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High-risk relapsed or refractory (R/R) classical Hodgkin lymphoma (HL) is associated with poor outcomes after conventional salvage therapy and autologous hematopoietic cell transplantation (AHCT). Post-AHCT consolidation with brentuximab vedotin (BV) improves progression-free survival (PFS), but with increasing use of BV early in the treatment course, the utility of consolidation is unclear. CD25 is often expressed on Reed-Sternberg cells and in the tumor microenvironment in HL, and we hypothesized that the addition of 90Y-antiCD25 (aTac) to carmustine, etoposide, cytarabine, melphalan (BEAM) AHCT would be safe and result in a transplantation platform that is agnostic to prior HL-directed therapy. Twenty-five patients with high-risk R/R HL were enrolled in this phase 1 dose-escalation trial of aTac-BEAM. Following an imaging dose of 111In-antiCD25, 2 patients had altered biodistribution, and a third developed an unrelated catheter-associated bacteremia; therefore, 22 patients ultimately received therapeutic 90Y-aTac-BEAM AHCT. No dose-limiting toxicities were observed, and 0.6 mCi/kg was deemed the recommended phase 2 dose, the dose at which the heart wall would not receive >2500 cGy. Toxicities and time to engraftment were similar to those observed with standard AHCT, though 95% of patients developed stomatitis (all grade 1-2 per Bearman toxicity scale). Seven relapses (32%) were observed, most commonly in patients with ≥3 risk factors. The estimated 5-year PFS and overall survival probabilities among 22 evaluable patients were 68% and 95%, respectively, and non-relapse mortality was 0%. aTac-BEAM AHCT was tolerable in patients with high-risk R/R HL, and we are further evaluating the efficacy of this approach in a phase 2 trial. This trial was registered at www.clinicaltrials.gov as #NCT01476839.

INTRODUCTION: Despite advances in therapy for multiple myeloma, patients have continued to experience relapse. We sought to better understand this. OBJECTIVE: To identify factors that predict early relapse in patients with multiple myeloma who receive autologous hematopoietic peripheral stem cell transplant (HSCT). METHODS: Retrospective analysis of Kaiser Permanente Southern California patients who received HSCTs between 2008 and 2012. RESULTS: A total of 141 patients were included. Factors found to be associated with inferior progression-free survival were disease status less than complete response at the time of HSCT, no use of maintenance therapy after HSCT, International Staging System stage III, and high Freiburg Comorbidity Index. Disease status less than complete response, stage III, higher Freiburg Comorbidity Index, no use of maintenance therapy, and male sex were the most predictive factors for early relapse (< 18 months). DISCUSSION: Our results identified a subgroup of high-risk individuals with multiple myeloma who will continue to do poorly after HSCT with the best available treatment using a combination of proteasome inhibitors and immunomodulatory drugs. These results highlight the need for consideration of alternative therapy in such instances.

Purpose/Objective(s) Allogeneic hematopoietic cell transplantation (alloHCT) offers the highest curative rate for AML with intermediate or high-risk cytogenetics in remission. GvHD is a main cause of alloHCT mortality and morbidity. This trial evaluated the feasibility of a novel conditioning regimen of total marrow and lymphoid irradiation (TMLI) at 20 Gy combined with post-transplant cyclophosphamide (PTCy), which was designed to reduce the chronic GvHD risks using PTCy and reduce relapse rates with TMLI, thereby improving GRFS rates compared to standard myeloablative conditioning regimens. Materials/Methods Eighteen patients with AML in first or second complete remission were treated with TMLI 20 Gy (2 Gy twice daily) to bone, lymph nodes and spleen (liver and brain 12 Gy) on days -4 to 0; stem cell infusion on day 0; PTCy 50 mg/kg/day on days +3 and +4; and tacrolimus 1 mg continuous infusion on days +5 to +90. Endpoints included toxicity, GRFS at 1 year, engraftment, overall survival (OS), and non-relapse mortality (NRM). GRFS was defined as grade 3-4 acute GvHD (aGvHD), chronic GvHD (cGvHD) requiring systemic treatment, relapse, or death (from any cause). Results The median age was 40 (range 19-56). Seventeen of 18 patients had intermediate to high-risk cytogenetics. The average (range) Dmean organ doses (Gy) were lungs 8.1 (7.5-9.5), kidneys 7.5 (6.3-9.2), heart 7.3 (6.6-8.3), oral cavity 4.4 (3.0–6.7), esophagus 6.4 (4.7-7.6), upper GI 9.1 (7.3-12.0), lower GI 10.2 (8.9-12.1), and bladder 10.0 (6.8-14.6). Median follow-up was 12.5 months (range 5.9 to 25.4) for surviving patients (n = 17). All patients engrafted. Bearman toxicity data were available for all patients. Grade 2 toxicities were bladder (n = 3) and stomatitis (n = 1). No grade 3-4 toxicities or toxicity-related deaths were observed. aGvHD developed in 2 patients with grade III-IV in only 1 patient (100-day Grade III-IV aGvHD: 5.6%, 95% CI: 0.3-23.1). Five patients developed chronic GvHD with one patient developing moderate to severe cGVHD (1-year cGvHD rate: 28.6%, 95% CI: 7.5%-54.7%). The GRFS rate at 1 year was 60.6% (95% CI: 34.6-79.0). One-year estimates of OS and relapse-free survival were 100% and 83.3% (95% CI: 62.8-96.1), respectively. Disease relapse at 1 year was 16.7% (95% CI: 3.9-37.2). The estimates of NRM at 100 days and 1 year were both 0%. Relapsed disease after transplant occurred in 3 patients (16.7%). One patient died after relapse. Conclusion This TMLI 20 Gy only conditioning regimen, together with PTCy and tacrolimus, is associated with low toxicity and NRM. All patients achieved engraftment. Participants with ≥ 1-year follow-up have discontinued immunosuppressive therapy. The results suggest an improved GRFS rate compared to traditional myeloablative regimens reported. A larger phase II trial is planned.

Background: Blinatumomab, a bispecific anti-CD19/CD3 antibody, demonstrated single-agent efficacy with 42% CR/CRh in R/R B-ALL. Upregulation of immune inhibitory molecules has been shown to confer resistance to blinatumomab. Here, we set out to test the combination of pembrolizumab and blinatumomab in a phase 1/2 trial (NCT03512405). Methods: Pts [≥18 years old (yo); ECOG Results: As of February 1, 2021, 7 pts were enrolled to phase 1, with one unevaluable. Six treated and evaluable pts received a median of 2 (1–5) cycles of treatment. At baseline, the median age was 51 yo (29–74) with median 2 (2–4) prior lines of regimens and median 29% (0–83) BM blasts. Two pts had extramedullary disease. In cycle 1, all 6 pts experienced grade (gr) 1–2 cytokine release syndrome. Neurologic toxicities were all reversible with only 1 ≥ gr3 AE. All-non-hematologic gr3 toxicities, were reversible. No dose-limiting toxicity, ≥ gr4 non-hematologic toxicity, or treatment-related deaths were seen. Five of 6 evaluable pts (83%) achieved MRD-negative CR after a median of 1 (1–2) cycle. Three pts in CR received alloHCT, all engrafted. With a median follow-up of 2.8 (1.1–9.6) months, 4 CRs are ongoing (1 post-transplant), and 5 of 6 pts are still alive at the data cut-off. Conclusions: The combination of pembrolizumab and blinatumomab in phase 1 of this study in pts with B-ALL was deemed safe with a manageable side effect profile and encouraging anti-leukemic activity. The study is now open for phase 2 with the primary objective of overall response rate.

