Holmium-166 (166Ho)-DOTMP Skeletal Targeted Radiotherapy (STR™) with Melphalan and Autologous Peripheral Stem Cell Transplant (PBSCT) for Multiple Myeloma (MM).

Abstract Background: 166Ho-DOTMP is a beta-emitting radiophosphonate that localizes specifically to the bone surfaces and can deliver high dose radiation both to the bone and bone marrow. Follow-up data from 3 clinical trials with STR as conditioning for patients with MM undergoing autologous PBSCT are presented. Methods: In 2 Phase I/II dose-escalation trials, 83 patients received a dose of 166Ho-DOTMP STR calculated to deliver 20, 30, or 40 Gy to the red marrow; 82 pts received melphalan (140 or 200 mg/m2) ± 8 Gy TBI (n=25), followed by PBSCT. As of June, 2004, 77 subjects have been followed for at least 48 months. In a separate Phase II dosimetry trial, 12 patients received two 30 mCi tracer doses of 166Ho-DOTMP STR to determine the reproducibility of biodistribution and pharmacokinetics (PK). All pts received a 25 Gy therapy dose with concurrent IV hydration and continuous bladder irrigation, followed by 200 mg/m2 melphalan and PBSCT. These patients have been followed for at least 18 months. Results: Up to 2.3 Ci/m2, 166Ho-DOTMP STR was given in the Phase I/II trials; 29/83 (35%) patients achieved complete response (CR) and overall response rate (CR + PR) was 64% (7 pts not evaluable). The Kaplan-Meier estimate of median survival is 5.2 years for all 83 patients. In patients who are at least 4 years post transplant who achieved a CR, the survival is 74% (n=27). In patients who achieved less than a CR at least 4 years ago, the survival is 34% (n=44). Dose-related radiation-induced kidney toxicity presented in some patients more than 6 months post-therapy. The dose of 166Ho-DOTMP STR in the Phase II dosimetry trial was 550 to 860 mCi/m2, 166Ho-DOTMP. Currently, 18 months of follow-up reveals no occurrence of hemorrhagic cystitis or > Grade 2 elevated creatinine. A CR rate of 17% with an overall survival of 92%, was observed. In 10 patients who received 166Ho-DOTMP STR 750 mCi/m2 ± 10% in the Phase I/II trial, the CR rate was 40%, and the 4-year survival was 70%. Monitoring for safety and duration of response is ongoing in all 3 trials. Conclusion: Follow-up from the Phase I/II trials confirms that 166Ho-DOTMP STR provides favorable efficacy and safety as part of the conditioning regimen for patients with MM undergoing PBSCT. A Phase III, randomized multicenter study is now open to enrollment, comparing the safety and efficacy of 166Ho-DOTMP STR plus melphalan to melphalan alone as conditioning for PBSCT in subjects with primary refractory MM who have failed to respond to induction therapy, including high-dose dexamethasone, and are within 18 months of diagnosis.

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Mitoxantrone and Melphalan as Conditioning Regimen for Autologous Stem Cell Transplant for Multiple Myeloma.

Blood ◽

10.1182/blood.v108.11.2945.2945 ◽

2006 ◽

Vol 108 (11) ◽

pp. 2945-2945

Author(s):

Anne W. Beaven ◽

Terrance Comeau ◽

Andrew Sharf ◽

Dominic T. Moore ◽

Jonathan Serody ◽

...

Keyword(s):

Multiple Myeloma ◽

Cardiac Toxicity ◽

Conditioning Regimen ◽

Progression Free Survival ◽

Complete Response ◽

Autologous Stem Cell Transplant ◽

High Dose ◽

Cell Transplant ◽

The Mean

Abstract High dose Melphalan (Mel) has demonstrated efficacy in the treatment of multiple myeloma (MM). Mitoxantrone (Mit), in combination with vincristine and prednisone, also has demonstrated activity in MM with the benefit of less cardiac toxicity than other standard regimens. In this trial Mel and Mit were combined as a transplant preparative regimen. Mit was given as a prolonged 6 hour infusion on 2 separate days to increase intracellular drug levels and decrease cardiac toxicity (Kaminer et al. Cancer1990; 65, 2619–2623; Koc et al. Hematol Oncol2004;22:43–53). PATIENTS: 35 patients with a diagnosis of MM were enrolled between 9/98–6/02. Median age was 59 (range, 38–69); 60% had received ≥ 2 previous regimens (range, 1–6). The median time from diagnosis to transplant was 9 months (95% CI, 8–12 months). 57% had stage III disease and 26% stage II at diagnosis; median Beta-2 microglobulin was 3.6 mg/L (available in only 13 patients). All patients completed therapy with Mit 30mg/m2/day infused over 6 hours on days -6 and -5 and Mel 180mg/m2 on day -1. RESULTS: The median follow-up for survivors was approximately 45 months (range, 3–84 months). The median times to granulocyte and platelet engraftment were 11 days and 14 days respectively. 2 patients failed to engraft; 1 proceeded to allogeneic transplant, the other died on day 28 secondary to sepsis. The 100-day TRM was 2.9%. The median progression free survival (PFS) was 20 months (95% CI, 13–31) (Figure 1) with a median overall survival (OS) of 57 months (Figure 2). 4 patients are alive and progression free more than 48 months out from transplant. 8/35 (23%) of patients achieved a complete response (CR). Of the 8 patients who had a CR, 7 (20% of total patients) are still alive and progression free with a median follow-up of 39 months after transplant (range, 12 to 80 months). The achievement of a CR was significantly associated with longer PFS but not with OS. The mean CD34 count of infused cells was 4.92 ×106/kg and did not appear to be significantly associated with CR rate, OS, or time to engraftment of platelets or granulocytes. Overall, therapy was well tolerated with a median of 8 days (range, 0–15) of any grade of mucositis and a median of 3 days of fever. The mean LVEF on MUGA was 64% pre-transplant and decreased to 58% post-transplant. 1 patient with diabetes and hypertension developed congestive heart failure after discharge from the hospital but with therapy the LVEF returned to normal. CONCLUSION: The combination of Mel and infusional Mit is an effective regimen with 23% CR rate despite multiple previous therapies. The median OS of 57 months compares well to other transplant trials and patients who achieved a CR demonstrated better long-term PFS. Figure Figure Figure Figure

