Active Surveillance Strategies Have Neither Clinical or Survival Benefit Following High-Dose Chemotherapy and Progenitor Cell Rescue in Follicular Lymphoma.

Abstract Introduction: Annual surveillance CT scans and bone marrow (BM) biopsies are frequently performed in follow-up of patients (pts.) receiving high-dose therapy (HDT) with autologous stem cell rescue for recurrent follicular lymphoma (FL). The impact of this active surveillance strategy on the outcome of a homogeneously treated population was analysed. Methods: Ninety-nine consecutive pts. who received HDT (cyclophosphamide and total body irradiation) with autologous stem cell rescue for recurrent FL at St Bartholomew’s Hospital between February 1986 and October 1991 were included. The surveillance policy at that time included an annual CT scan and BM biopsy. Time to relapse, time to next treatment and overall survival (OS) from the time of HDT were calculated and compared, according to whether disease progression had been diagnosed on the basis of surveillance investigations or on clinical grounds. Seventy out of 99 pts. are evaluable, the remainder are not, due to: relapse or death within one year of HDT (20 pts.), follow-up elsewhere (8 pts.) or patient’s wishes (1 pt.). 86% of pts. who commenced surveillance actually had annual CT scans and BM biopsies until disease progression or death. Results: After a median follow-up of 16.7 years (y), progression was documented in 35/70 pts. (50%). It was detected by surveillance alone in 14 pts. and clinically, in 21 pts. (40% and 60% of all recurrences, respectively). The commonest presentations of clinical relapse were peripheral lymphadenopathy (62%), pain (19%) and B-symptoms (10%). Surveillance relapses were diagnosed on the basis of a CT scan in 43% of pts., a BM biopsy in 36% and both in 14%. The median time from HDT to relapse was 2y for pts. with a clinically detected relapse and 2.8y in those with a surveillance relapse but the difference was not statistically significant (p=0.2). Treatment was started immediately in 13 of 21 pts. (62%) with a clinical relapse, contrasting with only one of 14 pts. (7%) diagnosed on surveillance. The main reasons for starting treatment were biopsy-proven transformation to diffuse large B-cell pathology (8 of the pts. with a clinical relapse and one with a surveillance relapse) and rapidly progressing lymphadenopathy. All other pts. were managed expectantly (observation). The median time from HDT until clinical progression was 8.2y in the 14 pts. whose relapse was detected by surveillance; 4 of the 14 have not yet developed signs or symptoms of recurrence. Thus, the clinical relapse rate in the cohort under surveillance is 44% (31/70). Six of the pts. with a surveillance relapse have still not started treatment (median follow-up: 13.8y; range: 1.9y–22.1y). Only 2 of the 21 pts. with a clinically detected relapse have not started treatment after 5.6y and 14.3y of follow-up. Thus, the median time from HDT to next treatment was significantly shorter for pts. with a clinical relapse (3.6y) in comparison with those in whom the recurrence was diagnosed by surveillance investigations (11.3y; p=0.0004). Median OS was 5.6y and 13.4y for pts. with a clinical and a surveillance relapse, respectively (p=0.03). Conclusions: In pts. with FL, relapses diagnosed on the basis of surveillance investigations usually have an indolent course and frequently do not require treatment. In contrast, clinically detected relapses have a more aggressive clinical course and treatment is initiated immediately in the majority of cases. Thus, annual surveillance investigations do not help to identify pts. that require treatment and do not improve the outcome of this population. They should therefore be abandoned. Time to relapse based on data from pts. on annual surveillance should be interpreted with caution because of the poor correlation with time to next treatment and OS.

Download Full-text

The Addition of Rituximab and/or Alpha-Interferon to High Dose Chemotherapy and Autologous Stem Cell Transplantation for Patients with Relapsed Follicular Lymphoma Produces Durable Progression Free Survival and Molecular Remissions

Blood ◽

10.1182/blood.v116.21.1357.1357 ◽

2010 ◽

Vol 116 (21) ◽

pp. 1357-1357 ◽

Cited By ~ 1

Author(s):

Sita Bhella ◽

Neil L Berinstein ◽

Nancy Pennell ◽

Matthew Cheung ◽

Kevin R. Imrie ◽

...

Keyword(s):

