scholarly journals Autologous Followed By Allogeneic Versus Tandem-Autologous Stem Cell Transplant in Newly Diagnosed FISH-del13q Myeloma

Blood ◽  
2014 ◽  
Vol 124 (21) ◽  
pp. 43-43 ◽  
Author(s):  
Stefan Knop ◽  
Peter Liebisch ◽  
Holger Hebart ◽  
Ernst Holler ◽  
Monika Engelhardt ◽  
...  
Keyword(s):  
Stem Cell ◽  
High Risk ◽  
Stem Cell Transplant ◽  
High Dose ◽  
Unrelated Donor ◽  
Cell Transplant ◽  
Fluorescence In Situ Hybridisation ◽  
Newly Diagnosed ◽  
Treatment Pathways ◽  
The Impact

Abstract Background In multiple myeloma (MM), the introduction of novel compounds into first-line intensive treatment pathways has clearly improved patients’ prognosis. Very recently however, specific molecular cytogenetic abnormalities, lactate dehydrogenase elevation and International Staging System 3 disease were identified to be associated with dismal prognosis despite upfront autologous (auto) stem cell transplant (SCT). Consolidative allogeneic (allo) following initial auto SCT was shown to extend progression-free survival (PFS) as well as overall survival (OS) in some prospective studies on newly diagnosed MM patients (pts). Relatively little is known on the impact of cytogenetic features other than chromosome 13q deletion (del13q) on the outcomes of pts undergoing upfront auto followed by allo (auto/allo) SCT. Patients and methods When the DSMM V treatment program was designed del13q detected by fluorescence in situ hybridisation (FISH) was accepted as one of the distinct risk factors in MM. We therefore used FISH del13q to define the study’s “high-risk” group and aimed to compare tandem high-dose melphalan 200 mg/m² (Mel) with one cycle of Mel followed by reduced-intensity conditioning (RIC) allo SCT. Allocation to either transplant regimen was by availability of an HLA-matched (at least 9/10 matches) related (MRD) or unrelated donor (MUD). Initially, all pts underwent non-novel compound cytoreduction and chemomobilization of peripheral blood stem cells (PBSC). RIC allo SCT was prepared by fludarabine and melphalan (plus ATG in MUD cases). PFS was the primary endpoint. The study was powered to detect an improvement of 2-year PFS from 20% (tandem Mel) to 40.3% (HR, 1.769). Results 199 out of 225 del13q pts with a median age of 53 (range, 30 – 60) yrs who had been enrolled between 10/2001 and 03/2007, were included in the intent-to treat population. Allo SCT was performed in 126/199 pts (63%), 74 of whom (59%) received MUD allografts. At a median follow-up of 49.2 months (mo), 2-year PFS (calculated from day 1 of second SCT) was 59% with auto/allo SCT versus 47% with tandem Mel. Median PFS with auto/allo SCT was 34.5 mo versus 21.8 mo, respectively (p=.005). Two-year non-relapse mortality (NRM) associated with auto/allo SCT was 11.9%. As of yet, there is no difference in OS between the groups, with the median not yet reached for either transplant modality. PFS/OS in auto/allo SCT were independent of donor source (MRD vs MUD). As definitions of cytogenetic risk have evolved over time, we analyzed further FISH abnormalities in pts’ baseline samples: in addition to uniform del13q, 13.6% of pts displayed del17p. Median PFS for del13q/del17p pts after HD Mel was 6 mo versus not reached with auto/allo SCT, respectively (p=.0002). Median OS in del13q/del17p after HD Mel was 23.4 mo versus not reached, respectively (p=.011). In translocation (4;14)/del13q pts (20.7%), median PFS with tandem Mel was 19.3 mo versus 19.1 with auto/allo SCT, respectively (p=.251). Conclusions This prospective trial shows auto/allo SCT to significantly extend PFS when compared to tandem HD Mel in a large cohort of del13q MM pts. It is the first study to demonstrate allo SCT in MM can be safely performed from matched unrelated donors at a reasonable rate of NRM. Utilizing a comprehensive set of FISH cytogenetics, our data for the first time demonstrate allo SCT to specifically benefit patients with high-risk features (del13q/del17p). Incremental gain of PFS when compared to tandem Mel was more than 20 months. Extended OS data on the whole study will be presented. Disclosures No relevant conflicts of interest to declare.

