Adding The KIT Inhibitor Dasatinib (DAS) To Standard Induction and Consolidation Therapy For Newly Diagnosed Patients (pts) With Core Binding Factor (CBF) Acute Myeloid Leukemia (AML): Initial Results Of The CALGB 10801 (Alliance) Study

Abstract Among the prognostic cytogenetic and molecular aberrations in AML, t(8;21)(q22;q22) and inv(16)(p13q22) and their corresponding molecular rearrangements RUNX1/RUNX1T1 and CBFB/MYH11 (each involving a gene encoding a protein chain of the key transctiption factor CBF), predict for a favorable outcome in pts receiving consolidation with high-dose cytarabine (HiDAC) after achievement of complete remission (CR). However, approximately 40% of these pts eventually relapse. Approximately 25% of CBF AML pts carry gain-of function mutations in the KIT gene. These mutations result in a constitutively active tyrosine kinase (TK) that contributes to aggressive leukemia growth, and is associated with unfavorable outcome. In addition, CBF AML pts with wild type KIT overexpress this protein, and this is also associated with an inferior outcome. Therefore, inhibiting KIT with DAS is a rational therapeutic strategy in CBF AML. We report here on a phase II trial that combined DAS with standard chemotherapy for CBF AML. Enrollment required molecular confirmation of CBF AML by the Alliance Molecular Pathology central lab using RT-PCR and Sanger sequencing-based assays. Overall, 779 patients were screened for CBF; 69 were found to be CBF-positive and 61 were subsequently enrolled. Newly diagnosed RUNX1/RUNX1T1 or CBFB/MYH11-positive pts received induction chemotherapy with cytarabine (C) 200 mg/m2/day continuous intravenous (IV) infusion on days 1-7, daunorubicin (DNR) 60 mg/m2/d IV bolus on days 1-3 and DAS 100 mg/d PO on days 8-21. Pts with residual disease (>5% blasts) on day 21 after first induction received a re-induction treatment with same doses of C on days 1-5, DNR on days 1-3 and DAS on days 6-19. Pts who achieved CR received consolidation therapy with HiDAC 3000 mg/m2 over 3 hours (if <60 yrs old) or 1000 m/m2 (if older) q12h on days 1,3,5 and DAS 100 mg/d PO on days 6-26 x 4 courses. Pts who remained in CR after consolidation treatments received continuation treatment with DAS 100mg/d PO x 12 months. The primary goal of this study was to insure that the CR rate and survival during induction were not inferior to historical outcomes. Between April 2011 and January 2013, we completed the planned accrual of 61 adult CBF AML pts. Median age was 51 years (yrs; range: 19.6 to 85 yrs), and 15 pts (24%) were older (>60 yrs). Half of pts were male (51%) and a majority were Caucasian (75%). Of all 61 pts, 65% were CBFB/MYH11-positive and 35% were RUNX1/RUNX1T1-positive. Treatment was started on average 4 days from molecular diagnosis (range: 0 to 11 days). To date, 51% of pts are still undergoing treatment; 4 pts died on treatment (2 older), 7 (4 older) had an adverse event requiring treatment interruption, and 6 refused to complete the treatment (mainly the continuation component). Observed toxicities were those expected with C and DNR (hematologic and non-hematologic) and with DAS (nausea, liver toxicity). 55 pts are currently evaluable for treatment-related toxicity. The most common grade 4 toxicities were sepsis (5), acute kidney injury (3), and respiratory failure (3). Grade 5 toxicities included respiratory failure (1) and sepsis (2). Two of these pts died during induction (respiratory failure, sepsis); both were older and CBFB/MYH11. One pt died from sepsis during consolidation in CR (CBFB/MYH11, 48 yrs). The 30-day survival rate was 97% (95% CI: 89% to 99.6%) overall (98% in younger and 93% in older pts). Of 59 pts currently evaluable for response, 54 (92% of all pts; 96% younger and 80% older) achieved CR. Of the 5 patients who failed to achieve CR, 2 had RUNX1/RUNX1T1 and 3 had CBFB/MYH11. Among the 54 CR pts, no younger pt has relapsed, while 2 older pts with CBFB/MYH11 have relapsed. The median follow-up (f/u) was 11.2 months (range: 1.2 to 23.2 mos.). The 1-yr DFS and OS rates were respectively 90% and 87% for all pts; 97% and 95% for younger pts, and 63% and 62% for older pts, respectively. Early results from this study show that 1) rapid screening for CBF AML is feasible within a cooperative group, 2) DAS plus chemotherapy in CBF AML pts is tolerable including in older pts, and 3) the initial clinical outcomes are at least comparable to those historically observed in this patient population. Patients continue to be followed for survival endpoints. Molecular characterization for KIT mutations and expression levels of marrow and blood blasts is ongoing and will be correlated with toxicity and clinical outcome. Disclosures: No relevant conflicts of interest to declare.

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The Use of Purine Analogues Does Not Aggravate Infectious Complications During Induction and Consolidation Therapy of Acute Myeloid Leukemia.