Stem Cell ◽

Follicular Lymphoma ◽

Median Time ◽

Residual Disease ◽

High Dose Chemotherapy ◽

Salvage Chemotherapy ◽

High Dose ◽

Stem Cell Collection

Abstract Abstract 1357 Introduction: High dose chemotherapy (HDT) with autologous stem cell transplantation (ASCT) is historically effective treatment for patients with relapsed follicular lymphoma (FL) but relapse is common possibly due to contaminated stem cell grafts or inadequate eradication of primary disease. The addition of immunotherapy to HDT/ASCT may augment “in vivo” graft purging and achieve more effective eradication of minimal residual disease (MRD) post ASCT. This may lead to improved PFS and OS. Methods: We conducted 3 sequential prospective phase 2 trials of HDT/ASCT combined with immunotherapy in patients with relapsed FL from 1997–2010. Protocol 1 (n=13) used a-interferon 3 MU/m2 SC TIW for 2 years post ASCT. Protocol 2 (n=23) used a single infusion of rituximab (R) 375 mg/m2 for ‘in vivo’ purging 3–5 days pre-stem cell collection and 2 sets of 4 weekly R at 2 and 6 months post ASCT respectively. Protocol 3 (n=32) used 3 infusions of R 375 mg/m2 pre stem cell collection, followed by a-interferon 3 MU/m2 SC TIW × 2 years + R 375mg/m2 × 6 weekly infusions post ASCT. Eligibility included adult patients age 18–65 with stage III or IV follicular lymphoma grades 1–3a in first or second relapse. Salvage chemotherapy was either CHOP or DHAP depending on prior anthracycline exposure. High dose therapy was cyclophosphamide, carmustine, and etoposide (CBV). Minimal residual disease (MRD) assessment of t(14; 18) by quantitative PCR was serially performed in blood, PBSC and marrow. Studies were REB approved and all patients gave informed consent. Results: Sixty-eight patients from the 3 trials are included. Median age at study enrolment was 47 (30-71) and patients were a median of 31 mo (9-197) from diagnosis. 54% were male. Median FLIPI score was 2. Median # of prior chemotherapies was 1. Median number of cycles of salvage chemotherapy was 4 (2 - 10). 63 patients proceeded to ASCT. 5 patients were not transplanted either do to disease progression (2), or failed stem cell mobilization (3). Baseline characteristics of the patients enrolled in the three trials were similar, with the exception of rituximab(R) exposure in 22% of the patients in Protocol 3. 4 (6%) patients were lost to follow up. Median time to death or last follow was 84.5 mo (7-166). 32 patients (47%) relapsed and 20 (29%) have died. Median follow up times for each trial were 116, 99 and 57 mo. Actuarial median OS for Protocol 1 was 136 mo from enrolment and has not yet been reached for Protocols 2 and 3. Actuarial median PFS for Protocols 1 and 3 are 49 and 78 mo respectively and has not yet been reached for Protocol 2. MRD assessment by PCR was collected on 48 patients. Compared with study 1, the increased use of R pre SC collection improved in vivo purging by 2 logs. In Protocols 1 and 2, most still had detectable disease in the graft to a sensitivity of 1 cell/100,000. In Protocol 3, 56% had MRD negative apheresis products. 91% of 46 evaluable patients achieved molecular remission post stem cell transplant. Thirteen patients (19%) developed secondary malignancies post ASCT with a median time to malignancy of 88.5 mo (39-144). 1 patient developed 2 distinct malignancies. Secondary malignancies present were: MDS (4), AML (1), ALL (1), basal cell carcinoma (2), squamous cell carcinoma (3), thyroid cancer (1), non small cell lung cancer (1) and adenocarcinoma of unknown origin (1). Five (7%) patients transformed to DLBCL, with a median time to transformation post ASCT of 43.5 mo (17-142). The majority of patients who received rituximab immunotherapy pre and post ASCT developed persistent hypogammaglobulinemia. 17 patients (26%) developed interstitial pneumonitis or >2 respiratory complications post rituximab. 4 patients (6%) require monthly IVIG to treat recurrent respiratory infections. 10 patients (15%) developed herpes zoster <90 days post ASCT. 15% and 30% of patients in Protocols 1 and 3 did not complete the 2 years of alpha-IFN post ASCT secondary to one or more of depression, fatigue or cytopenias. Conclusion: HDT + ASCT combined with R +/− a-IFN produces durable PFS and molecular remissions but is associated with prolonged hypogammaglobulinemia and higher rates of interstitial pneumonitis. Three infusions of R pre SC collection achieve higher rates of molecular remission. Compliance with 2 years of a-IFN added to R post ASCT is poor and may not add clinical benefits to R alone. The additional role of HDT/ASCT in the era of R-chemotherapy for FL needs to be explored. Disclosures: No relevant conflicts of interest to declare.

Download Full-text

Prospective Use of a Triple FISH Probe to Predict sMDS/AML Following High Dose Therapy with Autologous Stem Cell Rescue for Lymphoma.

Blood ◽

10.1182/blood.v116.21.3459.3459 ◽

2010 ◽

Vol 116 (21) ◽

pp. 3459-3459

Author(s):

Paul Greaves ◽

Silvia Montoto ◽

Janet Matthews ◽

Andrew Wilson ◽

Daniel L P Brown ◽

...