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Unconventional Anticancer Agents: A Systematic Review of Clinical Trials

Journal of Clinical Oncology ◽

10.1200/jco.2005.03.8406 ◽

2006 ◽

Vol 24 (1) ◽

pp. 136-140 ◽

Cited By ~ 20

Author(s):

Andrew J. Vickers ◽

Joyce Kuo ◽

Barrie R. Cassileth

Keyword(s):

Clinical Trials ◽

Phase I ◽

Cancer Patients ◽

Phase Ii ◽

Dose Finding ◽

Phase Iii ◽

High Dose ◽

Free Text ◽

Phase Ii Trials ◽

Off Label

Purpose A substantial number of cancer patients turn to treatments other than those recommended by mainstream oncologists in an effort to sustain tumor remission or halt the spread of cancer. These unconventional approaches include botanicals, high-dose nutritional supplementation, off-label pharmaceuticals, and animal products. The objective of this study was to review systematically the methodologies applied in clinical trials of unconventional treatments specifically for cancer. Methods MEDLINE 1966 to 2005 was searched using approximately 200 different medical subject heading terms (eg, alternative medicine) and free text words (eg, laetrile). We sought prospective clinical trials of unconventional treatments in cancer patients, excluding studies with only symptom control or nonclinical (eg, immune) end points. Trial data were extracted by two reviewers using a standardized protocol. Results We identified 14,735 articles, of which 214, describing 198 different clinical trials, were included. Twenty trials were phase I, three were phase I and II, 70 were phase II, and 105 were phase III. Approximately half of the trials investigated fungal products, 20% investigated other botanicals, 10% investigated vitamins and supplements, and 10% investigated off-label pharmaceuticals. Only eight of the phase I trials were dose-finding trials, and a mere 20% of phase II trials reported a statistical design. Of the 27 different agents tested in phase III, only one agent had a prior dose-finding trial, and only for three agents was the definitive study initiated after the publication of phase II data. Conclusion Unconventional cancer treatments have not been subject to appropriate early-phase trial development. Future research on unconventional therapies should involve dose-finding and phase II studies to determine the suitability of definitive trials.

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Long-Term Follow-Up of a Randomized Phase III Multicenter Study Comparing a Standard Versus an Intensified Conditioning Regimen for High-Dose Chemotherapy in Patients with Multiple Myeloma.

Blood ◽

10.1182/blood.v104.11.945.945 ◽

2004 ◽

Vol 104 (11) ◽

pp. 945-945

Author(s):

Roland Fenk ◽

Peter Schneider ◽

Martin Kropff ◽

Ali-Nuri Huenerlituerkoglu ◽

Ulrich Steidl ◽

...

Keyword(s):