Blood ◽

10.1182/blood.v114.22.1011.1011 ◽

2009 ◽

Vol 114 (22) ◽

pp. 1011-1011

Author(s):

Marek Seweryn ◽

Jerzy Wojnar ◽

Dariusz Kata ◽

Slawomira Kyrcz-Krzemien

Keyword(s):

Acute Myeloid Leukemia ◽

Induction Therapy ◽

Myeloid Leukemia ◽

Conflicts Of Interest ◽

Infectious Complications ◽

Induction Treatment ◽

High Dose ◽

Consolidation Therapy ◽

Purine Analogues ◽

Acute Myeloid

Abstract Abstract 1011 Poster Board I-33 Background: Addition of purine analogues to standard induction therapy of acute myeloid leukemia (AML) had previously been demonstrated to increase complete remission rate. The aim of this study was to analyze whether the use of cladribine or fludarabine during induction and consolidation increases the risk of infectious complications. Material and methods: 118 AML patients, included in two consecutive randomized trials between 1999-2006 in a single centre were analyzed. Induction therapy consisted of daunorubicin + cytarabine (DA-7, n=53) alone or in combination with cladribine or fludarabine (DAC-7 + DAF-7, n=65 ). Consolidation included one course of high-dose AraC + mitoxantrone and one course of high-dose AraC +/- purine analogues. A median age was 45(17-58) years and 48(20-60) years for patients treated with and without purine analogues, respectively. Results: The frequency of neutropenic fever as well as microbiologically documented bacterial, fungal and viral infections during induction and consolidation did not differ between two compared groups - receiving or not purine analogues. Time to infection occurrence and infection duration were similar in both study groups. During induction and both consolidation treatments significant lower values of lymphocytosis were observed in the group of patients treated with purine analogues. There was a slight tendency to increased rate of mucositis for patients treated with purine analogues (60% vs. 44.3%, p=0.07) during induction treatment, while infections affecting skin and soft tissues were significant frequent for patients treated without purine analogues (43.3% vs. 18%, p=0.03) during second consolidation treatment (high dose AraC). The usage of intravenous anti-infectious medications (antibiotics, antifungal, antiviral) and periods of hospitalization did not differ between two groups in this study. Conclusions: We conclude that the use of purine analogues, either cladribine or fludarabine along with conventional induction and consolidation therapy does not aggreviate infectious complications in adults with AML. Disclosures: No relevant conflicts of interest to declare.

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Targeting Complete Response with Upfront Bortezomib Followed By Autologous Transplantation and Consolidation Therapy for Untreated Multiple Myeloma (TUBA study)

Blood ◽

10.1182/blood.v128.22.3463.3463 ◽

2016 ◽

Vol 128 (22) ◽

pp. 3463-3463

Author(s):

Hideki Nakasone ◽

Kiriko Terasako-Saito ◽

Teiichi Hirano ◽

Atsushi Wake ◽

Seiichi Shimizu ◽

...

Keyword(s):

Multiple Myeloma ◽

Partial Response ◽

Progression Free Survival ◽

Complete Response ◽

Induction Treatment ◽

High Dose ◽

Induction Phase ◽

Consolidation Therapy ◽

Newly Diagnosed ◽

Free Survival

Abstract [Background] Multiple myeloma (MM) is generally considered incurable. Recently, novel drugs, including bortezomib, have demonstrated a survival benefit for newly diagnosed MM patients compared with classical treatments. Complete response (CR) after treatment is known to be associated with superior progression-free survival. Thus, we prospectively evaluated the efficacy and safety of boretezomib + dexamethasone (BD) for patients with newly diagnosed MM, followed by autologous hematopoietic stem cell transplantation (ASCT). We added BD consolidation therapy to aim CR if CR was not achieved after ASCT. [Patients and methods] This clinical study prospectively recruited newly diagnosed MM patients eligible for ASCT between 2010 and 2012. Due to health insurance issues in Japan, two courses of high-dose dexamethasone (HD-DX) had been administrated prior to BD induction treatment until Nov. 2011, while BD was administrated as an initial induction treatment since Dec. 2011. BD induction treatment included 1.3 mg/m2 of bortezomib on days 1, 4, 8, and 11 with 20mg of dexamethasone on days 1, 2, 4, 5, 8, 9, 11, and 12. This BD induction cycle was repeated every 3 weeks for 4 courses. Thereafter, filgrastim-based mobilization and ASCT following high-dose melphalan administration was performed. If patients did not achieve CR after ASCT, BD consolidation therapy (bortezomib: 1.3 mg/m2 on days 1, 8, and 15; dexamethasone 20 mg/day on days 1-2, 8-9, and 15-16) every 4 weeks was added to target CR (Figure 1) (UMIN-CTR: UMIN000002442). [Results] The median observational duration among survivors was 1536 days (range: 464-2023) at this analysis. Of the 47 enrolled MM patients, 46 (male 27; female 19) were eligible for BD induction treatment, while the remaining one achieved CR before BD induction. The median age of the patients was 59 (range: 35-67) years. Of the 44 patients whose karyotype analyses were available, normal karyotype was observed in 35. Abnormal karyotype included complex type in 4, diploid in 1, and other abnormalities in 4. FISH revealed deletion of p53 in 5 of 39 patients whose information was available; deletion of 13-chromosome in 16 of 42, IgH-MAF fusion in 1 of 40; IgH-FGFR3 fusion in 5 of 41; IgH-BCL1 fusion in 9 of 39. Of the 46 MM patients, 19 received HD-DX prior to BD induction, and 34 received ASCT after BD induction treatment (Figure 1). During the BD induction phase, 3 patients experienced disease progression, and BD treatment was discontinued in 9 patients because of their consent withdrawal (n=2) and adverse events (n=7) including interstitial pneumonia in 2, persistent neuropathy in 1, CMV enterocolitis in 1, heart failure in 1, diabetes mellitus in 1, and liver dysfunction in 1. After BD induction phase (n=46), their response was >= CR in 4 (8%), very good partial response (VGPR) in 10 (22%), partial response (PR) in 18 (39%), stable disease (SD) in 2 (4%), and progression or withdrawal in 12 (26%). After ASCT, their response was >=CR in 9 (20%), VGPR in 11 (24%), PR in 12 (26%), SD in 1 (2%), and additional progression or withdrawal in 1 (2%). Of the 24 patients who received ASCT and whose response was less than CR, 21 received BD consolidation therapy for a median of 4 courses (range: 1- 8). BD consolidation was discontinued in 4 patients due to persistent neuropathy or cytopenia. Finally, maximum response after ASCT with or without BD consolidation was >= CR in 19 (41%), VGPR in 7 (15%), PR in 6 (13%), < SD in 2 (2%, Figure 2). Through BD consolidation, CR was achieved in 8 of 11 patients with post-ASCT VGPR and 2 of 12 patients with post-ASCT PR. In total, 4-year progression-free survival (PFS) and overall survival (OS) was 43% (95%CI: 28-57%) and 80 % (95%CI: 64-90%), respectively. Focusing on CR patients after ASCT and those who actually received BD consolidation, PFS adjusted for karyotype and age were not different between CR patients after ASCT and after BD consolidation, while patients with VGPR or less after consolidation had significantly lower PFS (Figure 3). [Conclusion] BD induction and ASCT provided CR rate of 27% among ASCT patients, although BD induction may expectedly cause adverse events including persistent neuropathy and viral infections. Patients who achieved CR after ASCT showed good PFS, and targeting CR through BD consolidation might improve CR rate. It is worthwhile to prospectively compare the efficacy of BD consolidation only for patients who failed to achieve CR or universal consolidation strategy. Disclosures Kanda: Otsuka Pharmaceutical: Honoraria, Research Funding.

