MDS (n=14), the DFS and OS is 71%. For patients undergoing a second transplant (n=14), the DFS and OS is 57%. In conclusion, this regimen is associated with acceptable toxicity but high rates of GVHD in high-risk patients undergoing URD HSCT. Encouraging disease control for patients with advanced myeloid malignancies was observed.

The prognosis of patients with primary refractory acute myelogenous leukemia (AML) is poor. Our initial report suggested that some patients could achieve durable remission after allogeneic stem cell transplantation (SCT). Herein, we update our initial experience and report further analysis of this group of patients to determine whether there are pre-SCT prognostic factors predictive of posttransplantation relapse and survival. We reviewed the records of 68 patients who consecutively underwent transplantation at the City of Hope Cancer Center with allogeneic SCT for primary refractory AML between July 1978 and August 2000. Potential factors associated with overall survival and disease-free survival were examined. With a median follow-up of 3 years, the 3-year cumulative probabilities of disease-free survival (DFS), overall survival (OS), and relapse rate for all 68 patients were 31% (95% confidence interval [CI], 20%–42%), 30% (95% CI, 18%–41%), and 51% (95% CI, 38%–65%), respectively. In multivariate analysis, the only variables associated with shortened OS and DFS included the use of an unrelated donor as the stem cell source (relative risk, 2.23 [OS] and 2.05 [DFS]; P = .0005 and .0014, respectively) and unfavorable cytogenetics before SCT (relative risk: 1.68 [OS] and 1.58 [DFS]; P = .0107 and .0038, respectively). Allogeneic SCT can cure approximately one third of patients with primary refractory AML. Cytogenetic characteristics before SCT correlate with transplantation outcome and posttransplantation relapse.

Autologous hematopoietic stem cell transplantation (autoSCT) is an effective treatment for patients with various hematologic malignancies. Despite the significant improvement in the overall outcome, disease progression after transplantation remains the major cause of treatment failure. With longer follow-up, therapy-related myelodysplasia/acute myelogenous leukemia is becoming an important cause of treatment failure. The prognosis for these 2 groups of patients is very poor. Allogeneic hematopoietic stem cell transplantation (alloSCT) is a potential curative treatment for these patients. However, the outcome with conventional myeloablative alloSCT after failed autoSCT is typically poor because of high transplant-related mortality. In an attempt to reduce the treatment-related toxicity, we studied a reduced-intensity conditioning regimen followed by alloSCT for patients with progressive disease or therapy-related myelodysplasia/acute myelogenous leukemia after autoSCT. This report describes the outcomes of 28 patients with hematologic malignancies who received a reduced-intensity alloSCT after having treatment failure with a conventional autoSCT. Fourteen patients received a hematopoietic stem cell transplant from a related donor and 14 from an unrelated donor. The conditioning regimen consisted of low-dose (2 Gy) total body irradiation with or without fludarabine in 4 patients and the combination of melphalan (140 mg/m2) and fludarabine in 24. Cyclosporine and mycophenolate mofetil were used for posttransplantation immunosuppressive therapy, as well as graft-versus-host disease (GVHD) prophylaxis, in all patients. All patients engrafted and had >90% donor chimerism on day 100 after SCT. Currently, 13 patients (46%) are alive and disease free, 7 patients (25%) developed disease progression after alloSCT, and 8 (32%) died of nonrelapse causes. Day 100 mortality and nonrelapse mortality were 25% and 21%, respectively. With a median follow-up of 24 months for surviving patients, the 2-year probabilities of overall survival, event-free survival, and relapse rates were 56.5%, 41%, and 41.9%, respectively. Six patients (21%) developed grade III to IV acute GVHD. Among 21 evaluable patients, 15 (67%) developed chronic GVHD. We conclude that (1) reduced-intensity alloSCT is feasible and has an acceptable toxicity profile in patients who have previously received autoSCT and that (2) although follow-up was short, a durable remission may be achieved in some patients who would otherwise be expected to have a poor outcome.

PURPOSE To evaluate in a prospective study the efficacy of autologous bone marrow transplantation (BMT) in adult patients with acute myelogenous leukemia (AML) in first remission, using a single course of high-dose Cytarabine (HD Ara-C) consolidation therapy as in vivo purging. PATIENTS AND METHODS Sixty consecutive adult patients with AML in first complete remission (CR) were treated with HD Ara-C consolidation therapy as a method of in vivo purging before marrow collection. High-dose therapy consisted of fractionated total-body irradiation (FTBI) 12 Gy, intravenous etoposide 60 mg/kg, and cyclophosphamide 75 mg/kg, followed by reinfusion of cryopreserved marrow. RESULTS Sixty patients underwent consolidation treatment with HD Ara-C with the intent to treat with autologous BMT. Sixteen patients were unable to proceed to autologous BMT (10 patients relapsed, one died of sepsis, one developed cerebellar toxicity, two had inadequate blood counts, and two refused). Forty-four patients underwent autologous BMT and have a median follow-up time of 37 months (range, 14.7 to 68.7) for patients who are alive with no relapse. The cumulative probability of disease-free survival (DFS) at 24 months in the intent-to-treat group is 49% (95% confidence interval [CI], 37% to 62%) and in those who actually underwent autologous BMT is 61% (95% CI, 46% to 74%). The probability of relapse was 44% (95% CI, 31% to 58%) and 33% (95% CI, 20% to 49%) for the intent-to-treat and autologous BMT patients, respectively. CONCLUSION This approach offers a relatively high DFS rate to adult patients with AML in first CR. The results of this study are similar to those achieved with allogeneic BMT.