Background: Allogeneic hematopoietic cell transplantation (alloHCT) is the approach that offers the highest curative rate for acute myelogenous leukemia (AML) with intermediate or high-risk cytogenetics. Graft versus host disease (GvHD) has remained the main cause of post-transplantation mortality and morbidity, despite advances in prophylaxis and therapy, adding significant economic burden and affecting quality of life. It would be desirable to reduce the rate of GvHD among patients in complete remission (CR) without increasing the risk of relapse. In this study, we have developed a novel conditioning regimen of total marrow and lymphoid irradiation (TMLI) at 2000 cGy, together with post-transplant cyclophosphamide (PTCy), to 1) reduce the possibly increased risk of relapse from PTCy, by using escalated radiation doses of TMLI, as increasing radiation doses has the potential to decrease the post-transplantation relapse rate (Blood, vol 76, pp. 1867-1871, 1990); and 2) reduce the risk of chronic GvHD by using PTCy. The major goal of this pilot study of TMLI and PTCy (clinicaltrials.gov: NCT03467386), was to thus improve GvHD-free/relapse-free survival (GRFS), reported to be 45% from total body irradiation (TBI) and tacrolimus/sirolimus prophylaxis (BBMT, vol 26(2), pp. 292-299, 2020), in patients with AML in remission. Patients and Methods: A total of 18 patients were enrolled and treated (see Table) between March 2018 and December 2019. Key criteria were ages 18 to 60, first or second CR, minimal residual disease negative by multi-color flow cytometry, and normal organ function. TMLI was administered on days -4 to 0 without addition of chemotherapy. The radiation dose for all patients (n=18) was 2000 cGy, delivered in 200 cGy fractions twice daily. The radiation dose delivered to the liver and brain was kept at 1200 cGy. Remaining organs were considered non-targeted. All patients received peripheral blood stem cells on day 0. Cyclophosphamide was given on days +3 and +4, 50 mg/kg each day for GVHD prevention. Tacrolimus, 1 mg continuous infusion adjusted to maintain levels from 5 to 10 ng/mL was given from day +5 to day +90, and G-CSF 5 µg/kg daily was administered at day +5 until recovery of neutrophil counts. Endpoints included toxicity, GRFS at 1 year, engraftment, overall survival (OS), and non-relapse mortality (NRM). Toxicities were defined according to the Bearman and CTCAE 4.03 scales, the latter for hematologic toxicity. A patient safety lead-in segment (n=6) was conducted to ensure that there were no unexpected toxicities, allowing for a dose de-escalation to 1800 cGy. GRFS was defined as grade 3-4 acute GvHD, chronic GvHD requiring systemic treatment, relapse, or death (from any cause), whichever occurred first. Results: Bearman toxicity data are available for all patients. Among these patients, grade 2 toxicities were bladder toxicity and stomatitis. No grade 3-4 toxicities or toxicity-related deaths were observed. Acute GVHD (aGVHD) developed in 2 of patients (100-day Grade II-IV aGVHD: 11.1%, 95%CI: 1.7-30.4); of those, only 1 patient developed Grades III-IV (100-day Grade III-IV aGVHD: 5.6%, 95%CI: 0.3-23.1). Five patients developed mild chronic GVHD (1-year cGVHD rate: 28.6%, 95%CI: 7.5%-54.7%). The GRFS rate at 1 year was 59.3% (95% CI: 28.8-80.3) (Figure). The median follow up was 11.3 months (range 4.7 to 25.4) for surviving patients (n=17). All patients engrafted. Time to neutrophil and platelet recovery were 14 days (range 13-32 days) and 20 days (range 11-49 days), respectively. One-year estimates of OS and relapse-free survival were 100% and 80.8% (95% CI: 50.5-93.6), respectively (Figure). Disease relapse at 1 year was 19.2% (95% CI: 4.1-42.6). The estimates of NRM at 100 days and 1 year were both 0%. Relapsed disease after transplant occurred in 3 patients (16.7%). One patient died after relapse. Conclusions: 1) This chemotherapy-free conditioning regimen, together with PTCy and tacrolimus, is safe and feasible, with no NRM. 2) All patients achieved engraftment. 3) Participants with ≥1 year follow-up have discontinued immunosuppressive therapy, reducing financial burden and leading to improved quality of life. The preliminary results suggest an improved GRFS rate. A larger phase 2 trial is in preparation to corroborate these data. Disclosures Stein: Amgen: Consultancy, Speakers Bureau; Stemline: Consultancy, Speakers Bureau. Al Malki:Neximmune: Consultancy; Jazz Pharmacuticals, Inc: Consultancy; Rigel Pharma: Consultancy. Ali:Incyte Corporation: Consultancy. Aribi:Seattle Genetics: Consultancy. Marcucci:Novartis: Speakers Bureau; Takeda: Other: Research Support (Investigation Initiated Clinical Trial); Pfizer: Other: Research Support (Investigation Initiated Clinical Trial); Abbvie: Speakers Bureau; Merck: Other: Research Support (Investigation Initiated Clinical Trial); Iaso Bio: Membership on an entity's Board of Directors or advisory committees. Nakamura:Alexion: Other: Support on a meeting presentation; Kyowa-Kirin: Other: Support on a meeting presentation; Merck: Other: advisory board meeting; Celgene: Other: Support on seminar; Magenta Therapeutics: Other: Advisory board meeting; Viracor: Consultancy; Kadmon Corporation: Other: Advisory board meeting; NapaJen Pharma: Consultancy. Pullarkat:AbbVie, Inc.: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Genetech: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Pfizer: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Jazz Pharmaceuticals: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Novartis: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Servier: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Dova: Consultancy, Honoraria; Amgen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau. Salhotra:Celgene: Research Funding; Kadmon: Membership on an entity's Board of Directors or advisory committees.

Standard-dose 90yttrium-ibritumomab tiuxetan (.4 mci/kg) together with high-dose BEAM (BCNU, etoposide, cytarabine, and melphalan) (Z-BEAM) has been shown to be a well-tolerated autologous hematopoietic stem cell transplantation preparative regimen for non-Hodgkin lymphoma. We report the outcomes of a single-center, single-arm phase II trial of Z-BEAM conditioning in high-risk CD20+ non-Hodgkin lymphoma histologic strata: diffuse large B cell (DLBCL), mantle cell, follicular, and transformed. Robust overall survival and notably low nonrelapse mortality rates (.9% at day +100 for the entire cohort), with few short- and long-term toxicities, confirm the safety and tolerability of the regimen. In addition, despite a high proportion of induction failure patients (46%), the promising response and progression-free survival (PFS) rates seen in DLBCL (3-year PFS: 71%; 95% confidence interval, 55 to 82%), support the premise that the Z-BEAM regimen is particularly effective in this histologic subtype. The role of Z-BEAM in other strata is less clear in the context of the emergence of novel agents.

Therapy-related myelodysplastic syndrome is a long-term complication of cancer treatment in patients receiving cytotoxic therapy, characterized by high-risk genetics and poor outcomes. Allogeneic hematopoietic cell transplantation is the only potential cure for this disease, but the prognostic impact of pre-transplant genetics and clinical features has not yet been fully characterized. We report here the genetic and clinical characteristics and outcomes of a relatively large cohort of patients with therapy-related myelodysplastic syndrome (n=67) who underwent allogeneic transplantation, comparing these patients to similarly treated patients with de novo disease (n=199). The 5-year overall survival was not different between patients with therapy-related and de novo disease (49.9% versus 53.9%; P=0.61) despite a higher proportion of individuals with an Intermediate-2/High International Prognostic Scoring System classification (59.7% versus 43.7%; P=0.003) and high-risk karyotypes (61.2% versus 30.7%; P

Chronic graft-versus-host disease (cGVHD) continues to be a major complication after allogeneic hematopoietic cell transplantation, significantly affecting patients' quality of life. A regimen of systemic corticosteroids is considered first-line therapy but is often associated with inadequate responses and multiple side effects. In patients with refractory disease, an evidenced-based consensus is lacking as to the single best approach to managing symptoms. Ruxolitinib, a selective JAK1/2 inhibitor, has recently gained favor as a second-line approach in patients with steroid-refractory cGVHD. In this retrospective study, we evaluated the outcomes of 46 patients who received ruxolitinib for cGVHD between March 2016 and December 2017 at our institution, and evaluated ruxolitinib's impact at 6 and 12 months, based on the National Institutes of Health Severity Scale, including organ-specific responses, and mean prednisone dose. Furthermore, we present the first reported probability of ruxolitinib's treatment failure-free survival (FFS) in patients with cGVHD. After 12 months of ruxolitinib therapy, complete response, partial response, and stable disease was observed in 13% (n = 6), 30.4% (n = 14), and 10.9% (n = 5) of patients, respectively. The 1-year probability of FFS was 54.2% (95% confidence interval, .388 to .673), and ruxolitinib use was associated with a reduction in prednisone dose. In conclusion, our data, which represent the largest cohort of patients with cGVHD reported to date, support the use of ruxolitinib for cGVHD refractory to steroids and currently available salvage therapies, discontinued due to lack of response and high cost.

The purpose of this study is to assess the impact of palifermin on oral mucositis (OM) and its sequelae in patients undergoing allogeneic hematopoietic stem cell transplantation (allo-HSCT) who were conditioned with fractionated total body irradiation (FTBI) and etoposide. This retrospective chart review study compared the effect of palifermin on the development of OM in patients who received this agent during an allo-HSCT (n = 99) to those who did not (n = 30). The primary end points were severity and duration of OM. Secondary end points included requirements for opioids, total parenteral nutrition (TPN), and intensive oral care; incidence of infection; length of hospital stay; and overall survival. There was no significant difference in the incidence of all grades of OM, but incidence of severe OM was decreased in palifermin-exposed patients (34 vs 80 %, p

Current conditioning regimens provide insufficient disease control in relapsed/refractory acute leukemia patients undergoing hematopoietic stem cell transplantation (HSCT) with active disease. Intensification of chemotherapy and/or total body irradiation (TBI) is not feasible because of excessive toxicity. Total marrow and lymphoid irradiation (TMLI) allows for precise delivery and increased intensity treatment via sculpting radiation to sites with high disease burden or high risk for disease involvement, while sparing normal tissue. We conducted a phase I trial in 51 patients (age range, 16 to 57 years) with relapsed/refractory acute leukemia undergoing HSCT (matched related, matched unrelated, or 1-allele mismatched unrelated) with active disease, combining escalating doses of TMLI (range, 1200 to 2000 cGy) with cyclophosphamide (CY) and etoposide (VP16). The maximum tolerated dose was declared at 2000 cGy, as TMLI simulation studies indicated that >2000 cGy might deliver doses toxic for normal organs at or exceeding those delivered by standard TBI. The post-transplantation nonrelapse mortality (NRM) rate was only 3.9% (95% confidence interval [CI], .7 to 12.0) at day +100 and 8.1% (95% CI, 2.5 to 18.0) at 1 year. The cumulative incidence of grades II to IV acute graft-versus-host disease (GVHD) was 43.1% (95% CI, 29.2 to 56.3) and for grade III and IV, it was 13.7% (95% CI, 6.9 to 27.3). The day +30 complete remission rate for all patients was 88% and was 100% for those treated at 2000 cGy. The overall 1-year survival was 55.5% (95% CI, 40.7 to 68.1). The TMLI/CY/VP16 conditioning regimen is well tolerated at TMLI doses up to 2000 cGy with a low 100-day and 1-year NRM rate and no increased risk of GVHD with higher doses of radiation.