Multiple Myeloma ◽

Stem Cell ◽

Conditioning Regimen ◽

High Dose Chemotherapy ◽

Phase Iii ◽

Study Endpoint ◽

Primary Study ◽

High Dose ◽

Significant Difference

Abstract High-dose chemotherapy (HDT) improves the outcome of patients with multiple myeloma (MM) in comparison to conventional chemotherapy. Dose-escalating strategies including tandem HDT are currently evaluated to further improve remission rates and survival of patients. Therefore we conducted a randomized multicenter trial to compare an intensified conditioning regimen with the current standard high-dose melphalan. The primary study endpoint was response rate, with overall survival (OS), event-free survival (EFS) and toxicity analysed as secondary endpoints. Between 1997 and 1999 a total of 56 patients with stage II and III disease, who were matched for age (median 56 years), number of previous therapies (median time from diagnosis to transplant 7 months) and different risk factors (beta2-microglobulin, LDH, CRP, cytogentic abnormalities, chemoresistant disease, IgA-subtype, renal impairment), were randomized. All patients received 2 courses of oral idarubicine/dexamethasone and 2 courses of intravenous cyclophosphamide/adriamycine in combination with G-CSF followed by peripheral stem cell collection. Thirty patients were treated with melphalan 200mg/m2 (HD-M) whereas 26 patients received idarubicine 42mg/m2, melphalan 200mg/m2 and cyclophosphamide 120mg/kg (HD-IMC) followed by autologous blood stem cell transplantation. Acute toxicity was higher with HD-IMC, including 5 (20%) treatment-related deaths due to infections versus none (0%) in the HD-M group. This lead to early termination of the study. Severity of mucositis (grade III-IV 19 vs. 8 pts., p=0.001), CRP (20 vs. 7 mg/dl, p<0.001), days of fever (11 vs. 3, p<0.001), days with iv-antibiotics (13 vs. 4, p<0.001), number of erythrocyte-transfusions (6 vs. 2, p<0.001), number of platelet-transfusions (16 vs. 4, p<0.001) and days to granulocyte engraftment (18 vs. 11, p=0.007) were significantly higher after HD-IMC. After a follow-up of 5 years analysis restricted to patients surviving the first 30 days after HDT showed a trend to higher response rates (CR+vgPR: 47% (95%CI 24–72%) vs. 35% (95%CI 18–56%), PR 37% (95%CI 17–63%) vs. 48% (95%CI 29–68%) and time-to-progression (median 31 vs. 15 months, p=0.1) in the HD-IMC treatment arm in comparison to HD-M, but there was no significant difference in EFS and OS (median 22 vs. 30, p= 0.31 and 66 vs. 66 months, p=0.8, respectively). Univariate analysis demonstrated that LDH levels > 200 U/L (p=0.04) and chemoresistant disease (p=0.05) were a bad prognostic factor for EFS. Beta2-Microglobulin levels > 5mg/dl (p=0.01), abnormal conventional cytogenetics (p=0.02) and LDH levels > 200 U/L (p=0.03) were predictive for an inferior OS. In conclusion intensified conditioning for HDT had an intolerable high treatment-related mortality and did not improve EFS and OS in patients with multiple myeloma.

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5-Azacytidine Before or After Stem Cell Transplantation in Acute Myeloid Leukaemia (AML) and Myelodysplastic Syndromes (MDS)

Blood ◽

10.1182/blood.v118.21.4267.4267 ◽

2011 ◽

Vol 118 (21) ◽

pp. 4267-4267

Author(s):

Ana Garrido ◽

Miguel Ortín ◽

Rodrigo Martino ◽

Josep Nomdedeu ◽

Ana Aventin ◽

...

Keyword(s):

Stem Cell ◽

Stem Cell Transplantation ◽

Disease Progression ◽

Cell Transplantation ◽

Conflicts Of Interest ◽

Conditioning Regimen ◽

Complete Response ◽

Cell Transplant ◽

Safe Procedure

Abstract Abstract 4267 The acceptable toxic profile of 5-aza-citidine (5-aza) allows its use in fragile or elderly patients in whom intensive chemotherapy should be avoided. Whether it is possible to take advantage of this low toxicity in patients awaiting for donor search and/or stem cell transplant (SCT) and in those experiencing leukemia recurrences after the procedure remains unknown. We analysed the clinical results of using 5-aza in these two settings to define the feasibility, safety and results of this approach. Patients and methods: From 2007 to 2011, 15 patients (11 males, 4 females) received 5-aza as last treatment prior to an allogeneic SCT (n=13) or as rescue after an early post-transplant relapse (n=2) at our centre. Diagnosis was MDS in 3 cases (median age 62; range 58–63) and AML in 12 cases (median age 58; range 37–67). Patients with MDS received a median of 6 courses of 5-aza (range 3–8) as the only treatment from diagnosis, except for one patient who had received panobinostat prior to 5-aza. Amongst patients with AML, 12 patients received 5-aza either as treatment for AML (2/12) or after remission (8/12) because of the high relapse risk while awaiting for a suitable donor to be found. Two patients with AML received 5-aza as treatment for early post-SCT relapse. AML patients treated with 5-aza before SCT received a median of 5 courses (range 1–19), whilst patients receiving treatment for relapse received 1 and 3 courses, respectively. Ten patients received a nonmyeloablative conditioning regimen, 1 received a conventional conditioning regimen, 2 patients are still in the process of donor search and the other 2 patients received 5-aza after an autologous stem cell transplantation relapse. RESULTS: All MDS patients engrafted and are in complete remission (CR) after a median of 696 days of follow-up (range 377–1227). One of those patients died because of aGvHD. Nine of 12 AML patients receiving 5-aza prior to SCT are alive after a median 373 days follow-up (133–995). One patient showing refractoriness to 3 different lines of treatment died from disease progression after 211 days. All patients receiving 5-aza as treatment for early relapse are dead, 41 and 401 days after starting treatment. Most interestingly, AML patients receiving 5-aza as maintenance of an already-achieved CR while awaiting transplantation did not experience disease progression despite the median time they remained on this treatment was prolonged (9 months). Graft-versus-host disease ≥ grade II was seen in 3 patients. No graft failures were seen and all patients who received an allogeneic stem cell transplantation remain in complete response. CONCLUSION: The use of 5-aza for maintaining or achieving a response in patients with AML who are awaiting SCT is a safe procedure and adds flexibility to schedule the treatment without the need to administer potentially toxic therapy. The use of 5-aza before transplant did not appear to interfere either with engraftment, incidence of GvHD or short-term relapse after transplant. Disclosures: No relevant conflicts of interest to declare.