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CR As Major End-Point After Consolidation for Multiple Myeloma Patients Eligible to High Dose Therapy

Blood ◽

10.1182/blood.v118.21.1858.1858 ◽

2011 ◽

Vol 118 (21) ◽

pp. 1858-1858

Author(s):

Benjamin Hebraud ◽

Murielle Roussel ◽

Gaelle Dörr ◽

Anne Huynh ◽

Jill Corre ◽

...

Keyword(s):

Conflicts Of Interest ◽

Residual Disease ◽

Progression Free Survival ◽

High Dose ◽

Consolidation Therapy ◽

High Dose Therapy ◽

Dose Therapy ◽

End Point ◽

Depth Of Response ◽

Almost All

Abstract Abstract 1858 Introduction: High dose therapy (HDT) with autologous stem cell transplantation (ASCT) is a standard treatment option for eligible frontline myeloma patients (pts). However, almost all patients ultimately relapse. Thus, new strategies are required to control the residual disease after HDT. Consolidation therapy, given early after HDT, could enhance the depth of response and further improve progression free survival (PFS) and overall survival (OS). We previously reported that either Thalidomide or Lenalidomide given after HDT was able to reduce this residual disease (IFM 99-02 and 2005-02 trials). During last EHA meeting (abstract #510)., Cavo M et al., updated results of their recently published phase 3 trial. Consolidation by Bortezomib-Thalidomide-Dexamethasone (VTD) after VTD induction and double ASCT improved response in 31 % of pts and 61 % of them achieved CR. This translated into a gain of PFS (62 % at 3 years) and a reduction of the relative risk of progression or death of 36 %. The aim of this study was to evaluate the efficacy of early consolidation therapy and its impact on PFS. Patients and Methods: In this prospective monocenter study, pts were eligible to receive early consolidation if they had the following: 1) at least partial response (PR) after HD melphalan (HDM), 2) no grade ≥ 2 peripheral neuropathy (PNY). The consolidation regimen was: vTD 61%, Lenalidomide 23%, Lenalidomide plus Dexamethasone 13% and Bortezomib-Lenalidomide-Dexamethasone (VRD) 3%. Consolidation had to be started within 3 months from HDM with no following maintenance. Response was assessed according to International Myeloma Working Group uniform response criteria 1 month after the last cycle of consolidation. The duration of PFS was calculated for all patients from time to HDT to time of progression, relapse, death from any cause or to last contact. PFS was analysed using Kaplan-Meier curves. Results: From February 2007 to December 2010, 100 frontline MM pts under 65 received HDM followed by ASCT. Seventy six pts were eligible for consolidation (conso group), 24 pts were not (no conso group). After HDT, response rates were: VGPR=29%, and CR=71% in the no conso group, vs PR=20%, VGPR=55%, and CR=25% in the conso group (p<0.001). Early consolidation upgraded response in 17% of pts with PR=11%, VGPR=49%, and CR=36%. Three pts had progressive disease after or during consolidation. Median follow up is similar for the 2 groups (20 months). Maybe due to unbalanced response repartition, there was no impact of consolidation on PFS (median 25 mos in the 2 groups). Nevertheless, estimated median PFS was not reached in pts achieving CR after consolidation vs 27 mos in pts in CR after HDT in the no conso group (ns). If we focus on response after consolidation, estimated median PFS was not reached in CR pts versus 20 mos in PR pts, and 21 mos in VGPR pts (p=·006; figure 1), irrespective of post HDT status (already in CR or not). Moreover, if we compare pts in VGPR after ASCT (42) we observe two groups: those who upgrade their response to CR (19%) and those who stay in VGPR. The first group achieve the same PFS than patients in CR post ASCT and staying in CR after consolidation (28 mos). Interestingly, those pts (pts upgrading their response) present a longer PFS than those staying in VGPR post consolidation 28 mos versus 20 mos (p=0,032). Conclusion: Our data suggest that achieving CR after consolidation therapy is a major end-point to improve PFS, maybe even in pts already in CR after HDT. So we could propose to treat pts with consolidation until they obtain CR, they achieve a plateau or they present toxicities. Disclosures: No relevant conflicts of interest to declare.