The prevalence of vancomycin-resistance Enterococci colonization (VRE-C) in patients undergoing allogeneic hematopoietic cell transplantation (aHCT) is between 23-40%. Pre-HCT VRE-C is shown to be associated with high risks of VRE bloodstream infection (VRE-BSI), non-relapse mortality (NRM) and lower overall survival. Recent studies investigating the association between VRE-C and risk of acute graft-versus-host disease (aGVHD) after aHCT has demonstrated conflicting results, possibly due to the heterogeneous transplant conditioning and GVHD prophylactic regimens. Here, we sought to examine the VRE-C prevalence and determine its impact on aHCT outcomes, in patients receiving tacrolimus and sirolimus (T/S) as aGVHD prophylaxis. To explore the association between pre-HCT VRE-C and transplant outcomes, we retrospectively reviewed medical records of a cohort of 1074 consecutive patients who underwent aHCT at City of Hope from 2014 to 2017. Patients with stool culture screening within 30 days pre-aHCT (n=862) were identified from the microbiology database and were grouped as VRE-C and non-colonized (VRE-NC). Data was not available on VRE-C in 185 patients and they were not included in analysis. Overall survival (OS) and progression-free survival (PFS) were examined by Kaplan-Meier curves and log-rank tests. Non-relapse mortality (NRM), VRE-BSI, and GVHD rates of the 2 groups were compared by cumulative incidence rates and Gray's test. Multivariate analyses were performed when adjusting for prognostic factors. Two-sided P value of ≤0.05 was considered significant. Of the 862 evaluated patients, 68 had VRE-C (7.9% prevalence). Median age of patients in VRE-C and VRE-NC groups were 53 and 55 years, respectively. Gender distribution, transplant indications, stem cell source, proportion of unrelated donors, GVHD prophylaxis with T/S and other clinical variables including intensity of conditioning regimen and HCT-CI were similar between the two groups (Table 1) . Karnofsky performance status (KPS) of 90-100 and 70-80 were seen in 40% and 53% of patients with VRE-C compared to 47% and 48% of VRE-NC patients (p=0.12). Overall, VRE-BSI episodes were rare (n=7) with 4 patients in VRE-C (6.1%) and 3 patients in VRE-NC (0.4 %); p At a median follow-up duration of 19.4 months (range: 2.7-48.4), similar 1-year OS was achieved in both groups (67.4% in VRE-C and 76.5% in VRE-NC; p=0.11) but 1 year PFS was significantly lower in the VRE-C cohort (55.6% Vs. 69.4%; p=0.038). Higher NRM was achieved in the VRE-C cohorts on days +100 and +365 (11.8% Vs. 7.2% and 25.1% Vs. 14.4%, respectively, p=0.041). (Figure 1) There were no differences in rates of day 100 aGVHD (grades II-IV) (Figure 2) and relapse rates at 12 months between the two groups. Conditioning regimen intensity, donor type, KPS, and primary diagnosis were significantly associated with NRM. When these variables were included in the multivariate model, VRE-C was found to be independently associated with higher NRM (HR=1.82, 95%CI: 1.12-2.93; p=0.015). In conclusion, in our cohort of patients receiving predominantly T/S-based aGVHD prophylaxis, no association was detected between VRE-C and aGVHD incidence. Higher rate of VRE-BSI in the VRE-C group is in accordance with published data, albeit lower rates of VRE-BSI was seen in our cohort. VRE-C contributed to higher NRM at days 100 and 365 post-aHCT and was an independent risk factor for poor HCT outcomes Since VRE-C is a potentially modifiable risk factor, our data supports continued efforts for specific interventional strategies (i.e. antimicrobial stewardship) to reduce drug resistant bacterial colonization, and for clinical research to reverse the impact of VRE-C, such as the use of agents, which may modulate gut microbiome. Disclosures Salhotra: Kadmon Corporation, LLC: Consultancy. Ali:Incyte Corporation: Membership on an entity's Board of Directors or advisory committees. Stein:Amgen Inc.: Speakers Bureau; Celgene: Speakers Bureau. Forman:Mustang Therapeutics: Other: Licensing Agreement, Patents & Royalties, Research Funding. Dadwal:AiCuris: Research Funding; Gilead: Research Funding; MERK: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Shire: Research Funding.

Purpose: To establish feasibility, maximum tolerated dose (MTD), and potential efficacy of ablative dose total marrow irradiation (TMI) delivered by helical tomotherapy in patients with multiple myeloma (MM). Experimental Design: Patients with responding or stable MM received tandem autologous stem cell transplants, first with melphalan 200 mg/m2, and 60 days or later with TMI. TMI doses were to be escalated from 1,000 cGy by increments of 200 cGy. All patients received thalidomide and dexamethasone maintenance. Results: Twenty-two of 25 enrolled patients (79%) received tandem autologous stem cell transplantation (TASCT): TMI was administered at a median of 63.5 days (44–119) after melphalan. Dose-limiting toxicities at level 5 (1,800 cGy) included reversible grade 3 pneumonitis, congestive heart failure, and enteritis (1), and grade 3 hypotension (1). The estimated median radiation dose to normal organs was 11% to 81% of the prescribed marrow dose. Late toxicities included reversible enteritis (1), and lower extremity deep venous thrombosis during maintenance therapy (2). The complete and very good partial response rates were 55% and 27% following TASCT and maintenance therapy. At a median of 35 months of follow-up (21–50+ months), progression-free and overall survival for all patients were 49% (95% CI, 0.27–0.71) and 82% (0.67–1.00). Conclusion: Ablative dose TMI as part of TASCT is feasible, and the complete response rate is encouraging. Careful monitoring of late toxicities is needed. Further assessment of this modality is justified at the 1,600 cGy MTD level in MM patients who are candidates for ASCT. Clin Cancer Res; 17(1); 174–82. ©2010 AACR.

Purpose This phase II trial evaluated the safety and efficacy of combining yttrium-90 (90Y) ibritumomab tiuxetan with high-dose carmustine, cytarabine, etoposide, and melphalan (BEAM) and autologous stem-cell transplantation in patients with non-Hodgkin's lymphoma who were considered ineligible for total-body irradiation because of older age or prior radiotherapy. Patients and Methods Between May 2002 and January 2006, 14 days before autologous stem-cell transplantation, 41 patients with non-Hodgkin's lymphoma received standard-dose 90Y ibritumomab tiuxetan (14.8 MBq/kg [0.4 mCi/kg]) followed by high-dose BEAM. Results The median age was 60 years (range, 19 to 78 years), and the median number of previous therapies was two (range, one to six). Disease histologies were diffuse large B-cell (n = 20), mantle cell (n = 13), follicular (n = 4), and transformed lymphoma (n = 4). With a median follow-up of 18.4 months (range, 5.5 to 53.3 months) the estimated 2-year overall and progression-free survival were 88.9% (95% CI, 75.3% to 95.2%) and 69.8% (95% CI, 56.4% to 79.7%). The median time to WBC engraftment was 11 days (range, 9 to 26 days) and time to platelet engraftment was 12 days (range, 3 to 107 days). Adverse events were similar to those seen historically with high-dose BEAM alone, and included grade 3 or 4 pulmonary toxicity in 10 patients. Conclusion Adding 90Y ibritumomab tiuxetan to high-dose BEAM with autologous stem-cell transplantation is feasible and has a toxicity and tolerability profile similar to that observed with BEAM alone. Rates of progression-free survival seen in these patients are promising and warrant additional study.

A double-blind, randomized trial showed that, compared with placebo, palifermin (recombinant human keratinocyte growth factor) reduced the frequency and duration of oral mucositis in patients with hematologic malignancies undergoing high-dose chemotherapy and total-body irradiation with autologous stem-cell support. This previously published study also showed a significant reduction in the incidence of adverse subsequent outcomes. The objective of this study was to estimate the impact of palifermin prophylaxis on hospital costs of transplantation in the trial. This was a retrospective, economic analysis of estimated costs for a previously published clinical trial. Costs were not collected during the trial. Therefore, we estimated the direct medical costs of hospitalization using hospital charges from similar patients' hospitalization charges selected from the National Inpatient Sample, a population-based, nationally representative sample of hospital claims. Costs were estimated from charges using Medicare's state-specific cost-to-charge ratios. These cost estimates were applied to the outcome data (incidence of febrile neutropenia, bacteremia/fungemia, or pneumonia, and use of total parenteral nutrition) from the clinical trial. Patients were those with hematologic malignancies who received high-dose chemotherapy and total-body irradiation with autologous stem cell transplant. We compared the estimated total hospital costs (in 2005 United States dollars) incurred by patients who received palifermin in the clinical trial with those incurred by patients who received placebo. Costs were analyzed from the provider's perspective. The mean cost of a hospital day in this population varied between $2,834, when no adverse outcomes occurred, and $4,663, when all 4 outcomes occurred. Reductions in adverse outcomes and their associated hospital stay offset the acquisition price of palifermin. A nonsignificant mean savings of $3,595 per patient (95% confidence interval: $2,090-$5,103) was observed. In sensitivity analyses, this observation was robust to all plausible values of per diem hospital costs and hypothetic per diem outpatient costs. In addition to its previously demonstrated clinical benefit, palifermin prophylaxis offers a favorable economic profile among patients with hematologic malignancies who receive total body irradiation and autologous stem cell support.