Graft-versus-host disease (GVHD) is a major obstacle to successful bone marrow transplantation (BMT) from matched unrelated donor (MUD). Currently available HLA-A, -B, and -DR serologic testing may not be sensitive enough to detect clinically relevant donor/recipient (D/R) nonidentity. Better HLA matching of D/R pairs using molecular typing for class II antigens in combination with intensive GVHD prophylaxis may potentially reduce the incidence of GVHD and lead to an improved outcome of MUD transplantation. Between July 1991 and August 1993, thirty consecutive patients with hematologic malignancies underwent MUD transplantation from donors who were identical for HLA -A, -B, and -DR by serologic typing. Twenty-five D/R pairs were matched for DRB and DQB by molecular typing (restriction fragment-length polymorphism and sequence-specific oligonucleotide probe hybridization analyses), whereas five were allele mismatched at either DRB or DQB. All patients also received GVHD prophylaxis with the combination of cyclosporine (CSA), methotrexate (MTX), and prednisone (PSE). The median age was 35 years (range, 15 to 50). The diagnoses were: chronic myelogenous leukemia (CML) in chronic phase (CP) (16), CML in more than CP (3), acute leukemia in more than first complete remission (CR) (8), acute leukemia in first CR (1), and advanced high-grade lymphoma (2). The preparative regimen consisted of 1,320 cGy fractionated total body irradiation (FTBI) and 60 mg/kg cyclophosphamide (CY) daily for 2 days in 17 good-risk patients (CML/CP and acute leukemia first CR); and 1,320 cGy FTBI in combination with 60 mg/kg etoposide and 20 to 60 mg/kg CY in 13 patients with advanced leukemia and lymphoma. All patients received CSA, PSE, and MTX on days 1, 3, 6 for GVHD prophylaxis, and 10 patients also received day +11 MTX. All patients engrafted except one who died early of regimen-related toxicity. The incidence of grade III or IV acute GVHD was 24% (95% confidence interval [CI], 10% to 44%) and that of extensive chronic GVHD was 65% (95% CI, 43% to 84%). At a median follow-up of 13.6 months, 57% of the patients are alive in remission with a median Karnofsky performance status of 90%. The cumulative probability of 2-year disease-free survival for all patients was 53% (95%) CI, 33% to 71%); for good-risk patients, 71% (95% CI, 46% to 87%) and for the poor-risk group, 34% (95% CI, 13% to 64%).(ABSTRACT TRUNCATED AT 400 WORDS)

PURPOSE To evaluate (1) the effect of granulocyte colony-stimulating factor (G-CSF) on peripheral-blood stem-cell (PBSC) mobilization; (2) the rate of hematopoietic recovery after G-CSF-mobilized PBSC transplantation; and (3) the outcome of high-dose myeloablative therapy and PBSC transplantation in patients with relapsed or refractory lymphoma. PATIENTS AND METHODS Ninety-five patients with lymphoma underwent high-dose therapy followed by PBSC transplant in three sequentially treated cohorts of patients in a nonrandomized study. The first 30 patients received nonmobilized PBSCs (unprimed) without G-CSF after transplant, the next 26 patients received PBSC that were mobilized with G-CSF 5 micrograms/kg/d (primed-5) plus G-CSF after transplant, and the last 39 patients received PBSC mobilized by G-CSF 10 micrograms/kg/d (primed-10) plus G-CSF after transplant. The conditioning regimen consisted of fractionated total-body irradiation (FTBI) 12 Gy in combination with etoposide 60 mg/kg and cyclophosphamide 100 mg/kg. Patients with prior radiotherapy received carmustine (BCNU) 450 mg/m2 instead of FTBI. RESULTS The use of G-CSF-mobilized PBSCs in combination with G-CSF posttransplant resulted in a significantly accelerated time to recovery of both granulocyte and platelet when compared with the unprimed group. The median number of days to an absolute granulocyte count (ANC) of greater than 0.5 x 10(9)/L was 10 days for G-CSF primed versus 20 days for the unprimed (P = .0001). The median days to platelet transfusion independence was 16 and 31 days (P = .0001) for the G-CSF primed and unprimed, respectively. There were also significant reductions in the number of platelet (P = .02) and RBC transfusions (P = .006) for the G-CSF primed. Multivariate analysis of prognostic factors identified CD34+ cell dose as the only additional factor predicting engraftment. Sixty-nine patients are alive at a median follow-up of 15.9 months (range, 7.4 to 63.7). The cumulative probability of 2-year disease-free survival is 59% (95% confidence interval [CI], 36% to 79%) and 39% (95% CI 25% to 55%) for patients with Hodgkin's disease and non-Hodgkin's lymphoma, respectively. CONCLUSION The use of G-CSF-mobilized PBSC after high-dose myeloablative therapy resulted in a rapid, complete, and sustained hematopoietic recovery. Disease-free survival over 2 years can be achieved in some patients with relapsed lymphoma after high-dose therapy and PBSC transplantation. However, longer follow-up is required to confirm the curability of this approach.