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Validation of MRD Quantification By Flow Cytometry for Pediatric BCP ALL Relapsed Patients Treated on the Intreall Protocol

Blood ◽

10.1182/blood.v126.23.1414.1414 ◽

2015 ◽

Vol 126 (23) ◽

pp. 1414-1414 ◽

Cited By ~ 1

Author(s):

Ester Mejstrikova ◽

Julie Irving ◽

Leonid Karawajew ◽

Marian Case ◽

Jenny Jesson ◽

...

Keyword(s):

Bone Marrow ◽

Flow Cytometry ◽

Clinical Decision Making ◽

Conflicts Of Interest ◽

Residual Disease ◽

Lymphoblastic Leukemia ◽

Induction Treatment ◽

High Dose ◽

Risk Patients ◽

To Receive

Abstract At acute lymphoblastic leukemia (ALL) relapse, about 40% of children can be salvaged with intensified multi-agent, high dose chemotherapy and in very high risk patients, with additional stem cell transplantation (SCT). To improve on this, the International BFM Study Group has led a consortium of 19 countries to develop the world's largest trial for relapsed ALL (IntReALL). Standard risk patients will be randomized to receive the ALL-REZ BFM 2002 or UK ALL R3 therapy and post induction will be randomised to receive the additional targeted anti-CD22 drug, Epratuzumab, during consolidation, to clear residual disease. Children with end of re-induction MRD positive bone marrow will undergo SCT following consolidation. Both ALL-REZ BFM 2002 and UK ALL R3 used MRD PCR-based quantification of clonal Ig/TCR rearrangements, with different cut offs (10-3 for ALL-REZ BFM 2002 and 10-4 for UK ALL R3) and this is the reference assay for IntReALL. However, flow MRD may also play a role for patients without PCR targets. Flow MRD relies on the discrimination of leukaemic blasts from hematogones and this can be hampered depending on the degree of haematopoietic regeneration which varies depending on the treatment protocol and is especially important after intensive induction treatment in relapsed protocols. Thus, prospective MRD quantification of patients entered onto the UKALLR3 and ALL-REZ BFM 2002 clinical trials was performed by a standardised, quality assured, 4-8colour Flow MRD assay in end of re-induction bone marrow aspirates, by laboratories in the IBFM FLOW consortium (n=221). Flow MRD in both treatment protocols was classed as a prospective biological add on study and not used for clinical decision making. Median MRD levels were 0.026 +/-9.9% SD for BFM versus 0.027+/-18% SD for UK protocols, with comparative MRD positivity rates of 45% versus 54%, respectively. Comparison with MRD levels as assessed by molecular analysis of antigen receptor gene rearrangements was performed in 170 samples (BFM,128; UK R3, 42). The Spearman rank correlation of all samples was 0.90 (p<0.0001) for patients treated on the BFM protocol, compared to 0.82 (p<0.0001) for those on UK ALL R3. Risk category concordance was 88% (ALL-REZ BFM) and 88% (UKALLR3). For the 21 discordant samples, 5 were MRD positive by flow but negative by PCR and 17 were negative by flow and positive by PCR. When analysing the accuracy, with which flow MRD classified specimens identically as PCR, the sensitivity of flow MRD in the ALL-REZ BFM protocol was 81% (cut off 0.1%) and in UK ALL R3 was 79% (cut off 0.01%). Specificity values were 93% versus 100%, respectively. Although sample processing and quantification of MRD differ between PCR and FC MRD, in both re-induction protocols, there was good correlation of MRD levels assessed by flow cytometry and PCR, validating the use of Flow MRD as a method of choice in patients without PCR targets in the IntReALL trial. Flow MRD also has the advantage of enabling levels of CD22 to be assayed on MRD cells, prior to treatment with Epratuzumab. This research has received funding from the European Union's Seventh Framework Programme for research, technological development and demonstration under grant agreement no 278514 - IntReALL", Deutsche Kinderkrebsstiftung for its funding support of the ALL-REZ BFM 2002 clinical trial and the minimal residual disease studies by PCR and the Deutsche Jose Carreras Leukämiestiftung for support of the international principal investigator, Leukaemia and Lymphoma Research and North East Children's Cancer Research Fund, NT 13462-4, NV15-28525A, NV15-26588A, UNCE 204012. Disclosures No relevant conflicts of interest to declare.

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Sequential High-Dose Dexamethasone and Response Adapted PAD (Bortezomib, Adriamycin, Dexamethasone) or VAD (Vincristine, Adriamycin, Dexamethasone) Chemotherapy Followed by High-Dose Therapy with ASCT for Newly Diagnosed Multiple Myeloma; Open-Labeled, Multicenter Phase 2 Study (KMM-94 Study)-Interim Analysis.

Blood ◽

10.1182/blood.v120.21.3106.3106 ◽

2012 ◽

Vol 120 (21) ◽

pp. 3106-3106

Author(s):

Jae Hoon Lee ◽

Junshik Hong ◽

Jin Seok Kim ◽

June-Won Cheong ◽

Cheolwon Suh ◽

...