We conducted a phase 1/2 trial of high-dose 90Y-ibritumomab tiuxetan in combination with high-dose etoposide (VP-16) 40 to 60 mg/kg (day -4) and cyclophosphamide 100 mg/kg (day -2) followed by autologous stem cell transplantation (ASCT) in 31 patients with CD20+ non-Hodgkin lymphoma (NHL). Patients underwent dosimetry (day -21) with 5 mCi (185 MBq) 111In-ibritumomab tiuxetan following 250 mg/m2 rituximab, followed a week later by 90Y-ibritumomab tiuxetan to deliver a target dose of 1000 cGy to highest normal organ. Bone marrow biopsy was done on day -7 to estimate radiation dose and stem cells were reinfused when the radiation dose was estimated to be less than 5 cGy. The median 90Y-ibritumomab tiuxetan dose was 71.6 mCi (2649.2 MBq; range, 36.6-105 mCi; range, 1354.2-3885 MBq). Histology included follicular lymphoma (n = 12), diffuse large B-cell (n = 14), and mantle cell (n = 5). The median number of prior chemo-therapy treatments was 2. The treatment was well tolerated. The median times to reach an absolute neutrophil count greater than 500/μL and platelet count more than 20 000/μL were 10 days and 12 days, respectively. There were 2 deaths and 5 relapses. At a median follow-up of 22 months, the 2-year estimated overall survival and relapse-free survival rates are 92% and 78%, respectively. We conclude that high-dose 90Y-ibritumomab tiuxetan can be combined safely with high-dose etoposide and cyclophosphamide without an increase in transplant-related toxicity or delayed engraftment. (Blood. 2005;106:2896-2902)

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.

Balanced translocations are rare in myelodysplasia (MDS) and acute myeloid leukemia (AML) with multilineage dysplasia; however, the t(3;5)(q25;q35) and insertion variant occur in a subset of patients. To evaluate the possible genes involved in this translocation, we studied 6 cases with a t(3;5) by fluorescence in situ hybridization with probes directed against the nucleophosmin (NPM), EVI1, and Ribophorin genes, as well as a newly developed myeloid leukemia factor 1 (MLF1) BAC clone. The histologic spectrum of the cases was variable, ranging from refractory cytopenia with multilineage dysplasia to AML with multilineage dysplasia in the World Health Organization classification. An NPM/MLF1 fusion was identified in 5 of 6 cases, whereas the EVI1 and Ribophorin genes were not involved in any of the cases. The NPM/MLF1-positive cases were predominantly young adult males (median age, 33 years) who responded well to hematopoietic stem cell transplantation. These findings suggest that an NPM/MLF1 fusion is the primary molecular abnormality in t(3;5) MDS and AML with multilineage dysplasia, and also that cases with NPM/MLF1 may be clinically distinct from other MDS-associated disease.

Purpose: To determine the disease-free survival (DFS) and toxicity of administering interleukin-2 (IL-2) immunotherapy early after autologous stem-cell transplantation (ASCT) to simulate a graft versus leukemia effect observed in allogeneic transplantation. Patients and Methods: Fifty-six patients with acute myeloid leukemia in first remission received a single consolidation of high-dose cytarabine-idarubicin at a median of 1.1 month postremission with the intent to proceed to ASCT and IL-2 9 × 106 U/m2/24 h for 4 days, followed by 10 days of IL-2 1.6 × 106 U/m2/24 h on hematologic recovery. Results: Eighty-four percent of patients received the intended ASCT, and 68% of patients received IL-2 treatment. With a median follow-up of 39.4 months (range, 1.2 to 76.3 months), the 2-year cumulative probability of DFS for all 56 patients is 68% (95% confidence interval [CI], 55% to 80%) and 74% (95% CI, 57% to 85%) for the 39 patients undergoing IL-2 treatment after ASCT. The 2-year cumulative probability of DFS for favorable, intermediate, and unfavorable cytogenetics is 88% (95% CI, 59% to 97%), 48% (95% CI, 26% to 67%), and 70% (95% CI, 23% to 93%), respectively. Toxicities from IL-2 were mainly thrombocytopenia, leukopenia, fever, and fluid retention. Two septic deaths occurred during neutropenia, which includes one during consolidation and one during transplant, for an overall 4% mortality rate. Conclusion: These results suggest that a moderate dose of IL-2 after high-dose cytarabine-idarubicin–mobilized ASCT is associated with a low regimen-related toxicity and may improve DFS. A phase III study of IL-2 is now warranted.

MSL-109 is a monoclonal antibody specific to the cytomegalovirus (CMV) glycoprotein H with high neutralizing capacity. In a prospective, randomized, double-blind study, allogeneic hematopoietic stem cell transplantation (HSCT) recipients with positive donor and/or recipient serology for CMV before transplantation received either 60 mg/kg MSL-109 (n = 59), 15 mg/kg MSL-109 (n = 60), or placebo (n = 60) intravenously every 2 weeks from day -1 until day 84 after transplantation. CMV pp65 antigenemia, CMV-DNA load in plasma, and viremia by culture were tested weekly. Primary end points were development of pp65 antigenemia at any level and/or viremia for which ganciclovir was given. There was no statistically significant difference in CMV pp65 antigenemia or viremia among patients in the 60-mg group (pp65 antigenemia, 47%; viremia, 15%), the 15-mg group (52%; 23%), and the placebo group (45%; 17%). There was also no difference in maximum levels of pp65 antigenemia, time to clearance of pp65 antigenemia after start of ganciclovir, CMV disease, invasive bacterial and fungal infections, time to neutrophil and platelet engraftment, acute graft-versus-host disease, days of hospitalization, and overall survival rate among the 3 groups. However, a subgroup analysis of CMV-seronegative recipients with a seropositive donor (D+/R-) showed a transiently improved survival rate by day 100 in MSL-109 recipients (mortality: 60-mg group, 1/13; 15-mg group, 1/12; placebo group, 6/10 [P = .02 for 60-mg versus placebo groups; P = .08 for 15-mg versus placebo groups]); by the end of follow-up, the difference was no longer statistically significant. The improved survival rate in D+/R- patients could not be attributed to a reduction in CMV disease; however, MSL-109 was associated with improved platelet engraftment and less grade III to IV acute graft-versus-host disease in this subgroup. In a subgroup analysis of CMV-seropositive recipients of MSL-109 (D+/R+ and D-/R+), overall mortality was increased compared to that of the placebo group (P = .12 for the 60-mg versus placebo groups, P = .05 for the 15-mg versus placebo groups, and P = .04 for the dose levels combined versus placebo). MSL-109 was well tolerated and no immune response to the drug was observed. Thus, MSL-109 was safe but did not reduce CMV infection in allogeneic HSCT recipients. The transient survival advantage seen early after transplantation in CMV D+/R- patients and the negative effect on survival in seropositive patients remain unexplained. Thus, there is no evidence that MSL-109 is beneficial in CMV-seropositive HSCT recipients.

We analyzed data on 612 patients who had undergone high-dose chemoradiotherapy (HDT) with autologous stem cell rescue for Hodgkin's disease (HD) and non-Hodgkin's lymphoma (NHL) at the City of Hope National Medical Center, to evaluate the incidence of therapy-related myelodysplasia (t-MDS) or therapy-related acute myeloid leukemia (t-AML) and associated risk factors. A retrospective cohort and a nested case-control study design were used to evaluate the role of pretransplant therapeutic exposures and transplant conditioning regimens. Twenty-two patients developed morphologic evidence of t-MDS/t-AML. The estimated cumulative probability of developing morphologic t-MDS/t-AML was 8.6% +/- 2.1% at 6 years. Multivariate analysis of the entire cohort revealed stem cell priming with VP-16 (RR = 7.7, P = 0.002) to be independently associated with an increased risk of t-MDS/t-AML. The influence of pretransplant therapy on subsequent t-MDS/t-AML risk was determined by a case-control study. Multivariate analysis revealed an association between pretransplant radiation and the risk of t-MDS/t-AML, but failed to reveal any association with pretransplant chemotherapy or conditioning regimens. However, patients who had been primed with VP-16 for stem cell mobilization were at a 12. 3-fold increased risk of developing t-AML with 11q23/21q22 abnormalities (P = 0.006). Patients undergoing HDT with stem cell rescue are at an increased risk of t-MDS/t-AML, especially those receiving priming with VP-16 for peripheral stem cell collection. (Blood. 2000;95:1588-1593)