Keyword(s):

Stem Cell ◽

Follicular Lymphoma ◽

Hodgkin Lymphoma ◽

In Situ Hybridisation ◽

B Cell Lymphoma ◽

High Dose ◽

Fatal Complication ◽

Stem Cell Rescue ◽

Autologous Stem Cell Rescue

Abstract Abstract 3459 Secondary myelodysplasia/acute myeloid leukaemia (sMDS/AML) is an almost universally fatal complication of high-dose chemotherapy with autologous stem cell rescue (HDT+ASCR) for lymphoma, occurring in 2–10% of recipients at five years (Pedersen-Bjergaard et al. Blood, 2000; 95: 3273-9). There are no reliable predictive factors except prior chemotherapy and radiotherapy. At St Bartholomew's Hospital, London (Barts) 33/230 (14%) patients (pts) having cyclophosphamide+total-body irradiation (Cy-TBI)-conditioned HDT+ASCR for lymphoma developed sMDS/AML after a median follow-up of 6 years, and a retrospective analysis in those in whom a pre-Cy-TBI sample was available showed cytogenetic abnormalities in all of them. Subsequently a triple fluorescent in-situ hybridisation cytogenetic probe (TF) for the commonest abnormalities seen in sMDS/AML (EGR1: 5q31, RB1: 13q14 and D7Z1: 7q31) was developed (Lillington et al. Ann Oncol, 2002; 13: 40-3). The aim of the current study was to analyse the prospective use of TF to identify those at greatest risk of MDS, by including the test as part of the standard pre-transplant workup for all patients receiving the successor to Cy-TBI at Barts: BEAM (BCNU, Etoposide, Ara-C, Melphalan) HDT+ASCR during a 7-year period 2002–2009. 133 pts (47% female, 53% male; median age: 47, range: 18–68) received BEAM HDT for lymphoid malignancies during this time (22% diffuse large B-cell lymphoma, 21% follicular lymphoma, 11% transformed follicular lymphoma, 33% Hodgkin lymphoma and 13% other non-Hodgkin lymphoma). Median time from diagnosis to HDT was 29 months (range: 7–275 months). TF was performed in 125 cases (94%), using a pre-transplant bone marrow sample in 95% and harvested stem cells in 5%. An abnormal result (5q31 del) was detected in one case (0.8%). After a median follow-up of 64 months (range: 24–103), 4/133 (3%) patients developed sMDS/AML at a median of 23 months (6-85) following treatment, including the single patient with an abnormal TF result before BEAM. The TF pre-BEAM showed no abnormalities in 2 cases developing sMDS/AML and was not performed before HDT in the fourth. The low incidence of pre-transplant TF abnormalities in BEAM candidates (0.8%) compared to historic Cy-TBI candidates, and the failure of the test to detect the remaining cases (2.4%) has demonstrated this not to be an effective risk-stratifying tool. Whether withholding a potentially beneficial treatment from patients in whom an abnormality is detected would prevent or delay sMDS/sAML is unknown. However identifying patients at greatest risk of this almost universally fatal complication remains a challenge and prospectively assessable risk factors should continue to be sought while outcomes remain so dire. Disclosures: Gribben: Roche: Consultancy; Celgene: Consultancy; GSK: Honoraria; Napp: Honoraria. Lister:Allos: Consultancy; Bioconnections: Consultancy; Astra Zeneca: Consultancy; Tenet: Consultancy; GSK: Chairman of Safety Monitoring Committee.

Download Full-text

Remission Duration ≤ 12 Months for Early Relapsed and Refractory Follicular Lymphoma Is Predictive of Early Failures Post-High Dose Therapy and Autologous Stem Cell Rescue.

Blood ◽

10.1182/blood.v120.21.3136.3136 ◽

2012 ◽

Vol 120 (21) ◽

pp. 3136-3136

Author(s):

Matthew A Lunning ◽

Jocelyn C Maragulia ◽

Craig H. Moskowitz ◽

Matthew J. Matasar ◽

Hugo Castro-Malaspina ◽

...

Keyword(s):