PURPOSE To identify risk factors that might predict for systemic fungal infections in marrow transplant recipients within the first 100 days and to assess the efficacy of low-dose amphotericin B used as prophylaxis for candidemia and infection with invasive Aspergillus species in patients at risk. PATIENTS AND METHODS A retrospective analysis of transplant outcomes for 331 allogeneic marrow recipients transplanted between 1983 and 1989 was performed to identify patients who might be at increased risk of fungal infection. Factors analyzed included disease, remission status, transplant regimen, graft-versus-host disease (GVHD) prophylaxis, duration of neutropenia, and development of GVHD. A trial of low-dose amphotericin (5 to 10 mg/d) begun on day +1 and continuing for 2 to 3 months posttransplant was begun in 1987 to evaluate its utility in reducing systemic mycoses. RESULTS There were 18 episodes of candidemia and 18 systemic mycoses documented by blood or tissue culture or by biopsy. The initiation of high-dose (0.5 to 1 mg/kg/d) corticosteroids early as a component of GVHD prophylaxis in 1986 was identified as the most important risk factor for fungal infections, with a sixfold increase in infections as compared with the previous GVHD regimen (P < .0001); this was despite a significant decrease in the incidence of grade II to IV GVHD (7% v 43%; P = .0001). Low-dose amphotericin B initiated before the start of high-dose corticosteroid GVHD prophylaxis reduced the incidence of fungal infections from 30% to 9% (P = .01) without renal toxicity. Cyclosporine levels were lower in the patients who received amphotericin, leading to an increase in the rate of GVHD to 19% (P = .02). Controlling for GVHD prophylaxis, prolonged neutropenia (P = .00), and grade II to IV GVHD (P = .01) were also identified as risk factors for fungal infection. CONCLUSION Amphotericin B can be used in low doses as prophylaxis for fungal infections early in the posttransplant course. However, cyclosporine doses need to be monitored to maintain target levels.

We retrospectively evaluated the outcome of reduced-intensity conditioning (RIC) followed by allogeneic hematopoietic stem cell transplantation (HCT) in 43 patients with myelodysplastic syndrome (MDS) or AML arising from MDS. All patients received fludarabine plus melphalan followed by an allogeneic HCT from an HLA-identical sibling (SIB: n=19) or unrelated donor (MUD: n=24). Median age was 58 years (range: 30-71). Diagnoses at transplantation were RA (n=8), RARS (n=1), RAEB (n=13), RAEB-T (n=6), or AML arising from MDS (n=15). Of 28 patients with MDS, two patients had low, 10 had intermediate-1, nine had intermediate-2 and seven had high-risk MDS by IPSS criteria. All patients initially engrafted with the median neutrophil recovery of 15 days (range: 9-27). The 2-year overall survival, disease-free survival, relapse and transplant-related mortality were 53.5% (CI 45.2-61.1), 51.2% (CI 43.3-58.5), 16.3% (CI 7.9-30.7) and 35.2% (26.4-45.7), respectively. Grade II-IV acute graft-versus-host disease occurred in 27 (63%) patients. There was no significant survival difference between SIB and MUD-HCT, but the relapse rate was higher among SIB donor recipients when compared to MUD (38.5 versus 7%, P=0.02). RIC with fludarabine plus melphalan was associated with durable disease control and acceptable toxicity in this high-risk cohort.

Although myelodysplastic syndromes (MDSs) are generally thought to be diseases of elderly patients, younger patients also have rarely been diagnosed with MDS. This is a report of the clinical, morphologic and cytogenetic features of 52 cases of primary MDS occurring in adults under the age of 50 years. Cases secondary to chemotherapy or radiotherapy were excluded. There were 31 males and 21 females. The median age at presentation was 39 years (range, 18 to 49 years). The interval between onset of symptoms and diagnosis was brief (median, 4 weeks; range, 1-32 weeks). Of the 49 patients for whom information about duration of symptoms was available, 13 (27%) were asymptomatic. Forty-two (81%) of the patients were classified using FAB criteria for blood and bone marrow morphology: refractory anemia (RA), 11; refractory anemia with ringed sideroblasts (RARS), four; refractory anemia with excess blasts (RAEB), 12; chronic myelomonocytic leukemia (CMML), three; refractory anemia with excess blasts in transformation (RAEB-T), 12 patients. Ten patients could not be categorized. Abnormalities involving chromosome 7 was the most frequent cytogenetic abnormality (31%). Partial chromosomal deletion and chromosome gain were also common abnormalities (22% and 9%, respectively). Translocations accounted for only 9% of the main cytogenetic abnormalities encountered in this patient population. For the 49 patients for whom information regarding AML transformation was available, 23 (47%) progressed to acute myeloid leukemia, with an overall median time to progression of 2 months (range 3 weeks to 3 years). In each category except for RARS, approximately half of the patients progressed, with a slightly less median time to progression in RAEB-T than for the other subtypes of MDS. Thirteen patients underwent bone marrow transplantation at the time of presentation of their disease.

The prognosis for patients with bcrabl positive acute lymphoblastic leukemia (ALL) treated with chemotherapy is extremely poor. Allogeneic bone marrow transplantation (BMT) may offer a curative option for patients who have appropriate donors available. Between 1984 and 1998,76 consecutive patients with bcr-abl positive ALL were treated with allogeneic BMT from HLA-matched donors: 26 patients in 1st complete remission (CR) with matched sibling donors (group A), 35 patients >lst CR with matched sibling donors (group B), and 15 patients (1st CR or more advanced) with matched related (MRD) or unrelated donors (MUD) (group C). The age range for all patients was from 3 to 56 years. Surviving patients have been followed for a median of four years. For patients in group A, the two-year probabilities of disease-free survival (DFS) and relapse are 68.6 % and 10.8 %, respectively. For patients transplanted after 1992, these probabilities are 81 % and 11% respectively. The relatively low relapse rate in this group of patients compared to published reports may reflect the enhanced anti-leukemic activity of etoposide in combination with FTBI compared to other conditioning regimens. The enhancement in overall survival for patients transplanted after 1992 may reflect improvements in supportive care, in particular, the prophylaxis of serious fungal and viral infections. For patients in Group B, the two-year probabilities for DFS and relapse are 36.7% and 38.2% respectively; and for Group C, the two-year probabilities for DFS and relapse are 6.7%and 59.4% respectively. Significant prognostic factors for DFS and risk of relapse include: disease status, allogeneic vs. MUD/MRD BMT, the occurrence of Grade II-IV acute GVHD, and the detection of pl90 bcr-abl post-BMT.