In this pilot trial of interleukin (IL)-2-treated autologous bone marrow (BM) and peripheral stem cell (PSC)-supported high-dose chemoradiotherapy, we report 36 patients with poor-prognosis leukemia and lymphoma who received BM and/or granulocyte colony-stimulating factor (G-CSF)-mobilized autologous PSCs that had been exposed to IL-2 for 24 hours ex vivo. Patients then received IL-2 by low-dose continuous intravenous (i.v.) infusion until hematologic reconstitution and then by intermediate-dose continuous i.v. infusion for six 2-week maintenance cycles given at 1-month intervals. The median Day to neutrophils over 500/microL was 22 with BM and 10 with PSCs (p = 0.01). The median Day to platelets >20,000/microL was 50 for BM and 25 for PSCs, and to platelets >50,000/microL was 138 for BM and 34 for PSCs (p not significant). After the first three patients received IL-2 at 2 mIU x m(-2) x day(-1) and had slow reconstitution, four patients were treated without IL-2 until the maintenance phase following reconstitution. The remaining 29 patients received the initial "post-infusion" IL-2 at 1 mIU x m(-2) x day(-1). Toxicities associated with the infusion of IL-2-activated cells consisted of chills and fever in about one-half of the patients and transient hypotension in 12%. Low-dose IL-2 by continuous i.v. infusion in the early posttransplant period was associated with exacerbation of fever, diarrhea, and altered mental status in a minority of patients. The major dose-limiting toxicities of maintenance IL-2 were fever, fatigue, gastrointestinal symptoms, skin rash, and dyspnea. Among 24 lymphoma patients, nine are in continuous complete remission (CCR) from 18-48 months, and 15 have died (12 due to relapse and three of therapy-related toxicities). Of 12 acute leukemia patients, two with acute lymphoblastic leukemia (ALL) are in CCR at 38 and 43 months, and one patient who was in cytogenetic but not molecular remission of Philadelphia chromosome-positive ALL died of progressive leukemia at Day 108. Three of nine with myeloid leukemia are in CCR at 21, 46, and 53 months; one is in hematologic and cytogenetic remission of acute promyelocytic leukemia at 55 months with multiple new cytogenetic abnormalities; one is alive at 54 months with pancytopenia after incomplete hematologic recovery followed by multiple new cytogenetic abnormalities (myelodysplasia); and one had an unrelated donor transplant after relapsing 4 months following protocol therapy. One myeloid leukemia patient remains without evidence of relapse, but is transfusion-dependent at 15 months following transplant. Biol Blood Marrow Transplant 1999;5(1):36-45.

We have identified three unbalanced translocations involving chromosomes 5 and 17, der(5)t(5;17), der(17)t(5;17), and dic(5;17), in the malignant cells from 17 patients with myeloid neoplasms. Six patients had a primary myelodysplastic syndrome (MDS) or acute myeloid leukemia (AML) de novo; ten patients had therapy-related MDS and/or AML (t-MDS/t-AML), and one patient had chronic myelogenous leukemia in myeloid blast phase. Two of the six patients with MDS or AML de novo had extensive exposure to industrial solvents, and one patient had Seckel syndrome. The primary diagnoses for the ten patients with t-MDS/t-AML were breast carcinoma and Hodgkin's disease in two patients each, and non-Hodgkin's lymphoma, multiple myeloma, chronic lymphocytic leukemia, ovarian carcinoma, thyroid carcinoma, and rhabdomyosarcoma in one patient each. Four patients had received both prior chemotherapy and radiotherapy, four others received prior chemotherapy only, and the remaining two patients only prior radiotherapy. Fluorescence in situ hybridization of centromere-specific probes for chromosomes 5 and 17 revealed that a dicentric rearrangement was the most common (13/16 patients examined). The genetic consequences of these chromosomal rearrangements are partial monosomy for 5q and 17p. Two of six patients examined had point mutations in TP53, suggesting that loss of function of TP53 in addition to loss of a tumor suppressor gene on 5q may be involved in the pathogenesis of the malignant disease in some of these patients.

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.

Thalidomide has been reported to be an effective agent for treatment of chronic graft-versus-host disease (CGVHD). To determine the efficacy of this agent in patients with refractory CGVHD a total of 80 patients who failed to respond to prednisone (PSE) or PSE and cyclosporine (CSA) were treated with thalidomide. Sixteen patients (20%) had a sustained response, 9 with a complete remission and 7 with a partial response. Twenty-nine patients (36%) had thalidomide discontinued because of side effects, which included sedation, constipation, neuritis, skin rash, and neutropenia. Side effects were reversible with drug discontinuation except for mild residual neuritis in one case. Rashes and neutropenia have not previously been reported as thalidomide side effects when used for CGVHD treatment. We conclude thalidomide is immunosuppressive and active in the treatment of CGVHD. A high incidence of reversible side effects limited dose intensity and reduced the number of patients who could benefit from treatment.

Background: Current hematopoietic cell transplant (HCT) regimens for patients with relapsed refractory acute leukemia have 3-year overall survival (OS) rates for acute myeloid leukemia (AML) and acute lymphoblastic leukemia (ALL) of 19% and 16% respectively. Previous studies demonstrated that intensification of total body irradiation (TBI) is not possible due to excessive regimen-related toxicity. Because image-guided targeted radiation therapy (e.g., total marrow and lymphoid irradiation (TMLI)) allows for the precise delivery of radiation through the sculpting of radiation to areas of high risk and disease burden, intensification of radiation dose to target structures as part of a HCT preparative may be possible without increased radiation-related toxicities or non-relapse mortality. Herein we report the results of a phase I trial that combines TMLI (1200-2000 cGy) with fixed doses of etoposide (VP16) and cyclophosphamide (CY); the primary objective is to determine the maximum tolerated dose/recommended phase II dose of TMLI. Methods: TMLI together with VP16 and CY before allogeneic HCT was assessed for patients with relapsed/refractory AML and ALL. TMLI was administered on days -10 to -6, VP16 60 mg/kg (adj bw) on day -5, and CY 100 mg/kg (ideal bw) on day -3. The initial radiation dose was 1200 cGy, delivered in 150 cGy fractions twice daily. The radiation dose was escalated in increments of 150 cGy, up to 1500 cGy, by use of a standard 3x3 design. At this point, the dose was raised in 100 cGy increments to a 2000 cGy maximum with a rolling 6 design. Bone marrow (n=3) or peripheral blood stem cells (n=48) were given on day 0. Tacrolimus and sirolimus were administered for graft versus host disease (GVHD) prophylaxis. Dose limiting toxicity (DLT) was defined according to the Bearman and CTCAE 3.0 scales, the latter for hematologic toxicity. The radiation dose delivered to the liver and brain was kept at 1200 cGy. Median normal organs received 16-60% of the dose (oral cavity 28%, lung 44%, esophagus 33%). Results: From 3/14/2008 to 1/30/2014, 51 patients underwent transplantation on this trial. (See table.) Our phase I trial/safety studies found the TMLI/CY/VP16 conditioning regimen to be well tolerated at TMLI doses up to 2000 cGy; 1-year estimates of non-relapse mortality and overall survival were 8.3% (95% CI: 2.6-18.4) and 54.4% (95% CI: 39.3-67.3) respectively (median follow-up: 23.5 months).Relapsed, progressed, or persistent disease after transplant occurred in 33 patients (bone marrow, 26; extramedullary disease, 6; concurrent bone marrow/extramedullary, 1). Of the 18 patients who were treated with a dose of 1700 cGy or higher, 17 achieved a complete remission at the day +30 evaluation. No radiological-based maximum tolerated dose (MTD) was defined. We determined that the median organ dose at 2000 cGy would be lower than that seen for total body irradiation (TBI), but a higher dose may result in reaching or exceeding TBI organ dose levels. We therefore stopped at 2000 cGy, above which non-targeted organs may no longer be protected. Acute GVHD (aGVHD) developed in 28 (55%) of patients; of those 7 (14%) developed grades 3-4. The most common toxicities across the tested dose levels were grade 1 GI toxicity and grade 2 stomatitis. One patient (treated at 1500cGy) developed grade 3 stomatitis. No additional DLTs were experienced across all dose levels. Conclusion: A dose of 2000 cGy targeted to lymph nodes and marrow in combination with CY and VP16 can be safely administered in the context of related and unrelated HCT, using tacrolimus and sirolimus for GVHD prophylaxis. We did not see increased incidence of aGVHD, and the day +100 NRM rate was Table. Patient characteristics Variable Median (range) or N Age at transplant (yrs) 34 (16-57) Disease diagnosis AML ALL Ph- ALL Ph+ biphenotypic undifferentiated 3313221 Disease status at HSCT 1 RL 2 RL IF 14334 Cytogenetic risk (SWOG criteria) favorable intermediate unfavorable unknown significance 122199 KPS at HSCT 80 (60-100) Donor source sibling HLA matched unrelated mismatched (1 allele) unrelated 25521 WBC at HSCT 1.4 (0.1-14.9) % Blasts in blood at transplant* 4 (0-93) % Blasts in marrow at transplant* 52 (8-98) Extramedullary disease at time of HSCT 11 *Excludes patients with solely extramedullary disease, n=4 Disclosures Stein: Amgen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Seattle Genetics: Research Funding. Snyder:Incyte: Membership on an entity's Board of Directors or advisory committees; Ariad: Membership on an entity's Board of Directors or advisory committees; BMS: Membership on an entity's Board of Directors or advisory committees. Forman:Mustang: Research Funding; Amgen: Consultancy.