Overall Survival ◽

Stem Cell ◽

Follicular Lymphoma ◽

Induction Therapy ◽

High Dose ◽

High Dose Therapy ◽

Free Survival ◽

Stem Cell Rescue ◽

Remission Duration

Abstract Abstract 3136 Background: Follicular lymphoma (FL) is the most common indolent non-Hodgkin lymphoma (NHL) in the Western hemisphere and is likely incurable with chemotherapy alone. Despite a median overall survival exceeding 12 years in the modern era, a fraction of patients experience an aggressive clinical course characterized by short remission duration(s) and/or chemorefractory disease. While high-dose therapy and autologous stem cell rescue (HDT-ASCR) is an accepted treatment modality for prolonging progression-free survival (PFS) it is unlikely to provide cure. Allogeneic stem cell transplantation (alloSCT) is a definitive therapy that has been shown to produce long-term disease free remissions. Unfortunately, alloSCT is limited by the risk of transplant-related mortality (TRM) despite the advent of non-myeloablative (NMA) conditioning regimens. Given that many FL patients whom fail HDT-ASCR may not proceed to alloSCT, and the inherent difficulty in deciding the appropriate consolidative transplant modality, we conducted a retrospective exploratory analysis of clinical features of early and multiply relapsed FL patients undergoing first HDT-ASR or alloSCT at a single center in the modern, post-rituximab era. Methods: We retrospectively reviewed all patients with early relapsed and/or refractory FL that proceeded to HDT-ASCR or NMA alloSCT as first transplant at MSKCC between 2006 and 2010. Chemosensitive disease was defined as a partial response (PR) or complete response (CR) to the last treatment regimen prior to transplant by computed tomography scans per IWG Criteria (Cheson et al JCO 1999). Events were defined as progression of FL post-transplant or death from any cause. Event-free survival (EFS) and overall-survival (OS) were estimated using Kaplan-Meier method. Results: We identified 40 patients with relapsed or refractory FL who had undergone either first HDT-ASCR (N=20) or alloSCT (N=20). All patients had FL grade 1–3a without pathologic evidence of transformation at the time of re-induction prior to transplant consolidation. Patient characteristics are outlined in the table below: All HDT-ASCR patients received BEAM (carmustine, etoposide, cytarabine, melphalan) conditioning. All alloSCT patients received a uniform non-myeloablative conditioning regimen (cyclophosphamide, fludarabine, total body irradiation 200 cGy). The median follow-up for survivors is 34 months. The estimated 3 year-EFS and OS was 60% and 62% with HDT-ASCR and 79% and 85% with alloSCT respectively (p=ns). FL patients with remission duration ≤ 12 months prior to re-induction therapy proceeding to consolidative HDT-ASCR had significantly shorter EFS compared to those patients with previous remission duration > 12 months (p<0.05, figure 1). Furthermore, when HDT-ASCR and alloSCT patients with a previous remission duration ≤ 12 months prior to re-induction therapy were compared the estimated 3-year EFS was 79% for alloSCT and 36% for HDT-ASCR (p<0.03, figure 2). With relatively short follow-up, there was no difference in OS for these two groups. In the HDT-ASCR cohort eight events were related to progression of FL with three of the eight patients subsequently undergoing alloSCT. In the alloSCT cohort four events occurred with one patient developing DLBCL and three TRM (2-related to graft-versus-host disease; 1-cytomegalovirus infection). Conclusion: The management of relapsed/refractory follicular lymphoma remains a clinically complex topic. In this exploratory analysis we demonstrated that remission duration of ≤ 12 months prior to re-induction chemotherapy is suggestive of inferior disease control with HDT-ASCR. Longer follow-up is necessary to determine the OS impact. Given the relatively unfavorable pre-transplant characteristics of the alloSCT cohort, FL appears to be exquisitely sensitive to an allogeneic effect. TRM continues to limit the benefit of alloSCT. Disclosures: Matasar: GSK: Research Funding; Genentech: Consultancy.

Download Full-text

Immunotherapy with Rituximab after Peripheral Blood Stem Cell Transplantation for Multiple Myeloma.

Blood ◽

10.1182/blood.v104.11.5232.5232 ◽

2004 ◽

Vol 104 (11) ◽

pp. 5232-5232

Author(s):

Celso Mitsushi Massumoto ◽

Edilson Pinheiro Junior ◽

Otávio C.G. Baiocchi ◽

Ronald Pinheiro ◽

Adelson Alves

Keyword(s):

Multiple Myeloma ◽

Stem Cell ◽

Stem Cell Transplantation ◽

Cell Transplantation ◽

Median Time ◽

Autologous Stem Cell Transplantation ◽

Clinical Characteristics ◽

Residual Disease ◽

High Dose

Abstract Introduction: autologous stem cell transplantation is a potentially curative or may augment the time to progression in Multiple Myeloma (MM) patients. The immunotherapy with rituximab may help control the minimal residual disease after high dose chemotherapy. Twenty percent (20%) of Multiple Myeloma patients express the CD20+ protein and can be target for immunotherapy. Objective: The aim of this study was to evaluate the use of rituximab after autologous stem cell transplantation for Multiple Myeloma. Patients and Methods: eight patients (4 male) with a median age of 53 (range 43–59) years diagnosed with MM. All of them had received at least one previous regimen were enrolled in the protocol study. All patients signed the consent form. Patients in relapse received a salvage regimen with C-VAD n=2 (cyclofosfamide 4 g/m2 e vincristine 0.4 mg/d (d 1–4), doxorrubicin 0.9 mg/m2 (d1-4) e dexametasone 40 mg (d1-4; 9-12; 17–22) or cyclofosfamide (1OO mg/kg, n=7) followed by stem cell harvesting. The preparative regimen was Busulfan 12 mg/kg and cyclofosfamide 120 mg/kg or Melphalan 200mg/m2. Rituximab at a dose of 375mg/m2 weekly x 4 was given every 6 months for 2 years after SCT. The clinical characteristics of the patients are shown on Table 1. Results: the median time to ANC and platelets engraftment was 11 (range 8–12) and 26 (range 17–35) days. Patients have been in CR at a median time of 11 months follow-up. Minor Rituximab-associated toxicities were seen:rigor, fever and short of breath that were controlled with acetaminophen and diphenidramine. Conclusion: the Rituximab given after autologous stem cell transplantation is safe in Multiple Myeloma patients and may prolong time to disease progression. A randomized study is required to evaluate the role of rituximab after ASCT. Table 1 - Clinical Characteristics of Patients Patients Age/gender Status Pre- BMT Status Post- BMT Salvage Tx Prep. regimen ANC/Platelets X1000 MM3/ml Follow-up (months) FRC 57/M PR PR C-VAD BU+MEL 12/28 EXPIRED MB 52/F CR1 CR1 C-VAD BU+MEL 12/60 EXPIRED AM 52/F PR PR C-VAD BU+MEL 9/26 EXPIRED IM 54/M PR CR Cyx2 BU+MEL 12/21 ALIVE GAD 50/F PR CR Cyx2 BU+MEL 12/35 ALIVE SCM 59/M CR CR Cyx2 BU+MEL 10/17 ALIVE MAD 63/F CR CR C-VAD MELPHALAN 12/25 ALIVE JFC 51/M CR CR C-VAD BU+MEL 12/18 ALIVE