Cytogenetic abnormalities are used to define prognostic subgroups of acute myelogenous leukemia (AML) with respect to achieving complete remission (CR) and remaining disease free. These prognostic groups for obtaining CR were based on an induction regimen mainly using standard dose cytosine arabinoside (Ara-C) + daunorubicin (DNR). We have reviewed our experience with 122 adult patients with de novo non-M3 AML who were treated with high-dose (HD) Ara-C 3 g/m2 given over 3 h every 12 h for a total of eight doses followed by DNR 60 mg/m2 daily for 2 days. CR was obtained in 80% while 16% had refractory disease and 4% died of sepsis during hypoplasia. CR rate for favorable, intermediate and unfavorable cytogenetic groups were 87%, 79% and 62%, respectively (P = 0.32). High white blood cell count, age, FAB subtype and LDH levels did not adversely affect CR rate. Eighty-five percent of patients achieved CR with one course of treatment and 87% of complete responders were able to receive post remission therapy. High-dose Ara-C/DNR appears to offer an excellent chance of achieving remission for patients with AML including those with poor risk cytogenetics, without an increase in early toxic deaths.

Between 1984 and 1997, 23 consecutive patients with Philadelphia chromosome-positive acute lymphoblastic leukemia in first complete remission were treated with allogeneic bone marrow transplants from HLA-matched siblings. All patients but one were conditioned with fractionated total body irradiation (1320 cGy) and high-dose etoposide (60 mg/kg). One patient received high-dose cyclophosphamide instead of etoposide, and another patient received both drugs. Nine patients died following BMT, two from relapsed leukemia, and seven from transplant-related causes. The 3-year probabilities of disease-free survival and relapse are 65% and 12%, respectively. For patients transplanted after 1992, these probabilities are 81% (48-95%, 95% confidence interval) and 11% (2-50%), respectively. The relatively low relapse rate in this group of patients compared to published reports may reflect the enhanced anti-leukemic activity of etoposide in combination with FTBI compared to other conditioning regimens. The enhancement in overall survival for patients transplanted after 1992 may reflect improvements in supportive care, in particular, the prophylaxis of serious fungal and viral infections.

Abstract 606 Background: alloHCT is offered with curative intent to patients with hematologic malignancies, and conventionally-computed survival estimates are offered for prognosticating outcomes. However, conventionally-computed survival estimates do not take into account elapsed time (and changing hazards with time survived); conditional survival overcomes these limitations, by calculating the probability of survival after having already survived a certain period of time – such data are unavailable for alloHCT recipients. We describe cause-specific (relapse-, GvHD-, treatment-related) conditional survival after alloHCT, providing clinically relevant information for patients who have survived 6 mos, 1, 2, and 5y after alloHCT. Methods: From 1976 to 2006, 2,427 consecutive patients received alloHCT for a hematologic malignancy at a single institution (median age: 34.7y [0.6–72.5]). Vital status and cause of death were determined using National Death Index, Social Security Death Index and medical records. Results: As of 12/31/2007, a total of 1413 deaths (58% of the cohort) were observed; 39% attributed to recurrent disease; 34% to GvHD; 12% to infection; 5% to cardiopulmonary disease; 2% to subsequent malignant neoplasm (SMNs); and 8% to other causes. Conventionally-computed probability of survival was 44.6% at 5y and 41.2% at 10y from alloHCT. On the other hand, conditional on survival for 6 mo, 1, 2, and 5y after alloHCT, 5-y survival rates were 62%, 75%, 83%, and 93%, respectively (Figure A). The cohort was at a 40-fold increased risk of any death compared with the general population (95%CI=38.2–42.4); at a 25.6-fold increased risk of death due to pulmonary complications, 3.3-fold risk due to SMNs, and 2.3-fold risk due to cardiovascular complications. Among patients followed for 15+y after HCT, the risk of all-cause mortality was 2.6-fold that of the general population (95%CI=1.8–3.7). Standardized mortality ratios (SMR) and cause-specific conditional mortality rates by primary diagnosis are summarized in the Table. Individuals who survived the first 5y had negligible (≤5%) risk of relapse- and GvHD-related mortality over the subsequent 5y. Treatment-related mortality increased over time; among those who survived 5y, treatment-related mortality rates exceeded relapse-related mortality (Figure B). After adjustment for demographics, underlying diagnosis and treatment era, individuals with chronic GVHD (cGVHD) had a significantly lower risk of relapse-related mortality (RR=0.43, 95%CI=0.4–0.5) compared to those without cGVHD. Conclusions: The projected 5-y survival rates improve conditional on time survived from alloHCT; 5-y survival exceeds 93% for those who have already survived 5y. However, alloHCT recipients who have survived 15+y continue to remain at increased risk of death compared to the general population. cGVHD is associated with decreased risk of relapse-related mortality. Both relapse-related and GvHD-related mortality rates decline with time, such that, among those who have survived 5y, treatment-related mortality exceeds relapse-related mortality. Conditional survival estimates provide clinically relevant prognostic information, helping inform preventive and interventional strategies. Disclosures: No relevant conflicts of interest to declare.