[Graphic][1] Background: Autologous stem cell transplantation (ASCT) has been used as consolidation following induction therapy to reduce relapse (Le Gouill S et al et al, ASH 2014) in mantle cell lymphoma (MCL). Rituximab maintenance therapy post induction has been shown to improve overall survival (Kluin-Nelemans et al. NEJM 2012). Bortezomib has been shown to be effective against patients with relapsed/refractory MCL (Fisher et al, JCO 2006). However, the efficacy of the combination of bortezomib and rituximab as maintenance therapy post ASCT has not been established. Although CCND1 overexpression is pathognomonic in MCL, quantitative monitoring of CCND1 mRNA has not been established as a method of MRD monitoring. We aim to increase the 2 year disease free survival (DFS) for patients with MCL post ASCT with maintenance bortezomib and rituximab, and to explore the use of quantitative CCND1 mRNA expression as minimal residual disease (MRD) monitoring in this study. We report our interim analysis of DFS, toxicity, and quantitative CCND1 mRNA monitoring here. Methods: This is a multicenter phase II study in patients with MCL post ASCT. All patients were in complete remission (CT scan and bone marrow biopsy) post ASCT prior to entering study. Bortezomib was given at 1.3 mg/m2subcutaneously once a week for 4 weeks every 3 month for 2 years. Rituximabwas given at 375 mg/m2 intravenously once a week for 4 weeks every 6 months for 2 years. CT scanning and/or FDG-PETwere performed at every 6 months intervals to assess for disease status. The primary endpoint was 2 year DFS after start maintenance therapy. Secondary endpoints included toxicity, relapse rate, OS, and CCND1 mRNA as MRD monitoring. Blood was collected at baseline post ASCT and on day 1 of each cycle (3 month interval) at City of Hope. CCND1 mRNA was assessed using droplet digital PCR technology (ddPCR) on RNA obtained from peripheral blood mononuclear cells. JVM2 (MCL cell line), normal healthy patient, and an untreated patient with MCL involvement served as controls. All values were normalized to HPRT1 (housekeeping gene) and then to level of JVM2 (100%). Results: Sixteen patients were accrued, with 15 eligible for analysis. See Table 1 for baseline characteristics. The median follow- up was 19.1 months from time of starting maintenance therapy to time of last contact. The 2 year DFS is 100% (95% CI: N/A) and 2 year OS is 100% (95% CI: N/A). There have been no relapses and no treatment- related deaths on the study. Treatment was well tolerated. Grade 3/4 toxicities possiblyattributable to study drug included neutropenia (n=4), lymphopenia (3), pneumonia (1), and skin infection (1). Grade 2 possibly related toxicities included neutropenia (1), thrombocytopenia (2), anemia (1), arthralgia (1), peripheral sensory neuropathy (1), pruritis (1), and hypertension (1). Peripheral neuropathy toxicities included grade 1 sensory neuropathy (4), grade 1 motor neuropathy (1), and grade 2 sensory neuropathy (1). For MRD analysis, 12/15 patients had up to 12 months time point and 8/12 patients had up to 24 months time point. Out of 105 samples collected, ddPCR yield quantifiable CCND1 mRNA results in all time points tested except 3 samples. High CCND1 mRNA was detected in untreated patient with MCL involvement and JVM2. Low CCND1 mRNA was detected in normal healthy control and all samples on maintenance therapy. In all 12 patients analyzed, the relative CCND1 mRNA level was never above 12% of control (JVM2), and majority of the samples were below 5% (Figure 1). There were also very little intra-patient fluctuations. Conclusions: The combination of bortezomib with rituximab for treating MCL is well tolerated post ASCT and has encouraging results with no relapses seen to date. Quantitative CCND1 mRNA monitoring by ddPCR is feasible and correlates with clinical outcome. | Characteristics | N (%) or Median (range) | | --------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------- | -------------------------------------------------------- | | Median age | 62 (45-66) | | Gender Male Female | 14 1 | | Stage II Stage III Stage IV | 1 4 10 | | Months from Transplant to Initial Maintenance | 3.1 (2.3-5.8) | | Extra Nodal Disease No Yes | 4 11 | | MIPI (At initial diagnosis) Low INT High | 8 6 1 | | ASCT in 1st CR(n=13) -R-bendamustine -R-HCVAD/MTX/ARA-C -NORDIC -RCHOP ASCT in 2nd CR (n=2 ) -RCHOP followed by R-HCVAD/MTX/ARA-C -RCHOP followed by R-bendamustine | 3 4 4 2 1 1 | | Median number of cycles | 6 (2-8) | Table 1. ![Figure 1.][2] Figure 1. Quantitative CCND1 mRNA monitoring by ddPCR Disclosures Chen: Seattle Genetics, Inc.: Consultancy, Other: Travel expenses, Research Funding, Speakers Bureau; Genentech: Consultancy, Speakers Bureau; Millennium: Consultancy, Research Funding, Speakers Bureau. Off Label Use: 90-Y ibritumomab tiuxetan is a radiotherapeutic antibody targeting CD20. It is part of a regimen indicated for treating patients with relapsed/refractory, low-grade or follicular B cell non-Hodgkin lymphoma (NHL), or patients with previously untreated follicular NHL who achieved a complete or partial response to first-line chemotherapy.. Holmberg: Up to date: Patents & Royalties; Millennium: Membership on an entity's Board of Directors or advisory committees, Research Funding; Merck: Research Funding; Seattle Genetics: Membership on an entity's Board of Directors or advisory committees, Research Funding; Genzyme: Membership on an entity's Board of Directors or advisory committees, Research Funding. Siddiqi: Seattle Genetics: Speakers Bureau; Kite pharma: Other: attended advisory board meeting; Pharmacyclics/Jannsen: Speakers Bureau. Nademanee: Gilead: Consultancy; Seattle Genetics Inc.: Research Funding; Spectrum: Research Funding; Celgene: Consultancy. Forman: Amgen: Consultancy; Mustang: Research Funding. [1]: /embed/inline-graphic-2.gif [2]: pending:yes

We report that there is an unexpectedly high incidence of second neoplasms in patients after treatment of hairy cell leukemia (HCL) with interferon alpha 2b (IFN). In a cohort of 69 patients with HCL entered in a protocol using IFN as the primary treatment, and followed thereafter for a median of 91 months (range, 0.2 to 109 months), 13 patients (19%) developed a second neoplasm. Six neoplasms were of hematopoietic origin, whereas the remaining seven were adenocarcinomas. The expected number of second tumors in this cohort is three (based on calculations from the National Cancer Institute's SEER data), so the excess frequency (observed:expected) is 4.33. However, the excess frequency is even greater for the hematopoietic neoplasms; the expected frequency is 0.15, whereas six hematopoietic tumors occurred, for an observed:expected ratio of 40. In general, the second neoplasms have behaved aggressively, and the median survival after diagnosis of the second neoplasm was only 8.8 months. Although we cannot entirely exclude the possibility that IFN therapy has some direct oncogenic effect, we suspect that increased frequency of second tumors is related to prolonged survival of patients who are immunocompromised because of HCL and thus prone to develop second tumors. If so, the frequency of second neoplasms in patients with HCL may be even greater in the future with continued improvements in therapy.

We report feasibility and response results of a phase II study investigating prolonged weekly bortezomib and dexamethasone followed by thalidomide and dexamethasone as maintenance therapy after single autologous stem cell transplantation (ASCT) in patients with multiple myeloma. Within 4 to 8 weeks of ASCT, patients received weekly bortezomib and dexamethasone for six cycles, followed by thalidomide and dexamethasone for six more cycles. Thalidomide alone was continued until disease progression. Forty-five patients underwent ASCT. Forty patients started maintenance therapy; of these, 36 patients received four cycles, and 32 completed six cycles of maintenance bortezomib. Of these 40 patients, nine (22%) were in complete response (CR) before ASCT, 13 (32%) achieved CR after ASCT but before bortezomib maintenance therapy, and 21 (53%) achieved CR after bortezomib maintenance therapy. Nine patients not previously in CR (33%) upgraded their response to CR with bortezomib maintenance. At 1 year post-ASCT, 20 patients achieved CR, and two achieved very good partial response. Twenty-seven patients experienced peripheral neuropathy during bortezomib therapy, all grade 1 or 2. Our findings indicate that prolonged sequential weekly bortezomib, dexamethasone, and thalidomide maintenance therapy after single ASCT is feasible and well tolerated. Bortezomib maintenance treatment upgraded post-ASCT CR responses with no severe grade 3/4 peripheral neuropathy.

Patients with poor-risk leukemia have a high relapse rate despite allogeneic transplant. We report on the phase II trial of an intensified allogeneic transplant regimen whose aim was tolerable toxicity and durable remission. Study patients (n=30) had unfavorable first remission cytogenetics, progression from myelodysplasia or active disease due to induction failure or relapse. Conditioning was intravenous busulfan, targeted to a first-dose plasma area under the curve (AUC) of 700–900 µM·min, VP-16 at 30 mg/kg of adjusted ideal body weight and fractionated total body irradiation (FTBI) at 1200 cGy in ten fractions. Graft-versus-host disease (GVHD) prophylaxis was cyclosporine A and mycophenolate mofetil. Regimen-related toxicities (Bearman) included grade 3 mucositis in 29 patients (97%) and grade 4 in one, grade 2–3 sinusoidal obstructive syndrome in 2 patients (7%), and grade 2–3 skin toxicity in 8 patients (27%). The 30- and 100-day transplant-related mortalities were 0% and 7% respectively. The median follow-up was 83.7 months (60.7–96.4) for surviving patients. The 5-yr overall and disease-free survival was 40% for all patients. Cumulative 5-yr relapse incidence was 23% and transplant-related mortality was 37%. We have shown promising overall survival and relapse incidence in these poor-risk patients, who typically have few curative options.