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A Phase I/II Study of the Combination of Oral Rigosertib and Azacitidine in Patients with Myelodysplastic Syndrome (MDS) or Acute Myeloid Leukemia (AML)

Blood ◽

10.1182/blood.v124.21.3252.3252 ◽

2014 ◽

Vol 124 (21) ◽

pp. 3252-3252 ◽

Cited By ~ 3

Author(s):

Shyamala C. Navada ◽

Guillermo Garcia-Manero ◽

Francois Wilhelm ◽

Katherine Hearn ◽

Rosalie Odchimar-Reissig ◽

...

Keyword(s):

Phase I ◽

Phase Ii ◽

Stable Disease ◽

Blood Count ◽

Single Agent ◽

Complete Response ◽

Leukemic Cells ◽

Cell Transplant ◽

Transfusion Requirements ◽

Count Recovery

Abstract Background:Rigosertib is a small molecule anti-cancer agent targeting PI3/polo-like kinase pathways that promotes G2/M arrest and has effects on the B-Raf and Ras pathways. It is currently being tested as a single agent with the intravenous (IV) formulation in patients (pts) who have relapsed or are refractory to hypomethylating agents (HMAs) as well as with the oral formulation in lower-risk, red-cell transfusion-dependent MDS patients. Azacitidine (AZA) is first-line therapy for pts with higher-risk MDS. In vitro, the combination of rigosertib with AZA acts synergistically to inhibit growth and induce apoptosis of leukemic cells (Skidan et al 2006). This effect appears to be sequence dependent, requiring exposure to rigosertib first, followed by AZA. These nonclinical results provided the rationale to combine the 2 agents in a phase I/II study in pts with MDS and AML. Methods: Pts with MDS and non-proliferative AML, who were previously untreated or had failed or progressed on an HMA were included in the phase I component of the study. Oral rigosertib was administered twice daily from day 1 through day 21 of a 28-d cycle. AZA 75 mg/m2/d was administered for 7 days starting on day 8 of the 28-d cycle. Pts were entered in 3 escalating-dose cohorts of rigosertib in a classic 3+3 design: [1] 140 mg twice daily; [2] 280 mg twice daily; [3] 560 mg qAM and 280 mg qPM. A CBC was performed weekly and a bone marrow (BM) aspirate and/or biopsy was performed at baseline and every 4-8 weeks afterwards. Results: Eighteen pts have been treated with the combination of oral rigosertib and AZA. Pts had diagnoses of intermediate-1 MDS (3), intermediate-2 MDS (6), high-risk MDS (2), CMML (1), and AML (6); median age was 70.5 years; 61% of pts were male. Pts have received 1-10+ cycles of treatment with the total number of cycles administered thus far being 58. Cytogenetic profiles by IPSS were good (8 pts), poor (8 pts), and intermediate (2 pts). 11of 18 patients were transfusion dependent at baseline [RBC (11), platelet (6)]. One patient became RBC transfusion independent after 3 cycles of treatment. 5 additional patients have had a reduction in their RBC and platelet transfusion requirements. 56% of patients received prior treatment with HMAs: AZA (6 pts), decitabine (4 pts). The most frequent adverse events (AEs) in Cycle 1 included constipation, diarrhea, nausea, fatigue, hypotension, and pneumonia. The AEs did not differ significantly among the 3 cohorts. Elevation in creatinine in 1 pt in cohort 1 was a possibly related grade 3 dose-limiting toxicity that required subsequent expansion of the cohort. Drug-related dysuria/cystitis was not reported in this pt population. Responses according to IWG 2006 criteria were observed in the BM and peripheral blood: Complete Response (CR) (1 pt), Cri (CR with incomplete blood count recovery) (4 pts), stable disease (2), hematologic improvement-erythroid (1). Six pts received fewer than 4 cycles of treatment and are too early to evaluate. Six pts came off study for the following reasons: progression of disease (1), pt request (1), death from pneumonia (2), received stem cell transplant (1), persistent fungal pneumonia (1). Two evaluable pts have responded to the combination after progression or failure on HMA alone. Conclusions: The combination oforalrigosertib at 560/280 mg BID (recommended phase II dose) and standard-dose AZA can be safely administered and appears to be well tolerated in repetitive cycles in pts with MDS and non-proliferative AML. The AE profile does not differ significantly from that of AZA alone. Data from the Phase I component of this study suggest activity in patients with MDS after HMA failure. Additional data are required to evaluate this observation. The Phase II segment of this study is underway to further assess the response of the combination. Table Patient ID Diagnosis Prior HMA % Blasts in BM at Baseline % Blasts in BM after Treatment IWG Response 1 MDS No 2 1 CRi 2 AML No 40 0 CRi 3 AML No 22 N/A NE 4 MDS Azacitidine 0 0 NE 5 AML No 59 N/A NE 6 MDS No 21 <5 CRi 7 MDS No 2 1 CR 8 MDS No 2.5 2 SD 9 AML Decitabine 25 N/A NE 10 MDS Decitabine 12 3 CRi 11 CMML Azacitidine 2 3 SD 12 MDS Azacitidine 4 1 HI-E 13 AML Azacitidine 47 40 TE 14 AML Decitabine 7 7 TE 15 MDS No 9 5 TE 16 AML No 25 6 TE 17 AML No 15 19 TE 18 AML Azacitidine 64 45 TE IWG = International Working Group CR = Complete Response CRi = Complete Response with incomplete blood count recovery NE = Not Evaluable SD = Stable Disease HI-E = Hematologic Improvement - Erythroid TE = Too Early Disclosures Wilhelm: Onconova Therapeutics, Inc: Employment, Equity Ownership. Demakos:Onconova: Consultancy. Azarnia:Onconova Therapeutics, Inc: Employment. Silverman:Onconova: with Icahn School of Medicine at Mount Sinai Patents & Royalties.