Abstract 2399 The quality and depth of response particularly achievement of complete remission (CR) have been associated with significant improvement in progression free survival (PFS) and overall survival in multiple myeloma patients undergoing autologous stem cell transplant. Achievement of CR is considered a valid surrogate endpoint for survival in clinical trials for patients with multiple myeloma. We performed a phase II study investigating the role of sequential bortezomib/dexamethasone followed by thalidomide/dexamethasone as maintenance therapy post single autologous PSCT. The objectives were to examine the feasibility, toxicities, CR, PFS and overall survival rates. Within 4–8 weeks of autologous PSCT using melphalan 200mg/m2, pts received weekly bortezomib (bor) at 1.3mg/m2 /wk × 3 weeks with 1 week rest and dexamethasone (dex) at 40mg/d × 4 d for 6 months, followed by thalidomide (thal) at 50 –200mg/d and dexamethasone (dex) at 40mg/dx4 d for 6 more months. Single agent thalidomide was then continued until disease progression. Between March 2008 and June 2010, forty-five pts were enrolled. Median age was 54 years (29-71). Median time from diagnosis was 6.1 mo. (3.5 – 145.9). Disease stage at diagnosis; by Salmon-Durie (I/II/III 2/8/34/1 not available) and by ISS (I/II/III 18/14/8/ 5 not available). Pts received prior induction treatment with thal/dex (15), bortezomib based (27) and lenalidomide based regimens (10). Median B2M at enrollment was 1.8 mg/L (1.05 -5.3). Disease status at enrollment included complete remission (CR) (11), very good partial response (VGPR) (11), partial response (PR) (23). Six pts had chromosome 13 abnormalities (1 pt by karyotype and 5 pts by FISH), 2 pts had t 4;14 (one with concurrent ch 17 p del) and 3 pts had complex cytogenetic abnormalities. Results: Forty-five pts have been enrolled and undergone transplant. Five pts were unable to start planned maintenance therapy due to development of grade II or more neuro toxicities (4), and persistent thrombocytopenia (1) after PSCT. Thirty nine pts started maintenance bor/dex within 4–8 weeks of PSCT. One pt is too early for maintenance therapy. Twenty-five pts have completed the planned 6 months of bor/dex. Ten pts stopped bor/dex because of low WBC (2), PN (4), diagnosis of adrenal cancer (1), myocardial infarction (MI) (1), and relapse (2). Six pts are still receiving maintenance bortezomib. With a median F/U of 8.5 mo. (0.2 -24.0) twelve of 44 evaluable pts (27%) have achieved CR post PSCT and 17 of 33 evaluable pts (51%) have achieved CR after bor/dex on an intention to treat (ITT) analysis. Fifteen of 25 pts (60%) who have completed 6 months of bor/dex have achieved CR. Nine of 25 pts (36%) have upgraded their response with bor/dex. Eight pts (24%) could not complete bortezomib due to toxicities. At one year post PSCT fourteen of 28 evaluable pts (50%) remain in CR. Six pts have relapsed of whom 2 died of relapsed myeloma (leptomeningeal disease 1 pt). One pt experienced MI while receiving bortezomib (grade IV). Grade III toxicities have occurred in 17 pts; low platelet (1), asthenia (2), mood alteration (1), GI (severe constipation due to partial bowel obstruction on thalidomide) (1), skin rash (1), hyperglycemia (1), lymphopenia (10), sinus bradycardia (1), elevated triglyceride (1), DVT (1), low phosphate (3), leukopenia (1), edema (1). Sixteen pts had peripheral neuropathy (PN) grade I prior to start of bortezomib. Only 8 pts have developed new PN on the study and all are grade I-II. No patient has experienced grade III-IV PN. Median bortezomib dose is 1.3 mg /m2 per week. Conclusion: Prolonged weekly bortezomib maintenance therapy is well tolerated and can upgrade response post single autologous PSCT with no severe peripheral neuropathy. Fifty one percent of pts have achieved CR and 36% have upgraded their response after six months of bortezomib/dexamethasone therapy suggesting this is an active maintenance strategy post PSCT. Disclosures: No relevant conflicts of interest to declare.

The onset of jaundice after bone marrow transplantation most frequently is due to graft-vs-host disease of the liver or hepatic venoocclusive disease [1 ]. Recurrent leukemia forming a mass of leukemic cells, or chloroma, surrounding the intrahepatic biliary tree has not been reported before as a cause of jaundice after bone marrow transplantation. The radiologic findings of intrahepatic peribiliary chloroma are the subject of this report.

The survival of patients with acute leukemia who do not achieve a remission with primary therapy is very poor. High-dose chemoradiotherapy followed by allogeneic bone marrow transplantation (BMT) has been shown to be effective therapy for patients with acute and chronic leukemia. Therefore, we determined the long-term disease-free survival of patients who did not achieve a remission and were then treated with high-dose therapy and bone marrow allografting from matched sibling donors. Twenty-one patients (median age, 28 years) who did not achieve a remission with induction chemotherapy were subsequently treated with allogeneic BMT. After BMT, 90% achieved a complete remission. Six died of complications of the therapy, and six patients relapsed between 27 and 448 days after BMT. Nine patients (43%; median age, 25 years) are alive between 556 and 4,174 days after BMT. The cumulative probability of disease-free survival at 10 years is 43%. This study suggests that allogeneic BMT can be an effective therapy to achieve long-term control of acute leukemia, even in those patients who do not achieve a remission with primary therapy.