Reconstitution of cytomegalovirus (CMV)-specific CD8(+) T cells is essential to the control of CMV infection in CMV-positive recipients (R(+)) after allogeneic hematopoietic stem cell transplantation (HCT). Six-color flow cytometry was used to assess the functional profile of CMV-specific CD8(+) T cells in 62 of 178 R(+) HCT recipients followed virologically for CMV reactivation. R(+) recipients receiving grafts from CMV-negative donors (D(-); D(-)/R(+)) reconstituted fewer multifunctional CD8(+) T cells expressing tumor necrosis factor-alpha (TNF-alpha), macrophage inflammatory protein-1beta (MIP-1beta), and CD107 in addition to interferon-gamma (IFN-gamma), compared with D(+)/R(+) recipients. Unlike monofunctional CD8(+) T cells secreting IFN-gamma, which were abundantly generated during CMV reactivation in D(-)/R(+) recipients, the relative lack of multifunctional CD8(+) T cells persisted until at least 1 year post-HCT. D(-)/R(+) recipients were more likely to require recurrent and prolonged use of antivirals. These findings were robust to statistical adjustment for pretransplant factors, as well as for posttransplant factors including graft-versus-host disease (GVHD) and its treatment by steroids. These analyses suggest that D(+)/R(+) transplants, on average, generate higher levels of multifunctional CMV-specific T cells and require less antiviral therapy compared with D(-)/R(+) HCT recipients. These results highlight the benefit of D(+) donors in improving outcomes of R(+) HCT recipients by reducing the duration and recurrent need of antiviral treatment, aided by increased levels of multifunctional CMV-specific T cells.

VGPR/CR rate of 61% and MRD negativity of 7.6%. The HR cytogenetics group exhibited an OR, VGPR/CR and MRD negativity rates similar to those shown in the SR group (92.8%, 85% and 21.4%, respectively, p>0.05) In conclusion, CyBorD is an efficacious regimen for patients with MM and overall seemed to be well tolerated. Our data is one of the first to show the impact of this regimen on MRD negativity rates and to highlight its role on HR cytogenetics patients who tended to respond to this therapy. However, sustainability of this response in such aggressive group treated with CyBorD needs further evaluation with longer follow-up. Table 1 Clinical Characteristics of patients with MM undergoing single auto-ASCT treated with CyBorD induction at our Institution

8581 Background: Ablative dose total body irradiation (TBI) of 800 cGy in combination with high-dose melphalan (MEL) was found to be too toxic. TMI, an image-guided targeted TBI using TomoTherapy i...

Although autologous stem cell transplant is an effective therapy for patients with multiple myeloma and extends progression-free survival (PFS) and overall survival (OS), patients show a continued pattern of recurrent disease. Twenty-nine patients were enrolled in a phase II study investigating the tolerability and efficacy of maintenance thalidomide following single autologous peripheral blood stem cell transplant. Six to eight weeks after transplant, patients were started on maintenance thalidomide at 50 mg a day. The dose was gradually escalated to a target dose of 400 mg a day and continued until disease progression or 6 months after achieving complete remission (CR) for a maximum total duration of 18 months. At 6 months, 13 patients (45%) achieved CR or near complete remission (positive immunofixation without any evidence of disease). The estimated 2-year OS was 83% and PFS was 49%. Median tolerated dose of thalidomide was 200 mg a day. In conclusion, thalidomide as maintenance therapy is feasible and may improve outcome after single autologous stem cell transplant.

Oral mucositis (OM) is a frequent complication of myeloablative therapy and HSCT. We evaluated the feasibility, reliability, and validity of a new patient self-reported daily questionnaire on OM and its impact on daily functions. This OM Daily Questionnaire (OMDQ), containing 10 items, was developed for use in palifermin clinical trials. In a phase 3 study, 212 patients received palifermin or placebo for three consecutive days before conditioning and three consecutive days after HSCT. Compliance rates were consistently >80% for most patients. Mouth and throat soreness (MTS) and MTS-Activity Limitations (MTS-AL) (swallowing, drinking, eating, talking, and sleeping) scores on consecutive days were highly correlated (days 7,8 = 0.70-0.86; test-retest reliability). Correlations among items measuring the same construct ranged between 0.5 and 0.8 (internal consistency reliability). The WHO Oral Toxicity scale was the clinical comparator to assess the criterion, discriminative, and evaluative validities of MTS-related questions. Most correlation coefficients between the WHO and MTS ranged between 0.45 and 0.55. Patients with more severe WHO OM grades had higher MTS mean scores. Changes in MTS scores were similar, but patients detected changes 1-3 days earlier than clinicians. In conclusion, the OMDQ is a feasible, reliable, valid, and responsive patient-reported measure of OM severity.

Purpose To describe patient-reported outcomes of mouth and throat soreness (MTS) and related sequelae on daily activities from a phase III study of palifermin in the autologous hematopoietic stem-cell transplantation (HSCT) setting and to compare patient self-evaluations with clinicians' assessments of oral mucositis using objective scales. Patients and Methods Patients (n = 212) received palifermin (60 μg/kg/d) or placebo for 3 days before total-body irradiation (12 Gy), etoposide 60 mg/kg, and cyclophosphamide 100 mg/kg, and 3 days after HSCT. Patients completed a daily questionnaire (Oral Mucositis Daily Questionnaire [OMDQ]) evaluating MTS severity and its effects on daily functional activities. Patients' self-assessment data were compared with clinicians' assessments of oral mucositis using the objective scales. Results Palifermin reduced the incidence and duration of severe oral mucositis, as assessed by both clinicians and patients. Comparisons between patient and clinician assessments demonstrated that the average daily scores between mucositis grade and subjective (MTS) instruments were similar, although patients reported MTS onset, peak, and resolution earlier (1 to 3 days) than clinicians' assessments. Patients receiving palifermin reported statistically significant improvements (P < .001) in daily functioning activities (swallowing, drinking, eating, talking, sleeping) and required significantly less narcotic opioids (P < .001); improvement in the patient's overall physical and functional well-being was also reported. This was confirmed by the results of the Functional Assessment of Cancer Treatment questionnaire. Conclusion These results support the clinical benefit of palifermin in the HSCT setting, providing evidence that a patient's self-assessment instrument (OMDQ) may serve as an alternative tool to assess oral mucositis severity in clinical trials.

The question of when immune reconstitution of cytomegalovirus (CMV)–specific CD8 T cells occurs after hematopoietic cell transplantation and, more specifically, to which CMV targets this immunity is likely to be directed remains poorly understood. The dependence of immune reconstitution on CMV reactivation is even less clear. To better understand these events, 44 CMV-seropositive HLA-A*0201 subjects were followed up at approximately days 40, 90, 120, 150, 180, and 360 after hematopoietic cell transplantation for CMV immunity as measured by 2 types of assays: (1) an HLA-A*0201 tetramer-binding assay for both CMV pp65 (pp65) and immediate-early 1 (IE-1) or (2) intracellular cytokine interferon γ responses induced by pp65 or IE-1–derived peptides. To verify the reliability of IE-1–specific assays relative to the pp65-based assays, a pilot study first compared the development of IE-1–specific immunity in a subgroup by using multiple HLA-A*0201–restricted peptides, and then these recipients were followed up for 1 year for immunologic function and for CMV infection. The IE-1–specific response occurred to each of the 3 HLA-A*0201–restricted peptides studied (IE-1-256, -297, and -316), and there was no predominant IE peptide response. However, the immunodominant HLA-A*0201–restricted pp65 peptide was recognized significantly more frequently than these IE-1 peptides. When this was compared with the occurrence of CMV infection, the overall immune reactivity, as measured by the mean or median number of CD8 + T cells reactive to either pp65 or IE-1 peptides by intracellular cytokine or tetramer binding assay, was not significantly different in those with and without CMV infection. For patients who demonstrated reconstituted immunity to CMV at 1 year, all were reconstituted by 6 months, and the timing of the first observed immune reactivity to either of the pp65 or the IE peptides was not different in those with and without detectable CMV infection.

Current treatment of chronic graft-versus-host disease (cGVHD) with prednisone (PSE) alone or with added cyclosporine or tacrolimus still has a very high failure and complication rate, and new treatment approaches are needed for both primary and salvage therapy. Mycophenolate mofetil (MMF) is an immunosuppressive agent currently in use for acute graft-versus-host disease prophylaxis. To determine whether MMF had activity in the treatment of cGVHD, we added MMF to standard cyclosporine, tacrolimus, and/or PSE as salvage/second-line (n = 24) or first-line (n = 10) therapy in 34 patients. Nine (90%) of 10 patients receiving first-line and 18 (75%) of 24 receiving second-line MMF therapy responded. Twelve (35%) patients had a complete remission, 15 (44%) had a partial remission, 5 (15%) had stable disease, and only 2 (6%) had progressive disease. Out of 30 patients receiving PSE, 22 (73%) were able to decrease PSE doses (median decrease of 50%; range, 25%–100%). With a median follow-up of 24 months (range, 6–28 months), 29 (85%) patients are alive. Three patients had to discontinue MMF because of abdominal cramps within 3 months of starting treatment. These data suggest that MMF is an active, well-tolerated agent in the treatment of cGVHD and may have a beneficial effect on the survival of patients with this complication.