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Long-term outcomes of survivors of autologous hematopoietic-cell transplantation for refractory and relapsed Hodgkin’s Disease

Journal of Clinical Oncology ◽

10.1200/jco.2006.24.18_suppl.6554 ◽

2006 ◽

Vol 24 (18_suppl) ◽

pp. 6554-6554

Author(s):

K. A. Goodman ◽

V. Serrano ◽

E. R. Riedel ◽

S. Gulati ◽

C. H. Moskowitz ◽

...

Keyword(s):

Hematopoietic Cell Transplantation ◽

Univariate Analysis ◽

Conditioning Regimen ◽

Hematopoietic Cell ◽

High Dose ◽

Cell Transplant ◽

Hematopoietic Cell Transplant ◽

Risk Of Death ◽

Increased Risk

6554 Background: With improvements in survival among refractory/relapsed Hodgkin’s Lymphoma (HL) patients after high-dose chemo-radiotherapy and autologous hematopoietic-cell transplant (AHCT), it is important to evaluate risk of late complications in this heavily treated population. Methods: From 1985–1998, 218 refractory/relapsed HL patients were treated on high dose chemo-radiotherapy and AHCT salvage protocols. 153 (70%) surviving ≥2 years after AHCT were analyzed. All received either radiotherapy with initial therapy or total lymphoid irradiation and involved field boost with the conditioning regimen (43%). Information from surviving patients was obtained through a self-administered questionnaire. The NDI was queried to determine vital status and cause of death. Primary endpoint was non-HL mortality, defined as mortality due to cardiac causes, infection or second malignancy (SM). Competing risk methods were used to calculate cause-specific mortality rates and examine its predictors. All events were calculated from 2 years post-AHCT to date of death/last follow-up. Results: Median follow-up time was 11 years. There have been 51 deaths, 32 due to HL and 19 due to other causes. Eleven deaths were due to SM: AML (3), MDS (2), NHL (2), NSCLC (2), gastric and colon cancer. There were 8 non-SM deaths: cardiac toxicity (4), infection, aplastic anemia, suicide, unknown causes (1 each). The 10 and 15-year overall survival (OS) rates are 64% and 57%, respectively. The 10-year cumulative incidence of death from HL and from non-HL causes were 22% and 13.5% ( table ). By univariate analysis, increased risk of death due to SM was associated only with higher age at AHCT (p=0.02). Conclusions: While HL initially accounts for the majority of deaths among patients surviving high-dose therapy, the HL mortality rate plateaus and risk of death from non-HL mortality increases after 5 years. Yet, even at 15-years, SM risk does not exceed that observed in patients treated with standard regimens. [Table: see text] No significant financial relationships to disclose.

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Dose-Dense Induction Followed by Autologous Stem Cell Transplant (ASCT) as 1st Line Treatment in Peripheral T-Cell Lymphomas (PTCL) - A Phase II Study of the Nordic Lymphoma Group (NLG).

Blood ◽

10.1182/blood.v108.11.401.401 ◽

2006 ◽

Vol 108 (11) ◽

pp. 401-401 ◽

Cited By ~ 5

Author(s):

Francesco d’Amore ◽

Thomas Relander ◽

Grete Lauritzsen ◽

Esa Jantunen ◽

Hans Hagberg ◽

...