Acute lymphoblastic leukemia has a poor prognosis in adults, with a two-year survival rate of 35–40% despite aggressive therapy (American Cancer Society: Cancer Facts and Figures 2008 Atlanta, GA: American Cancer Society, 2008). Reduced-intensity allogeneic stem cell transplantation (SCT) relies mainly on graft versus leukemia (GVL) for its efficacy; however, the role of GVL in ALL is less well-defined. Between 5/7/02 and 6/15/07, 25 adult ALL patients were uniformly treated with fludarabine 25mg/m2 daily for 5 days and melphalan 140mg/m2 followed by ALLO-SCT using peripheral blood stem cells. The indications for the reduced intensity regimen were: ≥ 50 years (10 pts) (40%), decreased organ function (9 pts) (36%) and previous ALLO-SCT (6 pts) (24%). Patient demographics include: median age, 47 years (range, 23–68 yrs.), remission status at ALLO-SCT: first complete remission (CR) (12 pts) (48%), first relapse (3 pts) (12%), second CR (5 pts) (20%), >second CR (4 pts) (16%), induction failure (one pt) (4%), t(9;22) or Philadelphia positive (Ph+) ALL(9 pts) (36%). Donor source was matched sibling in 9 pts (36%), and matched unrelated in 16 pts (64%). Graft versus host disease (GVHD) prophylaxis: was cyclosporine (CSA)/+ mycophenylate (MMF) (3 pts) (12%), CSA/MMF/methotrexate (MTX) (8 pts) (32%), CSA/MMF/ATG (one pt) (4%), tacrolimus/sirolimus (7 pts) (28%) and tacrolimus/sirolimus/MTX (6 pts) (24%). With a median follow-up for surviving patients of 28.5 months (range: 12.8–72.5 months), the two year cumulative probability of overall survival and disease-free survival were both 59% (95% CI: 46–69.2%). The relapse rate was 16% (95% CI: 6.4,–37.4%),. Incidence of acute GVHD was 60% for grade II–IV and 20% for grade III–IV. Of the patients at risk for chronic GVHD, 8% developed limited chronic GVHD and 60% developed extensive chronic GVHD. The 100-day, one year and two year non-relapse mortality rates were 12% (CI: 4.6–29.3%), 24.2% (CI: 14–39.9%) and 29.3% (CI: 18.4–44.6%), respectively. There was no difference in survival outcomes based on donor source. The results of this study show that reduced intensity ALLO-SCT using fludarabine/melphalan based conditioning with primed peripheral stem cells from a matched related or unrelated donor provides a curative option for patients with high risk ALL who are not eligible for full intensity transplant. Figure Figure

7027 Background: The poor prognosis for sAML (prior MDS or leukemogenic therapy, i.e., tAML) relates to disease (unfavorable cytogenetics and multidrug resistance (MDR) phenotype) and patient (pt) ...

7065 Background: sAML portends a poor prognosis due to disease (unfavorable cytogenetics and multidrug resistance (MDR) phenotype) and patient (pt) characteristics (elderly w/comorbid illnesses). Amonafide, a topoisomerase II inhibitor, is not a substrate for the MDR efflux pump, P-glycoprotein (see Chau et al, ASCO 2007). Phase 1 trials of amonafide alone or together with ara-C reported a 50% CR rate (10/20) in pts with sAML (Allen et al, ASCO 2006). The dose-limiting toxicities of amonafide were manageable. Methods: In a Phase II trial pts with sAML (prior MDS or leukemogenic therapy, i.e., tAML) received amonafide 600 mg/m2/day on days 1–5 and CIV ara- C 200 mg/m2/day on days 1–7. A 2nd course could be given if day 14 marrow showed persistent leukemia. CR pts received either stem cell transplant or intermediate/high dose ara-C depending on age. An independent Data Safety Monitoring Board and central morphology review participated in the study. Primary endpoint was CR rate. Results: Enrollment has been completed. 44 % of 80 pts achieved CR. Details are available for the 1st 40 pts: median age 63 yrs (range 26 –87); prior MDS, 57%; tAML, 43%; unfavorable cytogenetics, 40%. 16/40 (40%) achieved CR (15 CR+1CRp). Subgroup CR analysis: MDS→AML without and with prior therapy for MDS (mostly azacytidine), 64% & 33%; tAML, 29%; intermediate and unfavorable cytogenetics, 58% and 18%; 10% pts were hypotension 23%, pneumonia 18%, dyspnea 13%, and diarrhea 13%. Data on all patients will be updated. Conclusions: Amonafide and ara-C is well tolerated in patients with poor prognosis sAML. A 64% CR was achieved in pts with untreated MDS→AML. Lower CR occurred with prior therapy for MDS, tAML and unfavorable cytogenetics. Age ≥60 yrs did not affect CR. Amonafide and ara-C may be a promising alternative for patients with sAML, especially those with over-expression of P-glycoprotein. No significant financial relationships to disclose.