Keyword(s):

Induction Therapy ◽

Conflicts Of Interest ◽

Poor Response ◽

New Drugs ◽

Induction Treatment ◽

High Dose ◽

Fish Analysis ◽

Newly Diagnosed ◽

Younger Patients ◽

High Dose Dexamethasone

Abstract Abstract 3106 Background: Induction therapy followed by ASCT is the standard therapy for the newly diagnosed younger patients with MM. Recently, new drugs such as lenalidomide or bortezomib have shown the promising results as an induction treatment. However, these drugs are not available in many countries as a front line treatment and many different type of induction treatment regimens including old regimens are used. We evaluate the efficacy and safety of the brief course of high dose dexamethasone (HD) and the response adapted PAD (Bortezomib, Adriamycin, Dexamethasone) or VAD (Vincristine, Adriamycin, Dexamethasone) induction chemotherapy in the newly diagnosed younger patients with MM. Methods: One hundred fifty five newly diagnosed patients with MM from 23 institutions received 2 cycles of HD followed by PAD or VAD chemotherapy according to the response to the HD. PAD 4 cycles were given to nonresponsders and VAD 2 cycles were given to who achieved more than PR to HD. The primary endpoint was CR + nCR rate after ASCT. Among 155 patents enrolled this study from November 2009, 29 patients (19%) have been dropped out. This trial will be continued until total 210 patients will be enrolled. The trial is registered on National Cancer Institute website, number NCT01255514. Results: One hundred fifty five patients (88 male, 69 female) were enrolled (median age; 57). 34 (22%) patients had ISS stage I, 64 (41%) stage II and 55 (35%) stage III. Thirty six (26%) patients had abnormal cytogenetics. In FISH analysis, there were 25% del13, 9% del17, 21% t (4; 14), 13% t (14; 16) and 26% t (11; 14). Among the 115 evaluable patients, CR + PR rate was 53% (61/115) after 2 cycles of HD. 61 patients (53%) received subsequent VAD chemotherapy and 54 patients (47%) received PAD chemotherapy. Among the evaluable patients, CR + PR rate after induction therapy was 83% (79%, 48/61 in VAD group vs. 89%, 48/54 in PAD group). 95 patients finished ASCT. CR + nCR rate after ASCT were 74% (74% in VAD group vs 73% in PAD group). Mortality rate of this trial was 15% (17/115). The cause of death was disease progression (n=5), bleeding (n=1) and infections (n=11). Among 115 patients in whom VAD or PAD chemotherapy was actually performed, 1 year OS was 88.1%. (VAD arm 90.7% versus PAD arm 86.1% (P=0.105): median follow-up; 16.6 months). Conclusion: Risk adapted approach using initial HD response showed good response results after ASCT compared with previous trial (CR + nCR rate of IFM 2005-01 trial-Bortezomib+dexa induction & ASCT was 35%, J Clin Oncol. 2010;28:4621–9) The MM patients who showed poor response to HD also showed similar good response rate after ASCT compared with the patients who had good response to HD in this trial. PAD re-induction therapy after failure of initial steroid induction treatment might overcome the inferior results in the high risk MM patients. Our data shows that almost half of the patients who responded to HD can be saved of novel agents during induction treatment, and PAD can successfully rescue the other half who are not sensitive to HD. Therefore, initial steroid response adapted strategy might be the more cost-effective approach in the newly diagnosed ASCT eligible MM patients. Disclosures: No relevant conflicts of interest to declare.

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Rates of CR with and without Measurable Residual Disease after Induction Treatment with "7+3" or Azacitidine/Decitabine for Newly-Diagnosed AML

Blood ◽

10.1182/blood.v128.22.2792.2792 ◽

2016 ◽

Vol 128 (22) ◽

pp. 2792-2792

Author(s):

Todd Yezefski ◽

Roland B. Walter ◽

Pamela S. Becker ◽

Paul C. Hendrie ◽

Vivian Oehler ◽

...

Keyword(s):