Keyword(s):

Phase Ii ◽

Phase Ii Study ◽

Large Cell ◽

High Dose ◽

Cell Transplant ◽

Post Transplant ◽

Patient Cohort ◽

Alk Positive ◽

The Impact

Abstract Systemic PTCL, with the exception of alk-positive anaplastic large cell lymphoma (ALCL), have a poor prognosis. ASCT has been shown to have a favourable impact on relapsed PTCL. Therefore, the NLG designed a prospective multicenter phase II study to evaluate the impact of a dose-intensified induction schedule (6 courses of two-weekly CHOEP) consolidated in 1st PR/CR with high-dose therapy (BEAM) followed by ASCT in previously untreated systemic PTCL. This is the largest prospective PTCL-specific trial published so far. Newly diagnosed non-primary cutaneous PTCL cases aged 18–67 yrs were eligible for enrollment. Cases of alk-positive ALCL were excluded. From Oct 2001 to Feb 2006, 99 histologically confirmed PTCL cases were included in the study: PTCL unspecified (n=41), alk-neg ALCL (n=24), AILT (n=15), enteropathy-type (n=12), panniculitis-like (n=3), T/NK nasal-type (n=2), hepatosplenic (n=2). The M/F ratio was 1.8 and the median age 55 yrs (range 20–67 yrs). Although almost 2/3 of the cases presented with advanced-stage disease (62%), B-symptoms (61%) and/or elevated s-LDH (63%), the majority of them (65%) had a good performance score (WHO 0–1) at diagnosis. Of the 77 patients, where information was available for all 6 induction courses, 68 (88%) were in CR (31) or PR (37) after the 3rd and 66 (86%) after the 6th course. A total of 58 patients (75%) went through ASCT indicating that at least a fourth of this younger patient cohort has a primary refractory disease and fails therapy before reaching the transplant. Treatment-related toxicity after both induction and high-dose treatment was manageable. Of the 58 transplanted patients, 50 (86%) were still in remission at re-evaluation short after transplant. In 39 patients follow-up data one year post-transplant were available: 30 are still in CR and 9 have relapsed, suggesting that post-transplant relapses probably account for another 25% of the original patient cohort. In conclusion, the present data indicate that a time- and dose-intensified schedule is feasible and effective in previously untreated systemic PTCL. Continuous remissions are not uncommon, but a longer follow-up is needed to further characterize long-term remission rates and evaluate their impact on time-to-treatment failure and overall survival.

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Combination Therapy with BCNU/Etoposide/Melphalan (BEM) as Conditioning Regimen for Autologous Stem Cell Transplant In Multiple Myeloma.

Blood ◽

10.1182/blood.v116.21.4587.4587 ◽

2010 ◽

Vol 116 (21) ◽

pp. 4587-4587

Author(s):

Shanshan Liu ◽

Ann Mohrbacher ◽

Dan Douer ◽

Vishesh R Kothary ◽

Lisa Hanna ◽

...

Keyword(s):

Body Weight ◽

Stem Cell ◽

Stem Cell Transplant ◽

Conditioning Regimen ◽

Autologous Stem Cell Transplant ◽

Bone Lesions ◽

High Dose ◽

Cell Transplant ◽

Lytic Bone Lesions

Abstract Abstract 4587 Background: High-dose chemotherapy and autologous stem cell transplant (ASCT) remains an important therapeutic modality for MM patients. Traditionally high-dose single agent melphalan (200 mg/m2; Mel-200) has been used as the conditioning regimen prior to ASCT for MM. We investigated the combination regimen of BCNU, etoposide and melphalan (BEM) in this setting at our center. Methods: All patients who had undergone ASCT for MM utilizing BEM conditioning regimen at Norris Cancer Center, University of Southern California, Los Angeles were eligible. BEM consisted of BCNU 12 mg/kg (actual body weight or ideal body weight whichever was lower) iv on day -5, etoposide 60 mg/Kg iv on day -3, and melphalan 140 mg/m2 iv on day -1, prior to stem cell reinfusion on day 0. Overall survival (OS) was defined as time from MM diagnosis to death, or in patients still alive, the date of last follow-up. Progression-free survival (PFS) was defined as time from ASCT to date of relapse, or in patients without documented relapse, date of death or last follow up, whichever was sooner. Survival for patients with different clinical and disease-specific characteristics was explored using logrank test. Response was assessed according to International Uniform Response Criteria for MM. Results: A total of 44 MM patients underwent ASCT utilizing the BEM conditioning regimen. Of these, evaluable data was available for 42 patients (25 males; 60%, 17 females; 40%) with a median follow up of 27.6 mths. Median age at diagnosis was 54.5 yr (range 34–68) while median time from MM diagnosis to ASCT was 10.5 mths (range 2.8–47.8). MM subtypes included IgA (n=5, 12%), IgG (n=30, 71%) and light chain-only (n=7, 17%). Median bone marrow (BM) plasmacytosis at diagnosis was 42.5% (range 0%-100%). Durie-Salmon (DS) stages included stage I (12%), II (36%) and III (52%), while 4 patients (10%) had renal dysfunction at the time of initial MM diagnosis. Majority of the patients (71%) had lytic bone lesions at the time of diagnosis and 86% (n=36) hade secretory disease. Patients had received a median of 1 prior treatment (range 1–5), while 23 (55%) patients had received novel agents (proteasome inhibitors or IMiDs) prior to the BEM regimen. Response rates prior to and after the regimen are summarized in Table 1. After BEM-ASCT an additional 16 (38%) patients achieved a CR. Median duration of hospitalization and time to engraftment were 19 days (range 15–41) and 10.5 days (range 7–19), respectively. One patient died prior to discharge from the hospital post ASCT (Day 36 post ASCT) for a treatment related mortality of 2%. CR rate post BEM-ASCT was 64% with an ORR of 97%. Relapses have been noted in 25 patients to date. Median OS for all patients was 4.9 yrs (5.6 yrs for patients in CR and 6.6 yrs for patients in PR after BEM-ASCT). Median PFS was 23.9 mths for all patients (25 mths for patients in CR and 21.8 mths for those in PR after BEM-ASCT). No statistically significant differences were noted in OS based on patient gender (p=0.47), age at diagnosis (< or ≥60 yr), MM subtype (p=0.52), DS stage at diagnosis (0.09), patients without lytic bone lesions at diagnosis (p=0.054), secretor status (p=0.2), response status at the time of BEM-ASCT (p=0.9) or prior exposure to novel agents (p=0.62). Conclusions: BEM is a well-tolerated conditioning regimen prior to ASCT in MM and has efficacy comparable to Mel-200. BEM can be effectively employed in patients where Mel-200 is not feasible. We are particularly intrigued by its ability to deliver high CR rates (64%) compared to <30% (historical control). Very encouraging median OS (4.9 yr) and PFS (23.9 mth) rates were noted which were even better in patients who had a measurable response after this regimen. Further investigations will be needed to optimally define its potential as standard conditioning regimen in MM patients undergoing ASCT. Disclosures: No relevant conflicts of interest to declare.