Despite improvement in the proportion of patients achieving durable remission with dose intensive consolidation strategies, leukemic relapse still occurs in 40–70% of patients who achieve an initial remission. Studies utilizing ASCT for AML in CR1 have reported relapse free survival between 34–80% based on cytogenetic risk stratification. We report a 15 year experience of ASCT following high dose cytarabine (Ara-C) ± idarubicin (IDA) consolidation in 168 patients (intent to transplant, ITT) in CR1 treated between 3/89 and 6/03. The treatment consisted of a): consolidation with high dose Ara-C ± IDA followed by marrow (M) harvest (n=64) or collection of G-CSF primed stem cells (PSCs) (n=73), b) ASCT using FTBI 12Gy, Etoposide 60mg/kg, Cytoxan 75mg/kg (n=97) or Busulfan targeted to 1st dose AUC 700–900, FTBI 1200Gy and Etoposide 30mg/kg (n=40), and c) IL-2 9x106 IU/m2/24 hrs days 1–4 and IL-2 1.6 x 106 IU/m2/24 hrs days 9–18 beginning at hematologic recovery post ASCT (from 1995-present). Patient characteristics at ITT were median age 40.8 yr. (16.3–60.9); cytogenetics (SWOG criteria) favorable = 42(25%) (including 11 M3 pre 1993), intermediate=70(42%), unfavorable=16(10%), indeterminate and unknown=40(23%); WBC

We report a retrospective comparison of peripheral blood (PBSC) versus bone marrow derived stem cells for allogeneic transplant in a cohort of similarly treated patients based on eight year data from a single institution. Over the period 1995 to 2003, a total of 151 patients with AML or ALL in first CR underwent allogeneic matched sibling donor transplant, 98 AML patients and 53 with ALL. The source of stem cells was bone marrow in 69, G-CSF mobilized peripheral blood stem cells (PBSC) in 82. Of the AML patients, 40 (58%) received marrow, 58 (71%) received PBSC. Of the ALL patients, 29 (42%) received marrow, 24 (29%) got PBSC. The age of patients receiving marrow was 32.7 ± 13.6, and for those getting PBSC was 36.1 ± 16.1. The conditioning regimen was fully ablative (TBI/VP-16) in all but five patients (Fludarabine/Melphalan in 1 marrow and 4 PBSC pts). GVHD prophylaxis was with cyclosporine/methotrexate in patients receiving ablative conditioning, and CSP/MMF in the flu/mel patients. The time to achieving an ANC >1000 was significantly shorter (P value=.0001) in the PBSC group, 18.2 ±6.6 days vs. 27.2 ±48.7 in the marrow group. Time to achieving a platelet count greater than 25K was significantly shorter (P value=2x10−11) for the PBSC group, 20.9 ± 8.5 vs. 31.8 ± 11.2 for marrow. This was true as well for time to reach platelet counts greater than 100K (P value=10−8), 29.7 ± 28 days for PBSC, 55.8 ±55.6 for marrow. In fact there was a significant increase (P=.0001) in the number of patients, 29 (42%) of marrow recipients vs 11 (13%) of PBSC, who did not at any time achieve a platelet count of >100K. There was no significant difference in survival at 2 years or 4 years between marrow or PBSC-Kaplan-Meier survival probability at 2 and 4 years respectively for AML was.66 and.54 for marrow, and.67 and.54 for PBSC. In ALL, the 2 and 4 year K-M survival probability was.72 and.65 for marrow;.69 and.69 for PBSC recipients. There was no significant difference in acute GVHD, with grade I-II described in 19 (28%) of the marrow pts, 29 (35%) in the PBSC pts, and grade II-IV in 8 (12%) marrow pts and 11 (13%) receiving PBSC (p value =.57), or chronic GVHD (P value=.62). Interestingly, in a subset analysis of patients who were diagnosed with acute GVHD, there was a significant difference in disease free survival at 5 years (see graph), suggesting that there is a qualitative difference between acute GVHD observed as a result of bone marrow versus PBSC as a source of stem cells. Figure Figure

This is the first report of a successful bone marrow transplantation for chronic myelomonocytic leukemia. A 41-year-old woman with chronic myelomonocytic leukemia received, as primary treatment, a novel preparatory regimen consisting of high dose fractionated total body irradiation and high dose VP-16 chemotherapy followed by allogeneic marrow transplantation from her histocompatible brother. The patient is now more than two years after marrow transplantation with normal blood counts and a normal bone marrow which is of donor type. For younger patients with this disease who have a histocompatible sibling donor, bone marrow transplantation may represent a valid therapeutic option with curative potential.

During the past 10 years, 86 patients 30 to 54 years of age with hematologic malignancies were prepared with high-dose radiochemotherapy and received histocompatible bone marrow grafts. Thirty-four of these patients are surviving for 4 months to 9 years (median, 26 months) following marrow transplantation and 32 of them are in continuing complete remission (CR). Disease-free survival is 44% for 37 patients who were in first remission of acute leukemia or in the chronic phase of chronic granulocytic leukemia (CGL), 23% for 39 patients whose leukemia had relapsed at least once before transplantation or who had advanced stages of CGL, and 60% for ten patients who had hematologic malignancies other than leukemia. The median age of the surviving 34 patients is 36 years (range, 30 to 43 years). The incidence of moderate to severe acute graft-v-host disease (GVHD) was 48% and of chronic GVHD, 26%. The major causes of failure were interstitial pneumonia in 31 patients (24 of whom had antecedent acute GVHD) and recurrent leukemia in 12 patients (11 of whom had either never entered a CR or had relapsed at least once with acute leukemia or had progressive CGL before transplantation). Our data warrant further prospective studies in patients with hematologic malignancies who are older than 30 years.