Download Full-text

High-Dose Bi-Weekly THP-COP Induction Treatment Followed by High-Dose Therapy with Autologous Peripheral Blood Stem Cell Transplantation for Advanced-Stage Follicular Lymphoma as First-Line Therapy.

Blood ◽

10.1182/blood.v104.11.5207.5207 ◽

2004 ◽

Vol 104 (11) ◽

pp. 5207-5207

Author(s):

Sadao Aoki ◽

Jun Takizawa ◽

Masutaka Higashimura ◽

Akihito Momoi ◽

Nobuhiro Tsukada ◽

...

Keyword(s):

Stem Cell ◽

Stem Cell Transplantation ◽

Follicular Lymphoma ◽

Cell Transplantation ◽

High Dose ◽

Advanced Stage ◽

First Line ◽

First Line Therapy ◽

Line Therapy

Abstract Introduction: Most patients with advanced-stage follicular lymphoma(FL) cannot be cured by conventional chemotherapy and have median survival of 7 to 10 years. High-dose chemotherapy (HDT) supported by autologous stem cell transplantation(ASCT) gives a survival benefit for patients with aggressive lymphoma. Recent several multicenter studies have shown that clinical and molecular remissions can be attained in patients with FL receiving intensified high-dose sequential chemotherapy and autografting. We have reported the efficacy and safety of high-dose bi-weekly THP-COP with G-CSF support (HDBW-TCOPG) for non-Hodgkin’s lymphoma. Therefore, we performed a pilot clinical trial to evaluate the efficacy and toxicity of HDBW-TCOPG followed by HDT with ASCT as first-line therapy in patients with advanced-stage FL. Patients and methods: Between August 1998 and December 2003, 10 Japanese patients with previously untreated FL from whom informed consent was obtained were included in this single-center pilot study. Median age was 48 years. All patients had stage 3 or 4 disease, aaIPI LI 8 and HI 2. Histological subtypes of FL included grade 1 4; grade 2 4; grade 3a 2. HDBW-TCOPG consisted of pirarubicin 70 mg/m2 on day 1; cyclophosphamide 1000 mg/m2 on day 1; vincristine 1.4 mg/m2 on day 1; predonisolone 50 mg/m2 from day 1 to 5; lenograstim 2.0 mg/kg/day from day 3. Five patients who enrolled after rituximab was approved for indolent B-cell lymphoma in Japan received induction therapy combined HDBW-TCOPG with rituximab 375mg/m2 on day -2 (R-HDBW-TCOPG). Six cycles were administered at intervals of two weeks. PBSC were collected during the later cycles of HDBW-TCOPG or on the recovery of high-dose etoposide regimen (500mg/m2 for 3 days) administered after the completion of HDBW-TCOPG. Leukaphereses were performed until a minimum of 2.0x106/kg CD34+ cells had been collected. The conditioning regimen consisted of ranimustine 200mg/m2 on day-7 and -2; paraplatin 300mg/m2 on day -6, -5, -4, -3; etoposide 500mg/m2 on day −5, −4, −3; cytarabine 2.5 g/m2 every 12 hours on day −2, −1 (MCE-CA regimen) in 2 patients or cyclophosphamide 50mg/kg on day −2, −1 (MCEC regimen) in 8 patients. Results: Sufficient numbers of PBSC were collected in 5 of 7 patients mobilized with HDBW-TCOPG and in all 5 patients with high-dose etoposide. The median time to reach total number of leukocytes of 1.0 x109/l was nine days (range 8–11). All 10 patients who were in PR at the end of HDBW-TCOP(G) achieved CR post APBSCT. After a median follow up of 36.6 months (range 7–66 months) PFS and OS are 90% and 90%, respectively, for all patients. One patient developed secondary myeloid leukemia with t(3;21) and died at 35 months after APBSCT without signs of recurrence of lymphoma. Another patient who relapsed at 35 months after transplantation. IgH or BCL2 rearrangement was detected by PCR analysis prior to therapy in three patients and one of them still showed detectable disease after HDBW-TCOPG induction. However, all three patients demonstrated MRD negativity after HDT with ASCT. Conclusion: HDBW-TCOPG as induction therapy followed by HDT with ASCT is feasible for advanced-stage FL with acceptable toxicity, and this short term highly intensified therapy may induce cure of the disease by minimizing MRD, but longer follow up is needed to evaluate the impact on survival.

Download Full-text

Long-Term Follow-Up of Patients Treated with Bortezomib Alone and in Combination with Dexamethasone as Frontline Therapy for Multiple Myeloma.