BACKGROUND Oral mucositis is a complication of intensive chemotherapy and radiotherapy with no effective treatment. We tested the ability ofpalifermin (recombinant human keratinocyte growth factor) to decrease oral mucosal injury induced by cytotoxic therapy. METHODS This double-blind study compared the effect ofpalifermin with that of a placebo on the development of oral mucositis in 212 patients with hematologic cancers; 106 patients received palifermin (60 μg per kilogram ofbody weight per day) and 106 received a placebo intravenously for three consecutive days immediately before the initiation of conditioning therapy (fractionated total-body irradiation plus high-dose chemotherapy) and after autologous hematopoietic stem-cell transplantation. Oral mucositis was evaluated daily for 28 days after transplantation. RESULTS The incidence oforal mucositis of World Health Organization (WHO) grade 3 or 4 was 63 percent in the palifermin group and 98 percent in the placebo group (P

The primary objective of this study was to evaluate the outcome of patients treated with high-dose chemo-/radiotherapy or high-dose chemotherapy and autologous stem-cell transplant (ASCT) for relapsed, refractory, or poor-risk intermediate-grade (IG) and high-grade (HG) non-Hodgkin's lymphoma (NHL). The secondary objectives were to determine prognostic factors for relapse and survival. Between February 1987 and August 1998, 264 patients, 169 (64%) IG and 95 (36%) HG, underwent high-dose therapy and ASCT at City of Hope National Medical Center (COHNMC). There were 157 (59%) males and 107 (41%) females with a median age of 44 years (range, 5-69 years). The median number of prior chemotherapy regimens was 2 (range, 1-4), and 71 (27%) had received prior radiation as part of induction or as salvage therapy. The median time from diagnosis to ASCT was 10.8 months (range, 3-158 months). Ninety-four patients (36%) underwent transplantation in first complete/partial remission (CR/PR), 40 (15%) in induction failure, and 130 (49%) in relapse or subsequent remission. Two preparative regimens were used: total body irradiation/high-dose etoposide/cyclophosphamide (TBI/VP/CY) in 208 patients (79%) and carmustine/etoposide/cyclophosphamide (BCNU/VP/CY) in 56 patients (21%). One hundred sixty-three patients (62%) received peripheral blood stem cells (PBSC) and 101 (38%) received bone marrow (BM) alone or BM plus PBSC. At a median follow-up of 4.43 years for surviving patients (range, 1-12.8 years), the 5-year Kaplan-Meier estimates of probability of overall survival (OS), progression-free survival (PFS), and relapse for all patients are 55% (95% confidence interval [CI]: 49%-61%), 47% (95% CI: 40%-53%), and 47% (95% CI: 40%-54%), respectively. There were 27 deaths (10%) from nonrelapse mortality, including seven (3%) patients who developed second malignancies (five with myelodysplasia/acute myelogenous leukemia and two with solid tumors). By stepwise Cox regression analysis, disease status at ASCT was the only prognostic factor that predicted for both relapse and survival. The 5-year probability of PFS for patients transplanted in first CR/PR was 73% (95% CI: 62%-81%) as compared to 30% (95% CI: 16%-45%) for induction failure and 34% (95% CI: 26%-42%) for relapsed patients. Our results further support the role of high-dose therapy and ASCT during first CR/PR for patients with poor-risk intermediate- and high-grade NHL. Early transplant is recommended for patients failing initial induction therapy or relapsing after chemotherapy-induced remission. Relapse continues to be the most common cause of treatment failure. An alternative approach to prevent relapse, the incorporation of radioimmunotherapy into the high-dose regimen, is being investigated. The development of a second malignancy is a serious complication of high-dose therapy, which requires close surveillance.

PURPOSE: To evaluate the incidence and associated risk factors of solid cancers after bone marrow transplantation (BMT). PATIENTS AND METHODS: We analyzed 2,129 patients who had undergone BMT for hematologic malignancies at the City of Hope National Medical Center between 1976 and 1998. A retrospective cohort and nested case-control study design were used to evaluate the role of pretransplantation therapeutic exposures and transplant conditioning regimens. RESULTS: Twenty-nine patients developed solid cancers after BMT, which represents a two-fold increase in risk compared with a comparable normal population. The estimated cumulative probability (± SE) for development of a solid cancer was 6.1% ± 1.6% at 10 years. The risk was significantly elevated for liver cancer (standardized incidence ratio [SIR], 27.7; 95% confidence interval [CI], 1.9 to 57.3), cancer of the oral cavity (SIR, 17.4; 95% CI, 6.3 to 34.1), and cervical cancer (SIR, 13.3; 95% CI, 3.5 to 29.6). Each of the two patients with liver cancer had a history of chronic hepatitis C infection. All six patients with squamous cell carcinoma of the skin had chronic graft-versus-host disease. The risk was significantly higher for survivors who were younger than 34 years of age at time of BMT (SIR, 5.3; 95% CI, 2.7 to 8.6). Cancers of the thyroid gland, liver, and oral cavity occurred primarily among patients who received total-body irradiation. CONCLUSION: The risk of radiation-associated solid tumor development after BMT is likely to increase with longer follow-up. This underscores the importance of close monitoring of patients who undergo BMT.

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.

Background Palifermin has been shown to reduce the incidence and duration of severe oral mucositis in hematological stem cell transplantation (HSCT) recipients. A follow-up study was performed to rule out a potential long-term safety risk of palifermin use. Objectives to compare long-term disease outcome (overall survival, disease progression and incidence of secondary malignancies) between palifermin and placebo. Methods This is a long-term follow-up study of patients with hematological malignancies undergoing HSCT and treated with palifermin or placebo to prevent oral mucositis. The aim of the study was to detail any potential late complications due to palifermin exposure. Patients were enrolled between 1997-2003 into four randomized, placebo-controlled phase II/III studies conducted at 31 sites in Australia, Europe and the US. The survival outcomes were compared using hazard ratios (HRs) estimated with Cox model including the treatment group, baseline age, disease type (Hodgkin lymphoma, non-Hodgkin lymphoma, multiple myeloma, leukemia), ECOG performance status, country and presence of prior radiotherapy as covariates. The incidence of secondary malignancies was compared with chi-squared test. Results A total of 672 patients were randomized to the parent studies (429 palifermin, 243 placebo) and 543 (345, 198) were enrolled to the long-term follow-up. The median follow-up time for subjects alive was 7.9 years (range 0.1-14.9) for palifermin and 8.8 (0.1-14.8) for placebo. No significant differences were seen for either overall survival (HR = 1.01; 95% confidence interval (CI) 0.78-1.31; p=0.921) or progression-free survival (HR=1.04; 95% CI 0.83-1.31; p=0.733). Secondary malignancies were reported by 13% (palifermin) vs. 11% (placebo) of the patients (p=0.477). The most common secondary malignancies were acute myeloid leukemia/myelodysplastic syndrome (5% vs. 5%) and skin cancers (2% vs. 2%). Conclusion The overall survival, progression-free survival, and the incidence of secondary malignancies were comparable between palifermin and placebo in patients undergoing HSCT. After a follow-up of up to 15 years, no negative effect of palifermin on long-term outcomes was observed. Disclosures: No relevant conflicts of interest to declare.

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.

A syndrome indistinguishable from idiopathic polymyositis occurred in 11 patients as a manifestation of chronic GVHD. All patients had elevation of creatine phosphokinase (CPK). Immunohistology demonstrated the effector cells in the muscle infiltrates as cytotoxic T cells, a finding similar to idiopathic polymyositis. Polymyositis is a rarely reported complication of chronic graft-versus-host disease (GVHD) with only 8 cases described in the literature. We encountered this syndrome in a small but significant percentage of our patients with chronic GVHD. Polymyositis associated with chronic GVHD does not affect the overall prognosis for the patient. Moreover, polymyositis can be the only manifestation of chronic GVHD. Awareness of this complication is important because it can be confused with other causes of muscle weakness after bone marrow transplantation. Finally, prompt initiation of corticosteroid therapy results in a rapid improvement of the associated symptoms.

PURPOSE The optimal dose and schedule for cladribine (2CdA) therapy of malignant hematologic diseases have not been determined. This dose-escalation study was designed to assess toxicity when 2CdA is given using five daily 1-hour intravenous infusions. PATIENTS AND METHODS Forty-two adults with advanced hematologic malignancies were treated in one of nine cohorts, starting at 2.5 mg/m2/d for 5 days. Plasma drug concentrations were measured by high-performance liquid chromatography. Responses were assessed by bone marrow biopsy on day 15 of the first course and by clinical measurements after each course. Patients received one to four courses each. RESULTS Nonhematologic toxicity was mild, and dose-limiting nonhematologic toxicity was not observed, even at the highest dose level of 21.5 mg/m2/d. In particular, neurotoxicity was not observed. The maximum-tolerated dose (MTD) was not identified. However, prolonged cytopenias and severe infections were more common in the higher 2CdA dose cohorts. Logistic regression analysis suggested that severe hematologic toxicity was associated with pretreatment platelet count and performance status (PS). Good-risk patients were identified as having a PS of 0 and platelet count > or = 80,000/microL, PS of 1 and platelet count > or = 120,000/microL, or PS of 2 and platelet count > or = 160,000/microL. Sustained complete responses (CRs) and partial responses (PRs) were observed in eight patients. CONCLUSION 2CdA can be administered using five daily 1-hour infusions at 21.5 mg/m2/d without dose-limiting nonhematologic toxicity. Unlike continuous intravenous infusions, neurotoxicity was not observed using this schedule. Further dose escalation may be possible in good PS patients with adequate platelet counts.