Allogeneic bone marrow transplantation from histocompatible sibling donors was performed in six patients with extranodal involvement of high grade lymphoma during first complete remission. Five patients had lymphoblastic lymphoma and one had diffuse undifferentiated lymphoma. The cytoreductive/immunosuppressive regimen consisted of total body irradiation and high dose cyclophosphamide. Four patients are alive in complete remission at 8 months, 14 months, 21 months and 47 months post transplantation. One patient who relapsed 7 months after his initial transplantation underwent a second transplantation but another relapse 17 months later led to his death. One patient died of chronic graft-versus-host disease and at autopsy there was no evidence of lymphoma. These data demonstrate that allogeneic bone marrow transplantation can produce durable remissions in patients with high grade lymphoma who present with bone marrow, central nervous system and/or skin involvement.

Twenty patients (age range, 4 to 48 years; median age, 36 years) with de novo or drug-induced myelodysplastic syndromes or myeloproliferative disorders were treated with myeloablative immunosuppressive therapy followed by bone marrow transplantation (BMT). Four preparative regimens were used; three regimens consisted of combined total body irradiation (TBI) and chemotherapy and one of combination chemotherapy only. One patient received marrow from his identical twin brother, whereas the other 19 patients were grafted with marrow from histocompatible siblings. In 19 patients the abnormal clone was at least temporarily ablated, while in one patient the congenital myelodysplasia persisted. Eight patients are alive and well for +108 to +3,359 days post-transplantation. Nine patients died of transplant-related complications (six of interstitial pneumonia, two of gastrointestinal bleeding, and one of fungal sepsis) and three patients died with persisting or recurring disease. One patient with a late recurrence has undergone a second successful bone marrow transplant procedure. Outcome of BMT was not related to French-American-British (FAB) type, marrow fibrosis, cytogenetic abnormalities, or preparation regimen. Marrow transplantation as a means of providing long-term disease-free survival and possible cure should be considered in patients if a suitable donor is available.

In a phase I/II study, 47 patients (median age, 24 years) with hematologic malignancies (33 patients with acute leukemia not in first remission and 14 patients with other advanced malignant hematologic disorders) were treated with total body irradiation and high doses of etoposide (VP16–213) followed by bone marrow transplantation. At the time of analysis, 21 patients were alive, and 19 of them were in continued complete remission for 101 days to greater than 40 months (median, 12 months). The actuarial disease-free survival rate of the 33 acute leukemia patients is 43% (2 SEM, 18%) and the actuarial relapse rate is 32% (2 SEM, 20%). Five of the 14 patients with the other hematologic malignancies are alive, and four of them continue to be free of disease for 8 to 27 months. Pharmacokinetic studies established a strong correlation between the administered drug doses and their plasma levels and also demonstrated complete drug clearance prior to marrow grafting. An etoposide dose of 60 mg/kg body weight was found to be the maximum tolerated dose. This new preparatory regimen was well tolerated and was not associated with specific acute or long-term regimen-related toxicities. Our data suggest that total body irradiation with high-dose etoposide presents a viable alternative to other preparatory regimens. The role of this novel combination remains to be defined by future prospective randomized trials.

Fifty-five dogs with spontaneous tumors of varied histology were evaluated by platelet counts and 51Cr labeled autologous platelet survivals to determine if platelet hemostasis was altered. None of the dogs received cancer-directed therapy during the course of these studies. In 12 dogs with local tumors, platelet counts were 303,000/ul - 28,000 (normal 391,000/ul - 34,000, P > O.05), and platelet survival was 4.9 days - 0.2 (normal 5.6 days - 0.2, p < 0.05). In contrast, 23 dogs with metastatic tumor had platelet counts of 268,000/ul ± 26,000 (p < 0.005) and platelet survivals of 3.4 days ± 0.3 (p < 0.001). When the platelet survival was less than 4 days, the platelet count was also depressed with a correlation coefficient of 0.60.After baseline studies, 17 additional dogs with metastatic disease were treated with drugs (RA233 and sulfinpyrazone) that interfere with two different enzyme systems. Although there was some improvement in platelet survived in 6 of 9 dogs treated with RA233 or sulfinpyrazone alone (2.4 days ± 0.3 baseline vs. 3.5 days ± 0.4 treated, p < 0.05), platelet counts were not elevated (241,000/ul ± 54,000 baseline vs. 201,000/ul ± 46,000 treated). However, when the two drugs were given in combination to 8 other dogs, all had increased platelet survivals (2.7 days ± 0.4 baseline vs. 4.4 days ± 0.6 treated, p < 0.02), and this was associated with improved platelet counts in 6 of 8 (259,000/ul ± 46,000 baseline vs. 367,000/ul ± 47,000 treated, p < 0.05). Five had completely normal platelet survivalsThis study indicates that metastatic tumors, regardless of histology, are associated with significant platelet consumption resulting in depressed platelet counts. This consumption can be modified and platelet counts increased by treatment with a combination of two platelet active drugs that may act synergistically. We plan to determine whether similar treatment programs would maintain platelet counts and/or improve the survival of transfused platelets in human subjects with malignant disorders.

Acute myeloid leukemia (AML) remains the most common form of acute leukemia among adults and accounts for the largest number of annual deaths due to leukemias in the United States. The NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines) for AML provide recommendations on the diagnostic evaluation and workup for AML, risk assessment based on cytogenetic and molecular features, treatment options for induction and consolidation therapies for younger and older (age ≥ 65 years) adult patients, and key supportive care considerations.

We report the treatment outcome of allogeneic bone marrow transplantation in ten patients with Philadelphia chromosome-positive acute lymphoblastic leukemia. Six patients are alive and well for 6 to 30 months (median 19 months) after transplantation. Four patients died with transplant related complications. In view of the poor prognosis associated with this disease, marrow ablation followed by allogeneic or syngeneic marrow grafting may be the preferred treatment modality if a suitable marrow donor is available.