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Phase I Study of Aurora Kinase Inhibitor MLN8237 and Bortezomib in Relapsed or Refractory Multiple Myeloma

Blood ◽

10.1182/blood.v120.21.1859.1859 ◽

2012 ◽

Vol 120 (21) ◽

pp. 1859-1859

Author(s):

A. Keith Stewart ◽

Ravi Vij ◽

Jacob P. Laubach ◽

Craig C. Hofmeister ◽

Rachel Hagerty ◽

...

Keyword(s):

Multiple Myeloma ◽

Phase I ◽

Dose Level ◽

Phase Ii ◽

Kinase Inhibitor ◽

Single Agent ◽

Aurora Kinase ◽

Cell Transplant ◽

Days Of Therapy

Abstract Abstract 1859 Genome wide RNA interference studies identified Aurora Kinase (AURK) A and B as lethal targets in Multiple Myeloma (MM) while suppression of these genes also sensitized MM to bortezomib (BTZ). MLN8237 is an oral inhibitor of AURKA. We therefore conducted a Phase I clinical trial of MLN8237 in combination with BTZ. The study enrolled a total of 19 patients at 5 institutions. 9 patients are still receiving active treatment as of the date of this report. Study Design: The phase I portion of this study uses a standard 3+3 design to determine the maximum tolerated dose (MTD) of MLN8237 and BTZ in patients with relapsed/refractory MM. Eligibility required a minimum of 1 and maximum of 4 lines of prior therapy. Patients who have received prior BTZ therapy were allowed on trial as long as they did not progress during prior BTZ or ≤ 60 days of therapy discontinuation. The following laboratory values were required £7 days prior to registration. ANC3 1000/mL, Hgb ≥9 g/dl, PLT3 100,000/mL, Total bilirubin £1.5 × upper limit of normal (ULN), Creatinine £ 2.5 × ULN, a baseline LVEF ≥45%. Patients were required to be able to take oral medication and to maintain a fast as required for 2 hours before and 1 hour after MLN8237 administration. Treatment Overview: The first 3 patients received MLN8237 at 25 mg po days 1–14 and BTZ at 1.3 mg/m2/dose iv. days 1, 4, 8, 11 on a 28 day schedule. Based on data from other concurrent trials an amendment changed dosing of MLN8237 to 20, 30, 40 or 50 mg po twice daily on days 1–7 and BTZ was given at 1.5mg/m2 iv weekly on a 28 day schedule. Results: Median age of patients was 64, 63% were male, 31% had high risk genetics, 84% had prior stem cell transplant, 53% of patients were relapsed and 47% were relapsed and refractory to therapy. No DLTs were observed even at the highest dose level tested. However, one patient at the highest dose level required a platelet transfusion in order to initiate treatment on time in Cycle 2. Thus, a further 3 patients accrued at the highest dose level before declaring the MTD and proceeding to phase II. The highest dose level (Dose Level 3: MLN8237 50 mg po twice daily on days 1–7; BTZ 1.5 mg/m2 iv. given on days 1, 8, 15, 22) was the final dose level tested (the MTD of single agent MLN8237 is 50mg as defined in other Phase I trials). The ORR was 26% (1 CR, 4 PR); when minor responses are included the ORR was 52%. Median follow up was 4.3 months (range 0.9–23.4) and PFS was 5.5 months. At last follow up 12 patients showed no progression and 7 had progressed. Toxicity: 63% of patients experienced a grade 3AE and 5% a grade 4 AE. Grade 3 or 4 toxicity seen in more than one patient was all hematologic with thrombocytopenia and neutropenia being common. Other toxicity of any grade regardless of attribution occurring in more than 20% of patients included neuropathy 63%, fatigue 63%, diarrhea 53%, nausea 47%,vomiting 26%, infection 32%, alopecia 21%, Conclusions: The MTD of the combination is MLN8237 50 mg po twice daily on days 1–7 and BTZ at 1.5mg/m2 iv weekly. Phase II testing is underway and updated results will be presented. Disclosures: Stewart: Millenium: Consultancy, Honoraria, Research Funding; Onyx: Consultancy; Celgene: Consultancy. Vij:Millennium: Speakers Bureau. Hofmeister:Celgene: Advisory board Other, Honoraria.