scholarly journals Response to Lenalidomide, Doxorubicin and Dexamethasone (RAD) in Newly Diagnosed Multiple Myeloma Is Independent of Cytogenetic Risk and Retained after Double Stem Cell Transplant

Blood ◽  
2014 ◽  
Vol 124 (21) ◽  
pp. 177-177 ◽  
Author(s):  
Stefan Knop ◽  
Christian Langer ◽  
Monika Engelhardt ◽  
Lars-Olof Mügge ◽  
Albrecht Reichle ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Stem Cell ◽  
Stem Cell Transplant ◽  
In Situ Hybridisation ◽  
Unrelated Donor ◽  
Cell Transplant ◽  
Fluorescence In Situ Hybridisation ◽  
Newly Diagnosed ◽  
Target Dose ◽  
One Year

Abstract Background Induction triplets with at least one of the “novel drugs” and steroids with or without chemotherapy are deemed standard of care in newly diagnosed multiple myeloma (MM). Medically fit patients (pts) remain candidates for subsequent autologous (auto) stem cell transplant (SCT) while the use of allogeneic (allo) SCT is an ongoing matter of debate. We had previously shown the RAD regimen to be well tolerated and highly effective in relapsed and relapsed/refractory disease. Based on the overall results we decided to further evaluate the combination in first-line treatment. Methods The current phase II trial was designed to include pts up to 65 years of age with newly diagnosed, symptomatic MM. Four 4-week RAD induction cycles (lenalidomide 25 mg/day, d 1-21; infusional adriamycin 9 mg/m², d1-4; oral dexamethasone 40 mg, d1-4 and 17-20; pegfilgrastim 6 mg, d 6) were followed by stem cell chemomobilization. Pts received either tandem auto SCT (melphalan 200 mg/m²; Mel) or auto followed by allo SCT. Allo SCT (conditioning regimen: treosulfan/fludarabine) was reserved for pts featuring at least one cytogenetic or serologic risk factor who had a matched sibling or unrelated donor available. Target dose for subsequent lenalidomide maintenance (R-maint; for one year) was 10 mg/d for tandem Mel and 5mg/d for auto/allo pts. Primary endpoint was response (at least VGPR) following second SCT. Results 190 pts with a median age of 55 (range, 30-66) years were recruited by 17 German centers between 8/2009 and 4/2012. 103 pts (56%) had ISS stage II/III disease and 165 pts are evaluable for molecular cytogenetic abnormalities assessed by fluorescence in situ hybridisation (FISH). Incidences were as follows: 29.6% had deletion of (del) chromosome 13q, 11.5% showed translocation (t) (4;14), 9% presented with del 17p, and 0.6% had a t(14;16). 163 pts completed all 4 RAD cycles and 47 underwent allogeneic SCT. 60 pts following tandem Mel and 15 pts after auto-allo SCT proceeded to R-maint. Median number of maintenance cycles was significantly higher in tandem Mel compared with auto-allo pts (12 versus 3; p=.01). Rate of at least (≥) VGPR increased from 47.9% following RAD induction to 60.6% following double SCT. Accordingly, post-induction complete response (CR)/stringent CR rate of 7.9% increased to 31%. In pts with FISH results, ≥ VGPR rate was 44% with t(4;14)/t(14;16)/del 17p versus 53% without those abnormalities, respectively (p=.34). Following double SCT, ≥ VGPR was increased to 63% [t(4;14)/t(14;16)/del 17 pts.] versus 65%, respectively (p=.84). Response was not different with either transplant strategy. No treatment-related mortality occurred during RAD induction, while non-relapse mortality at one year from allo SCT was 10.6%. Incidences of pneumonia, venous thromboembolism, and febrile neutropenia were 11, 7.2, and 5.3%, respectively. Preliminary overall survival results will be presented. Conclusions Our data show RAD induction to be very effective in newly diagnosed MM and to be well tolerated. By subsequent double SCT, a high number of CR/sCR was added. Correlative studies suggests response to be independent of known unfavourable cytogenetic prognosticators, such as t(4;14) and del 17p while time-to-event data will be needed to ultimately confirm a lenalidomide-based triple regimen being able to overcome adverse cytogenetic risk. Administration of R-maint to auto-allo pts was challenging despite a lenalidomide target dose of 5 mg/day. Disclosures Knop: Celgene GmbH: Consultancy, Honoraria. Off Label Use: Use of lenalidomide, doxorubicin, and dexamethasone in newly diagnosed multiple myeloma. Einsele:Celgene GmbH: Consultancy, Research Funding. Bargou:Amgen Inc.: Consultancy, Honoraria, Other.