Induction Therapy ◽

Conflicts Of Interest ◽

Residual Disease ◽

Survival Rates ◽

Gemtuzumab Ozogamicin ◽

Response To Treatment ◽

Induction Treatment ◽

Newly Diagnosed ◽

Multiparametric Flow Cytometry ◽

Measurable Residual Disease

Abstract Introduction The importance of measurable residual disease (MRD) at time of complete remission (CR) as a predictor of relapse and/or survival either after allogeneic transplant (HCT) or chemotherapy without HCT is widely recognized (Chen et al. JCO 2015;33:1258-64). Hence, a goal of induction therapy might be not only to produce CR, but CR without MRD. Here we compare rates of CR with and without MRD after induction therapy with either (1) "7+3", (2) azacitidine (aza) or decitabine (dec) alone (aza/dec alone), or (3) regimens containing aza or dec with other low intensity treatment (aza/dec combos). Given reportedly similar survival rates with 7+3 and aza/dec alone, and the contribution of CR without MRD to survival, we hypothesized that while CR rates are higher with 7+3, there would be relatively less difference in rates of CR without MRD. Methods We analyzed 272 patients with newly diagnosed, high-risk MDS (10-20% blasts) or AML (> 20% blasts) treated with the following regimens: 7+3 (139 patients), aza/dec alone (64) or aza/dec combos (69), the latter most commonly involving gemtuzumab ozogamicin +/- vorinostat. Cytogenetic risk and response to treatment were assessed per ELN guidelines, and MRD was assessed via 10- color multiparametric flow cytometry as previously described (Chen et al. JCO 2015;33:1258-64). Results As expected, patients given 7+3 were younger, with median ages of 53 for 7+3, 63 for aza/dec alone, and 58 for aza/dec combos. In 7+3, cytogenetic risk was favorable in 29%, intermediate in 26%, and poor in 45%; for aza/dec alone 5% were favorable, 44% intermediate, and 51% poor; and for aza/dec combos, 12% were favorable, 30% intermediate, and 58% poor. As expected, CR rates were higher with 7+3: 72% vs. 14% for aza/dec alone and 17% for aza/dec combos. Rates of CR w/o MRD were also higher with 7+3: 58% vs. 9% for aza/dec alone and 13% for aza/dec combos (p<0.001), while rates of CR with MRD were more similar (14% 7+3 vs. 5% aza/dec alone and 4% for aza/dec combos. Rates of CR w/o MRD were higher with favorable risk cytogenetics (78%) than intermediate risk (24%) or poor risk (22%). The same was true considering only either the aza/dec alone group (67% vs 4% vs 9%) or the aza/dec combo group (50% vs 5% vs 10%.) Conclusion The higher CR rate seen with 7+3 than with aza/dec or its combinations is paralleled by a higher rate of CR without MRD. Multivariate analyses are currently analyzing the relation between relapse/survival and CR without MRD, cytogenetic risk, and treatment, and whether the effect of CR without MRD on these outcomes is the same with 7+3 and aza/dec or its combinations. Assuming, as expected, RFS and survival in the current population is approximately similar regardless of treatment with 7+3, aza/dec or its combinations, the failure of 7+3 to produce better survival despite higher rates of CR without MRD would suggest limitations in the use of CR without MRD as a surrogate for RFS and survival. The similar effect of cytogenetics on CR without MRD rates with 7+3, aza/dec alone or aza/dec combos suggests a qualitative similarity between these regimens that is perhaps more than often appreciated. Disclosures No relevant conflicts of interest to declare.

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Phase II Study of Combination of the HyperCVAD Regimen with Dasatinib in Patients with Philadelphia Chromosome (Ph) or BCR-ABL Positive Acute Lymphoblastic Leukemia (ALL) and Lymphoid Blast Phase Chronic Myeloid Leukemia (CML-LB).

Blood ◽

10.1182/blood.v110.11.2814.2814 ◽

2007 ◽

Vol 110 (11) ◽

pp. 2814-2814 ◽

Cited By ~ 4

Author(s):

Farhad Ravandi ◽

Deborah Thomas ◽

Hagop Kantarjian ◽

Stefan Faderl ◽

Charles Koller ◽

...

Keyword(s):

Phase Ii ◽

Residual Disease ◽

Lymphoblastic Leukemia ◽

Philadelphia Chromosome ◽

Clinical Activity ◽

High Dose ◽

Cell Transplant ◽

Newly Diagnosed ◽

Blast Phase ◽

Platelet Recovery

Abstract Combination of cytotoxic chemotherapy with imatinib has improved the outcome for patients with Ph+ ALL and resulted in eradication of minimal residual disease and durable remissions without allogeneic stem cell transplant in some patients (Thomas D, Blood, 2004; Yanada M, JCO, 2006; Wassmann B, Blood, 2006; de Labarthe A, Blood, 2007). The dual Src and Abl inhibitor dasatinib has a significantly higher in vitro kinase inhibition against BCR-ABL and has demonstrated potent clinical activity in patients with imatinib-resistant lymphoid blast phase CML (CML-LB) and Ph+ ALL with over 50% complete cytogenetic responses (CG CR) in phase I and II trials but with median progression free survival of only 3 to 4 months. We are conducting a phase II trial in which patients with newly diagnosed or relapsed Ph+ ALL or CML-LB receive dasatinib 50 mg po bid for the first 14 days of each of 8 cycles of alternating hyperCVAD and high dose cytarabine and methotrexate. Patients in complete remission (CR) continue to receive maintenance dasatinib 50 mg po bid daily and vincristine and prednisone monthly for 2 years followed by dasatinib indefinitely. To date 15 newly diagnosed patients with Ph+ ALL (cohort I) and 4 patients with relapsed Ph+ ALL or CML-LB (cohort II) have received a median of 4 cycles (range 1 – 8); 4 patients are receiving maintenance in CR. Median age for cohort I is 55 years (range 23 – 79) and for cohort II, 43 years (range 26 – 69); 13 and 3 patients were older than 50 years, respectively. Median WBC at diagnosis for cohort I was 4.3 × 109/L (range, 0.8 – 203.4 x 109/L). Three patients had CNS involvement. Fourteen and 3 patients in the 2 cohorts are evaluable for response to induction; 2 are too early. Thirteen patients (93%) in cohort I and all evaluable patients in cohort II have achieved CR after the first cycle; 1 patient in cohort I died on day 20 from infections before response assessment; her bone marrow exam on day 14 showed no detectable disease. Ten of 11 (91%) patients in cohort I have achieved CG CR after 1 cycle; 3 are too early. Three of 4 patients in cohort II have achieved CG CR after 1 cycle; 1 had a new CG abnormality and 1 is too early. Six patients have achieved complete molecular remission after the first cycle with the lowest BCR-ABL/ABL in the other patients ranging from 0.01 to 1.91. Median time to neutrophil and platelet recovery for cohort I is 18 and 25 days and for cohort II 18.5 and 30.5 days. Grade 3 and 4 toxicity has included 7 episodes of GI bleeding as well as infections, diarrhea, hypophosphatemia, hypocalcemia, elevated transaminases, and acute renal failure unrelated to treatment. With a median follow up of 4 months (range, 0 – 10), 15 patients are alive and in CR; 1 died at induction, 1 died in CR from an unrelated cardiac event, and 2 are too early. No patient has relapsed and no patient has received an allogeneic transplant. We conclude that the combination of the hyperCVAD regimen with dasatinib is feasible and can achieve early molecular remissions in patients with Ph+ ALL and CML-LB.