Blood ◽

10.1182/blood.v108.11.796.796 ◽

2006 ◽

Vol 108 (11) ◽

pp. 796-796 ◽

Cited By ~ 19

Author(s):

Sundar Jagannath ◽

Brian G.M. Durie ◽

Jeffrey Lee Wolf ◽

Elber S. Camacho ◽

David Irwin ◽

...

Keyword(s):

Stem Cell ◽

Survival Rate ◽

Median Time ◽

Response Rate ◽

Sensory Neuropathy ◽

High Response Rate ◽

High Dose ◽

Phase 2 ◽

Frontline Therapy

Abstract Introduction: Novel therapeutic agents, such as bortezomib (VELCADE®; btz), thalidomide, and lenalidomide, are being used in combination with dexamethasone (dex) as frontline therapies in MM. Phase 2 and 3 trials with limited follow-up have reported a high response rate and feasibility of high-dose therapy and stem cell transplantation (HDT-SCT). Here we present longer follow-up on our phase 2 trial of btz±dex as frontline therapy. Methods: Patients (pts) with measurable disease and KPS ≥50% received btz 1.3mg/m2 on days 1, 4, 8 and 11 of a 3-week cycle for up to 6 cycles. Oral dex 40mg was added on the day of and day after btz for pts achieving < partial response (PR) after 2 cycles or < complete response (CR) after 4 cycles. Responses were assessed using European Group for Blood and Marrow Transplantation criteria, with the addition of near CR (nCR; CR but positive immunofixation). Results: 48 pts were accrued and were evaluable for response; a further 2 registered on the trial declined to proceed. Median age was 60 years, 46% were male, 64% had IgG and 21% IgA, and 50% were Durie-Salmon stage III. At the end of btz±dex treatment, overall response rate (ORR; CR+nCR+PR) was 90% with 19% CR/nCR; an additional 8% achieved a minimal response (MR). Response to btz alone was rapid; response rate by end of cycle 2 was 50%, including 10% CR/nCR. Dex was added for 36 (75%) pts: 17 at cycle 3, 18 at cycle 5, and 1 at cycle 6. Addition of dex improved best responses to btz in 23 (64%) pts, with 12 improving from stable disease to MR or PR, 9 from MR to PR, 1 from PR to nCR, and 1 from nCR to CR. Median time to best response was 1.9 months. For all 48 pts, with a median follow-up of 24 months, median time to alternative therapy (TTAT) was 7 months (range: 2–25; this includes pts who went on to HDT-SCT), and median overall survival (OS) has not been reached; 1-year survival rate was 90%. For pts not proceeding to HDT-SCT, median TTAT was 22 months, median OS has not been reached; 1-year survival rate was 80%. 23/48 pts proceeded to HDT-SCT. Median CD34+ harvest was 12.6 x 106 cells/kg (range: 5.1–40.4 x 106) from a median of 2 collection days (range: 1–8). All pts had complete hematologic recovery; median time to neutrophil (ANC >1000/mm3) and platelet (>100,000/mm3) engraftment was 11 days (range: 8–13) and 17 days (range: 10–98), respectively. In the 23 HDT-SCT pts, median TTAT and OS have not been reached; post-transplant 1-year survival rate was 90%. The most common grade ≥2 adverse events for btz±dex were sensory neuropathy/neuropathic pain (37%), fatigue (20%), constipation (16%), nausea (12%), and neutropenia (12%). Two pts developed grade 4 events (1 neutropenia, 1 thrombocytopenia). Conclusion: Btz±dex is an effective frontline therapy for MM, with an ORR of 90%, including 19% CR/nCR, and OS rate of 80% at 1 year. The treatment is well tolerated and toxicities were manageable and reversible. Addition of dex to btz provides improved responses. TTAT for patients not undergoing HDT-SCT was 22 months. The regimen does not prejudice subsequent HDT-SCT; stem cell harvest and engraftment were successful in all pts proceeding to transplant. Consolidation with HDT-SCT further increases the response rate and durability of response. Btz+dex is being compared to VAD as induction therapy prior to HDT-SCT in a phase 3 study.

Download Full-text

Phase I/II Trial of High-Dose Melphalan (M) and Topotecan (T) Followed by Autologous Stem Cell Rescue in Patients ≤ 60 and > 60 Years of Age with Multiple Myeloma (MM).

Blood ◽

10.1182/blood.v110.11.943.943 ◽

2007 ◽

Vol 110 (11) ◽

pp. 943-943

Author(s):

Daniel Sullivan ◽

Melissa Alsina ◽

Claudio Anasetti ◽

Teresa Field ◽

Mohamed Kharfan-Dabaja ◽

...