Phase II Study of Combination of the Hypercvad Regimen with Dasatinib in the Front Line Therapy of Patients with Philadelphia Chromosome (Ph) Positive Acute Lymphoblastic Leukemia (ALL).

Blood ◽  
2009 ◽  
Vol 114 (22) ◽  
pp. 837-837 ◽  
Author(s):  
Farhad Ravandi ◽  
Hagop M. Kantarjian ◽  
Deborah A. Thomas ◽  
Stefan Faderl ◽  
Dan Jones ◽  
...  
Keyword(s):  
Stem Cell ◽  
Phase Ii ◽  
Research Funding ◽  
Stem Cell Transplant ◽  
High Dose ◽  
Cell Transplant ◽  
Newly Diagnosed ◽  
Allogeneic Stem Cell Transplant ◽  
Median Response ◽  
Platelet Recovery

Abstract Abstract 837 Background: Combination therapy with cytotoxic chemotherapy and tyrosine kinase inhibitors has improved the outcome for patients with Ph+ ALL with durable remissions in some patients even without an allogeneic stem cell transplant. The dual Src and Abl inhibitor dasatinib has ∼325 times more potent in vitro kinase inhibition than imatinib against BCR-ABL with significant clinical activity in patients with imatinib-resistant lymphoid blast phase CML (CML-LB) and Ph+ ALL. Aim: To determine the efficacy and safety of combining chemotherapy with dasatinib for treating patients with Ph+ ALL. Methods: In this phase II trial, patients with newly diagnosed Ph+ ALL receive dasatinib 50 mg po bid (or 100 mg daily) for the first 14 days of each of 8 cycles of alternating hyperCVAD and high dose cytarabine and methotrexate. Patients in CR continue to receive maintenance dasatinib 50 mg po bid (or 100 mg daily) and vincristine and prednisone monthly for 2 years followed by dasatinib indefinitely. Results: We have enrolled in the study 34 patients with untreated Ph+ ALL and 7 patients with 1 prior cycle of chemotherapy (before Ph+/BCR-ABL+ status was known). Patients younger than 50 years old have received a median of 6 cycles (range 2-8) and patients 50 years and older have received a median of 6 cycles (range 1-8). 20 patients are receiving maintenance in CR and two have completed the entire treatment regimen. Median age is 51 years (range 21 – 79); 22 patients were older than 50 years, Median WBC at diagnosis was 13.6 × 109/L (range, 1-276 × 109/L). 12 patients had CNS involvement at presentation. All patients are evaluable for assessment of response to induction; 39 (95%) achieved CR after first cycle or were CR at start. Two patients died before response assessment from infections. Thirty-one of 39 (79%) evaluable patients achieved cytogenetic (CG) CR after 1 cycle; 4 had a major CG response (3 had 5% and one had 15% Ph+), 2 had insufficient metaphases, and 2 are unknown (no CG exam on day 21 marrow). To date, 22 patients (56%) have achieved complete molecular remission (CMR) and another 8 (21%) have achieved a major (but not complete) molecular response (MMR) at a median of 14 weeks from initiation of treatment (range 2 – 59 weeks). Minimal residual disease assessment by flow cytometry is negative in 35 (90%) patients at a median of 3 weeks (range, 2-18 weeks). The median time to neutrophil and platelet recovery for cycle 1 is 18 and 23 days and for subsequent cycles is 15 and 20 days. Grade 3 and 4 adverse events have included bleeding (GI, GU, soft tissue and subdural hematomas)(18), pleural effusions (9), pericardial effusion (1), reversible rise in creatinine (10), deep vein thromboses (6), pulmonary emboli (3), as well as diarrhea, infections, hypophosphatemia, hypokalemia, hypocalcemia, hyperglycemia, and elevated transaminases. With a median follow up of 13 months (range 1-33), 29 patients (71%) are alive and 27 (66%) are in CR; 4 patients died in CR; 1 from an unrelated cardiac event and 3 from infections. Three patients have undergone an allogeneic stem cell transplant. The median disease free survival is 48+ weeks (range,1 to 140+) and the median overall survival is 52+ weeks (range, 3 to 143+). Eight patients have relapsed with a median response duration of 51 weeks (range 23-73) and 6 of them have died. In 5 patients morphological relapse was preceded by flow and molecular relapse. Five relapsed patients had ABL mutations (3 T315I, 1 F359V, and 1 V299L). Conclusion: Combination of chemotherapy with dasatinib is effective in achieving long term remissions in patients with newly diagnosed Ph+ ALL. Disclosures: Ravandi: Bristol Myers Squibb: Honoraria, Research Funding. Kantarjian:Bristol Myers Squibb: Research Funding. Wierda:Genzyme: Research Funding; Genentech: Consultancy, Honoraria. Cortes:Bristol Myers Squibb: Research Funding. O'Brien:Bristol Myers Squibb: Research Funding.