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A Phase I/II Study of Escalating Doses of Thalidomide (Thal) in Conjunction with Bortezomib (Vel) and High Dose Melphalan (Mel) As A Conditioning Regimen for Autologous Peripheral Blood Stem Cell Transplantation (PBSCT) in Patients with Advanced Multiple Myeloma (MM).

Blood ◽

10.1182/blood.v120.21.3104.3104 ◽

2012 ◽

Vol 120 (21) ◽

pp. 3104-3104 ◽

Cited By ~ 1

Author(s):

Sung H Hong ◽

David S Siegel ◽

Michele L Donato ◽

David H. Vesole ◽

Andrew L Pecora ◽

...

Keyword(s):

Phase I ◽

Disease Progression ◽

Board Of Directors ◽

Phase Ii ◽

Dose Escalation ◽

Synergistic Effects ◽

Phase Iii ◽

High Dose ◽

Combination Regimen ◽

Advisory Committees

Abstract Abstract 3104 Thalidomide is an active agent in the treatment of MM and shows additive and/or synergistic effects when combined with various chemotherapeutics in pre-clinical and clinical models. We conducted a phase I/II study of Thal in combination with Vel and high dose Mel with PBSCT in patients (pts) with either disease progression or less than complete response after a prior PBSCT. Inclusion criteria included a diagnosis of MM and the availability of adequate PBSC. Exclusion criteria were dose-intense therapy within 56 days, uncontrolled infections, uncontrolled CNS metastases, known cardiac amyloid deposition, severe organ dysfunction, Karnofsky score <70%, or severe sensory neuropathy. Conditioning for PBSCT consisted of Vel 1.6 mg/m2 IVP on days -4 and -1 with Mel 200 mg/m2 on day -2. Thal was given on days -5 through -1. Thal was administered in a planned dose escalation steps of 600, 800 and 1000 mg (in cohorts of 3 pts) daily for 5 days. Dexamethasone (Dex) 10–20 mg was given prior to Vel and Mel. All pts received G-CSF every other day starting day +3 until engraftment. Serious adverse events (SAEs) were graded according to CTCAE ver 3. No dose limiting toxicities (≥ grade IV non-hematological SAE) occurred in the phase I portion of this study allowing full dose escalation with 9 pts enrolled. All pts experienced somnolence, more prominent at the 800 mg/day dose. Subsequently, Dex 40 mg was given with first dose of Thal at the 1000 mg level with improvement in sedation. In the phase II portion of the study, an additional 19 pts were treated with Thal 1000 mg daily. No regimen related mortality occurred in either phase I or phase II portion of the study. All SAEs except lethargy and dizziness occurred after PBSCT and were not attributed to Thal. All transplant-related SAEs resolved by day +28 after transplantation. All pts achieved prompt hematological recovery with the median time to ANC >500/uL 10 days (range, 8–14 days), ANC >1000/uL 10 days (range 9–14 days), and plt >20,000 12 days (range 9–25 days). 28 pts (median age, 56) were enrolled in the phase I and phase II portions of the study. 18 pts were treated for disease progression after prior autologous transplant (median lines of prior therapy =2; range, 1–5); only 22% of pts achieved ≥PR to the most recent therapy prior to PBSCT. 7 pts were enrolled after achieving <CR after prior PBSCT. Restaging evaluation was completed at 1, 2, and 3 months and every 3 months thereafter using the modified IMWG criteria. At three months after PBSCT (compared to immediate pre-transplant) the overall response rate ≥PR was 44% (1 CR, 4 VGPR, and 6 PR). An additional 10 pt achieved SD and 4 pts experienced disease progression. 4 subjects subsequently underwent allogeneic transplant and are not evaluable for long term response. The median event-free (EFS) was 7 months. The median overall survival (OS) has not yet been reached. The estimated EFS and OS probabilities at 2 years are 5% and 60%, respectably. Our results indicate that high-dose Thal can be safely added up to 1000 mg daily for 5 days to dose-intense Mel and Vel with acceptable toxicities. Confirmation of potential synergistic effects of this combination regimen will require an appropriately designed phase III study. Disclosures: Siegel: Millennium: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Celgene Corp: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau. Vesole:Celgene Corp.: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Millennium: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau.

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