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Phase I Study of Bortezomib, (BTZ) Followed by High-Dose Melphalan, (HD Mel) and BTZ as Conditioning Regimen for Tandem Peripheral Blood Stem Cell Transplants (TanPSCT) in Patients with Primary Refractory Multiple Myeloma (MM) and Plasma Cell Leukemia (PCL).

Blood ◽

10.1182/blood.v110.11.5131.5131 ◽

2007 ◽

Vol 110 (11) ◽

pp. 5131-5131 ◽

Cited By ~ 1

Author(s):

Todd Alekshun ◽

Christine Mcisaac-Simonelli ◽

Mohamed Kharfan-Dabaja ◽

William Dalton ◽

Benjamin Djulbegovic ◽

...

Keyword(s):

Median Time ◽

Risk Group ◽

Single Agent ◽

Conditioning Regimen ◽

High Dose ◽

Fish Analysis ◽

Newly Diagnosed ◽

Poor Risk ◽

Early Results ◽

Pathway Gene

Abstract Background: Approximately 25% of patients with newly diagnosed (MM) fail to respond and progress while receiving conventional induction. As a result, these patients have primary refractory disease. Even though these patients still benefit from HD chemotherapy, their PFS ranges from 4–8 months, while OS is approximately 12 months. PCL accounts for approx. 2% of newly diagnosed MM patients and represents the most aggressive form of disase. These patients often do not respond to standard systemic cytotoxic therapies and their median survival is less than 12 months. Therefore, novel treatment approaches are paramount for patients with primary refractory MM and PCL. The proteasome inhibitor BTZ has been shown to sensitize myeloma cells to melphalan both in vitro and in vivo, but the mechanism is not well understood. In this study we examine the effects of BTZ, followed by BTZ and HDMel as conditioning regimen for TanPSCT in this poor-risk group. Methods: Patients with primary refractory MM or PCL received 2 cycles of BTZ at 1.3 mg/m2. followed by HD Mel (200 mg/m2) and one dose of BTZ at 0.7 mg/m2, 1.0 mg/m2 or 1.3 mg/m2, as a conditioning regimen prior to TanPSCT. The dose of BTZ was given immediately after the last dose of HD Mel. Bone marrow(BM) samples were collected at baseline, on day 4 and after 2 cycles of BTZ, and at 3 months after TanPSCT, for GEP and Fanconi anemia(FA) pathway genes assessment. Results: To date, 17 patients have been enrolled and treated, and 11 patients are evaluable for response. Median age is 59 years (46–70) with the following myeloma distribution: 55% IgA and 45% IgG. FISH analysis showed the following: del 13q (44%), t (4; 14) (11%), t (11; 14) (11%), trisomy 11 (11%), and polyploid (11%); standard karyotype was normal in 88% of patients and complex karyotype in 12%. Median time to WBC engraftment (days) was 13 and 12 after the first and second transplant, respectively. Median time to plt engraftment (days) was 20 and 17, after the first and second transplant, respectively. There were no dose limiting toxicities. Observed grade 3 toxicities were related to the conditioning regimen and similar to those observed with HDMel alone. One patient developed diffuse alveolar hemorrhage after the first cycle of BTZ, which resolved, but was removed from study. After 2 cycles of BTZ, 45% of patients achieved PR, and 55% had stable disease. Overall response rate at 3 months from the second transplant increased to 90%(CR=36%,VGPR=27% andPR=27%). Only 1 patient developed progressive disease after the first transplant. Evaluations of BM samples by GEP and FA pathway gene expression are underway. Conclusions: Single agent BTZ induced responses in 45% and the combination of HD Mel and BTZ as conditioning regimen for TanPSCT was well tolerated and improved response rates to 90%. These early results suggest that this regimen is very active in this poor-risk group. Evaluation of collected BM samples for GEP and FA pathway genes may provide important insight into the mechanisms associated with the observed synergy between BTZ and HD Mel. A Phase II study is underway.

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Combined Analysis of Treatments for Pediatric T-ALL in KYCCSG Protocols, ALL-96 and ALL-02.

Blood ◽

10.1182/blood.v114.22.4102.4102 ◽

2009 ◽

Vol 114 (22) ◽

pp. 4102-4102

Author(s):

Yasuhiro Okamoto ◽

Yoshihisa Nagatoshi ◽

Akinobu Matsuzaki ◽

Aiko Suminoe ◽

Hideki Nakayama ◽

...

Keyword(s):