Interim analysis of a phase 2 minimal residual disease (MRD)-adaptive trial of elotuzumab, carfilzomib, lenalidomide, and dexamethasone (Elo-KRd) for newly diagnosed multiple myeloma (MM).

2021 ◽  
Vol 39 (15_suppl) ◽  
pp. 8011-8011
Author(s):  
Benjamin Avi Derman ◽  
Jeffrey A. Zonder ◽  
Ankit J. Kansagra ◽  
David L. Grinblatt ◽  
Sunil Narula ◽  
...  
Keyword(s):  
Stem Cell ◽  
High Risk ◽  
Primary Endpoint ◽  
Adaptive Design ◽  
Cell Transplant ◽  
Phase 2 ◽  
Newly Diagnosed ◽  
Study Results ◽  
The Impact

8011 Background: The addition of a monoclonal antibody to triplet induction regimens in patients (pts) with MM with intent for autologous stem cell transplant (ASCT) has resulted in higher overall and deep response rates. In this study we are investigating the impact of the addition of Elo to KRd on complete response (CR) and/or MRD-negative rates in newly diagnosed MM regardless of transplant eligibility. Methods: Pts were enrolled from four MM Research Consortium sites into this phase 2 study. All patients receive 12 cycles of Elo-KRd in 28-day cycles: Elo per standard dosing, K 20/56/70 mg/m2 days 1, 8 and 15, R 25 mg days 1-21, and dexamethasone 40 mg days 1, 8, 15, 22. ASCT eligible candidates can undergo stem cell collection after cycle 4 and then resume treatment; pts who elect to proceed to ASCT are censored for response at that time. Pts MRD(-) (<10-5) by NGS after cycles 8 (C8) and 12 (C12) proceed to Elo-Rd until progression. Patients who convert from MRD(+) to MRD(-) between C8 and C12 receive an additional 6 cycles of Elo-KRd (total 18 cycles) followed by Elo-Rd, and pts MRD(+) after C12 receive an additional 12 cycles of Elo-KRd (total 24) followed by Elo-Rd. The primary endpoint of the study is sCR and/or MRD(-) rate after C8 E-KRd. MRD status was determined by ClonoSEQ next generation sequencing (NGS, <10-5) [Adaptive Biotechnologies]. An improvement in the sCR and/or MRD(-) rate by NGS from a historical 30% to 50% at the end of C8 will be considered promising. Results: 44 pts are enrolled, 39 of whom are evaluable for response (cutoff Jan 10 2021). Median age is 62 years (range 43-81, 23% age >70) and 23 (52%) have high-risk cytogenetic abnormalities (HRCA) including 13 (30%) with >2 high-risk abnormalities (6 pts unknown cytogenetics). 34/39 (87%) have MRD trackable by clonoSEQ. The rate of sCR and/or MRD(-) by NGS at the end of C8 is 19/33 (58%), meeting the statistical threshold for establishing efficacy (2 pts censored for elective ASCT before C8 and 4 pts receiving therapy but have not reached C8). With a median follow-up of 24 months, estimated 2-year progression free survival is 87% (100% for standard risk, 79% for HRCA) and estimated 2-year overall survival is 89% (82% for HRCA). No pt who was MRD(-) by NGS after C8 has progressed, including 6 pts with HRCA. Serious adverse events occurred in 30 pts (68%). 89% experienced treatment emergent AEs, the most common (>10%) of which was pneumonia (14%). One pt had grade 5 myocardial infarction. Conclusions: Elo-KRd demonstrates tolerability consistent with known toxicities of these agents and met the primary endpoint of sCR and/or MRD(-) of >50% after 8 cycles. With longer follow-up, the study results may validate that an MRD-adaptive design for de-escalation of therapy in MM can generate deep responses while reducing treatment exposure. Clinical trial information: NCT02969837.