Keyword(s):

Stem Cell ◽

Total Dose ◽

Dose Level ◽

Topoisomerase I ◽

Plasma Cells ◽

The Elderly ◽

High Dose ◽

Stem Cell Rescue ◽

Grade 3

Abstract MM is the most common indication for high-dose chemotherapy (HDC) and autologous stem cell rescue. Among 13,431 pts receiving HDC for MM, the 3-year probability of survival is 67% ± 1% with autotransplantation (IBMTR data). Pre-clinical data from our lab demonstrate a synergistic cytotoxic interaction from sequential M and topoisomerase I inhibitors in human MM cell lines. Thus, we conducted a trial where poor prognosis chemosensitive, relapsed, and primary refractory pts were primed for stem cell collection with cyclophosphamide (50 mg/kg/d X 2d) and GCSF. Pts were then treated with fixed doses of M (50 mg/m2/d X 3d; total dose = 150 mg/m2) followed immediately by dose-escalated T (6.7–56.7 mg/m2/d X 3d; total dose = 20–170 mg/m2) in separate cohorts of younger (≤ 60) and elderly (> 60) patients with MM. The standard dose of M was decreased to allow for dose-escalation of T. One hundred nineteen patients are evaluable for toxicity, response and survival (54 elderly and 65 younger). The maximum tolerated dose (MTD) in the elderly cohort is 30 mg/m2 total dose T (dose level 2); dose-limiting toxicity (DLT) at 40 mg/m2 was grade 3 musculoskeletal toxicity. The median age of the elderly pts was 65 yrs (range 61–77). The MTD in younger patients was a total T dose of 127.3 mg/m2 (dose level 7); DLT at 170 mg/m2 was grade 4 transaminitis. The median age of the younger pts was 53 yrs (range 33–60). The response rate (CR + PR) in elderly subjects (includes 38 pts enrolled at the MTD) was 65%, and 77% in those ≤ 60 (7 pts enrolled at the MTD thus far). Grade 3–4 mucositis was common at all dose levels of T and increased in incidence with T dose-escalation. Median days to ANC ≥ 500/ml X 3d for all patients was d+11, and for platelets ≥ 20K X 7d was d+16. No correlation between time of engraftment and dose level was observed. The 100 day non-relapse mortality was 1.7% (one patient died from sepsis and one from ARDS). At a median follow up of 25.3 and 35.3 months for the elderly and young cohorts, respectively, the 3-year overall survival is 70% for both groups. At a median follow up of 15.3 months for the elderly and 14 months for the young cohort, the 3-year event-free survival is 32% and 40%, respectively. The pharmacokinetics of high-dose M and T have been determined in all patients on this trial, and the AUC and CMAX of T appear to be linear with dose. Pts with stable disease after transplant were found to have an increased clearance of melphalan and a lower AUC of T lactone and T total drug. SNP analyses of 71 pts using the Nanogen DrugMet SNP genotyping assay showed that CYP3A5*3 carriers appear to have increased T metabolism that is associated with a poorer response to MT. The relative risk a CYP3A5*3 allele carrier would have a PR or SD was 1.77 with a 95% CI of 1.37–2.28. The remaining goals of this trial are to enroll 43 pts at the MTD for both the young and elderly cohorts, to determine topoisomerase I levels and distribution in CD138-selected plasma cells, and to define the levels and function of the ABCG2/BCRP pump in plasma cells (for which T is the best substrate). This trial was supported in part by NCI grant CA082533 and GlaxoSmithKline.

Download Full-text

Predictive Value of Molecular Remissions Post Consolidation Chemotherapy in Patients with Core Binding Factor (CBF) Acute Myeloid Leukemias – a Single Centre Analysis

Blood ◽

10.1182/blood.v124.21.3693.3693 ◽

2014 ◽

Vol 124 (21) ◽

pp. 3693-3693

Author(s):

Uday Deotare ◽

Marwan Shaheen ◽

Joseph M. Brandwein ◽

Bethany Gill ◽

Suzanne Kamel-Reid ◽

...

Keyword(s):