Efficacy of Ofatumumab and High-Dose Methylprednisolone for the Treatment of Relapsed or Refractory Chronic Lymphocytic Leukemia (CLL)

Blood ◽  
2011 ◽  
Vol 118 (21) ◽  
pp. 4619-4619
Author(s):  
Melissa L. Teichman ◽  
Viet Q. Ho ◽  
Lodovico Balducci ◽  
Celeste M. Bello ◽  
Javier Pinilla-Ibarz
Keyword(s):  
Monoclonal Antibody ◽  
Stem Cell ◽  
High Risk ◽  
Progressive Disease ◽  
Stem Cell Transplant ◽  
Prognostic Markers ◽  
High Dose ◽  
Cell Transplant ◽  
High Dose Methylprednisolone ◽  
Anti Cd20

Abstract Abstract 4619 Background: Ofatumumab is a fully-humanized anti-CD20 monoclonal antibody approved in refractory CLL. The combination of high-dose methylprednisolone (HDMP) and anti-CD20 monoclonal antibody rituximab has previously shown positive results in high-risk refractory CLL. Herein we report our institutional experience with the combination of ofatumumab and HDMP for the treatment of patients with relapsed or refractory CLL. Methods: Between October 2009 and June 2011, 10 consecutive patients with relapsed or refractory CLL received HDMP and ofatumumab at Moffitt Cancer Center. HDMP was dosed at 1 g/m2 IV weekly for 3 weeks every 28 days for two cycles, then monthly for 3 cycles. Ofatumumab was administered according to package insert instructions along with prophylactic antimicrobials. The primary endpoint was to evaluate response as defined by the updated National Cancer Institute Working Group Guidelines (NCIWG 2008). Secondary objectives were to assess treatment tolerance and toxicity. Descriptive statistics were used for baseline characteristics and response rates. Results: Eight of ten patients were male, with a median age of 60 years (range 43–81). All patients were previously treated with rituximab, and were intolerant to or failed fludarabine and/or alemtuzumab. The median number of prior treatments was 3.5 (range 1–5). Seven patients had high-risk prognostic markers including unfavorable cytogenetics or unmutated IgVH. Six patients had 17p deletion, 2 patients had 11q deletion, and 3 patients had an unmutated IgVH (6 patients had two prognostic markers). Eight patients were able to complete all planned treatments. One patient discontinued treatment due to worsening performance status and 1 patient discontinued treatment due to progressive disease. HDMP and ofatumumab were used as a bridge to allogeneic hematopoietic stem cell transplant in 4 patients. Based on NCIWG 2008 criteria, 2 patients had a partial response (PR), 1 patient had progressive disease (PD), and 6 patients had stable disease (SD). Five patients with stable disease had a clinical decrease of lymph nodes or a decrease in lymphocyte counts. Despite the use of prophylactic antimicrobials severe infectious complications occurred in 40% of patients. Infections included 1 patient with norovirus, 1 patient with cytomegalovirus viremia and a fusarium infection of the neck, 1 patient with aspergillus pneumonia, Pseudomonas aeruginosa bacteremia, and an Escherichia coli bacteremia, and 1 patient with a necrotizing pneumonia. Conclusion: This data demonstrates the benefit of HDMP and ofatumumab combination in patients with heavily pretreated CLL. The combination of ofatumumab and HDMP has a role as salvage therapy and as a bridge to allogeneic stem cell transplant. The incidence of infection was high despite the use of prophylactic antibiotics. Aggressive antibiotic prophylaxis is warranted including coverage for mould infections. Disclosures: Off Label Use: Ofatumumab in combination with high dose methylprednisolone for the treatment of relapsed/ refractory CLL. Pinilla-Ibarz:GSK: Speakers Bureau.

Impact of High Dose Cyclophosphamide on the Outcome of Autologous Stem Cell Transplant in Patients with Newly Diagnosed Multiple Myeloma,

Blood ◽  
2011 ◽  
Vol 118 (21) ◽  
pp. 4127-4127 ◽  
Author(s):  
Wendi A. Bacon ◽  
Gwynn D. Long ◽  
David A. Rizzieri ◽  
Mitchell E. Horwitz ◽  
John P. Chute ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Stem Cell ◽  
Retrospective Analysis ◽  
Stem Cell Transplant ◽  
Standard Of Care ◽  
Autologous Stem Cell Transplant ◽  
High Dose ◽  
Cell Transplant ◽  
Newly Diagnosed ◽  
Cell Mobilization

Abstract Abstract 4127 In the age of novel targeted agents, autologous stem cell transplant (ASCT) remains the standard of care for younger patients with newly diagnosed multiple myeloma (MM), offering similar treatment responses and overall survivals as standard chemotherapeutic agents but with the added benefit of a prolonged treatment-free period. Nevertheless, a standard of care for stem cell mobilization for ASCT has yet to be determined. Even in the era of new mobilization agents such as Plerixafor, Cyclophosphamide (Cy) and G-CSF combination remains the preferred mobilizing approach for patients with MM. Several studies have shown that Cy improves the stem cell yield at the expense of increased toxicity, but whether the administration of this chemotherapeutic agent pre-transplant has any impact on the long-term event-free and/or overall survival of myeloma patients remains controversial. In this study, we present a retrospective analysis of 186 patients with newly diagnosed MM who underwent ASCT with high-dose melphalan 200 mg/m2 (HDM) between December of 2000 and 2008 at our Institution. Eighty-three patients were mobilized with single agent G-CSF and 103 patients received high dose Cy (4 gm/m2) and G-CSF combination. Patient characteristics were similar between the treatment groups, including: age, gender, disease stage, and disease status prior to transplant. However, toxicity post-mobilization with Cy/G-CSF was significantly higher compared with G-SCF alone, including: febrile neutropenia (23%), hemorrhagic cystitis (8%), GI toxicity (57%), re-hospitalization due to complications and transplant delay (14%). The overall post-transplant toxicity was similar in the 2 groups, though the treatment related mortality was slightly higher in the Cy/G-CSF arm (4% versus 2%). Post transplant responses were not significantly different in the 2 groups, with 60% of patients achieving a VGPR or better after ASCT in the G-CSF group and 49% in the Cy/G-CSF group (p = 0.33). The median event-free survivals (EFS) for the Cy/G-CSF and G-CSF cohorts were 21.6 and 22.6 months, respectively, (p = 0.62) yielding no significant difference (Figure 1). Similarly, with a median follow up for surviving patients of 34.3 and 32.7 months, the median overall survivals were 68.2 and 62.3 months (p = 0.23) for the Cy/G-CSF and G-CSF cohorts, respectively (Figure 2). This retrospective analysis confirms that the addition of high dose Cy as part of the mobilizing regimen offers no improvement on the transplant outcome for patients with newly diagnosed myeloma and should therefore only be used in cases of difficult stem cell mobilization. Disclosures: No relevant conflicts of interest to declare.

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