Median Time ◽

High Dose ◽

Relapse Free Survival ◽

Consolidation Chemotherapy ◽

Free Survival ◽

Post Induction ◽

Binding Factor ◽

High Dose Cytarabine ◽

Time To Relapse

Abstract Background: Acute myeloid leukemia (AML) with t(8;21) or inv(16) is commonly referred to as core-binding factor AML (CBF-AML). Although this group represents a favorable cytogenetic AML subgroup, 30-40% of these patients nevertheless relapse after standard intensive chemotherapy. The incorporation of high-dose cytarabine for postremission therapy has substantially improved the outcome of CBF-AML patients, especially when administered as 2-4 repetitive cycles. Here we present retrospective data from a single centre, on this favourable AML subgroup. Methods: We analyzed retrospectively the outcome of 80 sequential patients with CBF-AML (46 t(8;21), 34 inv(16)/t(16;16)) treated over a 13 year period from 2000-2012. The median age was 48 years (range 20-80) with a median white cell count of 13x109/L(range 1-426x109/L). All patients underwent induction chemotherapy consisting of daunorubicin (60 mg/m2/d x 3 days) and continuous infusion cytarabine (100 or 200 mg/m2/d x 7 days, for ages <60y and ≥60y, respectively). Patients in CR then received 3 cycles of consolidation chemotherapy which included high dose cytarabine (3 or 1.5 g/m2 on days 1, 3 and 5, for ages <60y and ≥60y, respectively) with daunorubicin 45 mg/m2 on days 1 and 3 added during cycle 1. Results: Ninety percent of patients achieved morphological complete remission (CR) post induction, but 33.3% of these remained molecularly positive by quantitative reverse transcriptase polymerase chain reaction (qR-PCR). The majority of patients (93.6%) subsequently achieved molecular negativity by qR-PCR after the 3rd consolidation cycle. With a median follow-up of 5 years, the estimated 5-year relapse free survival (RFS) was 58% and 5-year overall survival (OS) was 66%. This is in keeping with the earlier AMLSG and UK MRC studies. Only 21% of patients relapsed and the median time to relapse was 10 months. Of the 16 patients who relapsed, 7 underwent allogeneic hematopoietic cell transplantation (HCT) from HLA- matched sibling or unrelated donors, and of these, 4 remain alive and in remission with a median follow up of 8 years. While relapse occurred in 2 of the 4 patients who did not achieve a molecular CR after 3 cycles of consolidation, 13 of 16 relapsing patients had been in a molecular CR after final consolidation and one patient was not evaluated. Therefore, molecular remission post consolidation does not guarantee long term disease free survival. Further molecular analyses and the roles of additional mutations in predicting relapse will be presented. Conclusion: Sustained remissions can be achieved in patients with CBF AML after 3 cycles of high dose cytarabine consolidation, but post consolidation molecular remission does not necessarily preclude relapse. Comprehensive molecular profiling may be better in predicting relapse risk in this group of patients. Table1: Patient characteristics & response N=80 Sex 45 M : 35 F Median age, years (range) 48 (20-80) WBC at diagnosis (x106 cells/L) (range) 13 (1-426) Cytogenetics t(8;21) inv16/t(16;16) 46 (58%) 34 (42%) Response post-induction chemotherapy CR Primary refractory 72 (90%) 8 (10%) Number of consolidation cycles (range) 3 (2-4) Molecular CR post –induction Yes No Not evaluated 16 (20%) 32 (40%) 32 (40%) Molecular CR post –consolidation –cycle 3 Yes No Not evaluated 59 (74%) 4 (5%) 17 (21%) Relapse Yes No Unknown 16 (20%) 59 (74%) 5 (6%) Median time to relapse, months (range) 10 (6-17) Median time to follow up, y (range) 5 (0.5-11.5) Figure 1 : Overall and Relapse free survival in CBF-AML patients. Figure 1 :. Overall and Relapse free survival in CBF-AML patients. Disclosures Gupta: Novartis: Consultancy, Honoraria, Research Funding; Incyte Corporation: Consultancy, Research Funding.

Download Full-text

High dose chemotherapy with autologous stem cell rescue (ASCR) for recurrent medulloblastoma

Journal of Clinical Oncology ◽

10.1200/jco.2006.24.18_suppl.11507 ◽

2006 ◽

Vol 24 (18_suppl) ◽

pp. 11507-11507

Author(s):

B. Diez ◽

M. Garcia Lombardi ◽

G. Chantada ◽

C. Dengra ◽

D. Fernandez Sasso ◽

...

Keyword(s):

Stem Cell ◽

Median Time ◽

Area Under The Curve ◽

High Dose Chemotherapy ◽

Local Relapse ◽

High Dose ◽

Term Survival ◽

Stem Cell Rescue ◽

Autologous Stem Cell Rescue

11507 Background: Medulloblastoma is a highly lethal disease when it recurs and very few patients survive with conventional treatment. This study evaluated the use of high-dose carboplatin, thiotepa, and etoposide with autologous stem-cell rescue (ASCR) in patients with recurrent medulloblastoma. Methods: Between 8/97 and 8/05 14 patients (M/F 12/2) with recurrent medulloblastoma, aged 2 to 33 years (median, 10.5 years) at ASCR, were treated. Thirteen had relapsed after chemotherapy and craniospinal + posterior fossa irradiation and one after chemotherapy (Baby POG) at a median time of 19 months (7 to 148). One had a local relapse and 13 had dissemination at relapse (M1: 1, M2: 7 and M3: 5) Chemotherapy consisted of carboplatin 500 mg/m2 (or area under the curve = 7 mg/ml × min via Calvert formula) on days −8, −7, −6; and thiotepa 300 mg/m2 and etoposide 250 mg/m2 on days −5, −4, and −3 respectively; followed by ASCR on day 0. Results: Four patients died of treatment-related toxicities at 0, +23, +42 and +51 days post ASCR (bacterial sepsis in 2, CMV infection in 1 and CNS hemorrhage in 1). It should be remarked that all the toxic deaths were observed in patients auto grafted before October 2000. Five of 14 patients (35%) are event-free survivors at a median of 70 months post-ASCR (range: 5 to 86 months). Tumor recurred in the remaining 5 patients at a median time of 2 months post ASCR (2 to 15). All died at +23, +16, +12, +9 and +4 month post ASCR. Conclusions: Our results seem consistent with those published by Dunkel IJ (J. Clin Oncol; 16:222 - 8 1998) and argue about the efficacy of high dose chemotherapy with ASCR to provide long-term survival for some patients with recurrent medulloblastoma. No significant financial relationships to disclose.

Download Full-text