Maintenance Therapy ◽

Chromosomal Abnormalities ◽

Conflicts Of Interest ◽

Residual Disease ◽

Lymphoblastic Leukemia ◽

Cranial Irradiation ◽

High Dose ◽

Costal Margin ◽

Hematopoietic Stem ◽

Combined Analysis

Abstract Abstract 4102 Background Previously we reported the result of Kyushu-Yamaguchi Children's Cancer Study Group (KYCCSG) protocol, ALL-96, for pediatric acute lymphoblastic leukemia (ALL) (ASH meeting in 2005). The 7-year event-free survival (EFS) and overall survival (OS) rates were 72% (95% CI; 68 - 76 %) and 85 % (95% CI; 80 - 90 %), respectively. Following protocol, ALL-02, was aimed to assess the usefulness of polymerase chain reaction (PCR)-based minimal residual disease (MRD) in the same context as ALL-96 protocol. Purpose In this combined analysis, we analyzed the outcome and risk factors for relapse/survival in children with T-ALL who were treated with the ALL-96/ALL-02 protocols. Study Design and Treatment A total of 42 patients (22 of 218 in ALL-96 and 20 of 165 in ALL-02, 26 males and 16 females) with median age of 8 years (range 1 - 14) were treated. Patients were classified into 2 groups, standard risk (SR) and high risk (HR). HR patients had one of the followings: high white blood cell (WBC) counts more than 50,000/μl, T-cell immunophenotype, central nervous system (CNS) disease at diagnosis, organomegaly (hepatomegaly or splenomegaly more than 5 cm below costal margin), M2/3 marrow at day 15 of induction therapy. Both protocols consisted of induction, early intensification, consolidation, late intensification and maintenance therapy. Predonisolone (PSL), weekly vincristine (VCR), 4 doses of daunorubicin (DNR), 8 doses of L-asparaginase (L-asp) and 2 or 4 doses of intrathecal (IT) methotrexate (MTX) depending on the CNS status, were given during induction. In early intensification, DNR, cytarabine (CA), etoposide and 6-mercaptopurine (6-MP) were given. Consolidation consisted of intermediate dose of MTX, combination of cyclophosphamide(CPM), CA and 6-MP, and high dose CA. Late intensification similar to induction included 2 weeks of dexamethasone (DEX), weekly VCR, 2 doses of pirarubicin, single dose of CPM, 5 doses of L-asp and IT-MTX followed by combination of CA, 6-MP, IT-MTX along with 18 Gy cranial irradiation in 12 fractions. In ALL-96 protocol, patients were randomized to receive maintenance therapy of either combination of 6-MP/MTX and DEX/ VCR pulse (A-arm) or LSA2L2-type therapy (B-arm). In ALL-02 protocol, A-arm was chosen as a maintenance therapy based on result of ALL-96. No patient underwent hematopoietic stem cell transplantation (SCT) in 1st complete remission (CR). Results Median follow-up periods were 96 and 38 months in ALL-96 and ALL-02, respectively. Two patients were off-protocol before achieving CR because of toxicity and chromosome abnormality with t(4;11). Induction rate in 40 patients was 95%. All 14 events were relapses and TRM rate was 0%. Last event occurred at 40 months. The sites of relapse were isolated BM in 9, isolated testis in 2, isolated CNS in 1 and combined sites in 2. Nine died from disease progression and 2 died from toxicity after SCT in 2nd CR. The 4-year EFS and OS rates in all patients were 55 % (95 % CI; 39 – 71 %) and 71 % (95 % CI; 56 -86 %), respectively. EFS of ALL-96 and ALL-02 were 50 %[95 % CI; 29 -71 %]) and 65 % [95 % CI; 45 - 85 %]), respectively. OS of ALL-96 and ALL-02 were 59 % [95 % CI; 39 – 80 %]) and 90 % [95 % CI; 77 - 103 %]), respectively (p = 0.063). EFS of patients treated in A and B arm were 60 % [95 % CI; 41 -71 %]) and 55 % [95 % CI; 25 - 84 %]), respectively. None of age, sex, organomagaly, WBC, chromosomal abnormalities, CNS status, protocol, and maintenance arm was identified as a risk factor for relapse or survival. Two of 10 (ALL-96) and 3 of 4 (ALL-02) relapsed patients have survived with allogeneic SCT. Conclusion Although T-ALL patients received an intensified treatment including cranial radiation, the outcome was unsatisfactory. One possible explanation for better OS in ALL-02 protocol is that the majority of relapsed patients in ALL-02 were salvaged by SCT in 2nd CR. Disclosures: No relevant conflicts of interest to declare.

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The Addition of Thalidomide to the Induction Treatment of Newly Presenting Myeloma Patients Increases the CR Rate Which Is Likely to Translate Into Improved PFS and OS.

Blood ◽

10.1182/blood.v114.22.352.352 ◽

2009 ◽

Vol 114 (22) ◽

pp. 352-352 ◽

Cited By ~ 8

Author(s):

Gareth J Morgan ◽

Faith E Davies ◽

Walter M Gregory ◽

Susan E Bell ◽

Alex J Szubert ◽

...

Keyword(s):

Flow Cytometry ◽

Conflicts Of Interest ◽

Residual Disease ◽

Response Rates ◽

Multiparameter Flow Cytometry ◽

Induction Treatment ◽

Overall Response ◽

Patient Pathways ◽

The Impact

Abstract Abstract 352 We present updated results from MRC Myeloma IX study evaluating the role of the addition of thalidomide to the induction and maintenance of patients with myeloma. The study ran from May 2003 – November 2007 and randomised 1,970 patients and now has a median follow up of more than 3.5 years giving it improved power to detect changes in outcome developing later after treatment. Projected median OS younger fitter patients 66 months, median OS older less fit patients 32 months. The trial comprised of 2 patient pathways, one for younger fitter patients comparing CTD (cyclophosphamide, thalidomide, dexamethasone) with CVAD (cyclophosphamide, vincristine, adriamycin, dexamethasone), all patients going on to receive an ASCT – median age 59 years. In older less fit patients, melphalan and prednisolone (MP) was compared to CTD attenuated – median age 73 years. In both pathways following initial treatment, eligible patients were randomised to low-dose thalidomide or no maintenance. Patient's response was monitored using electrophoresis, serum free light chain and multiparameter flow cytometry. Cytogenetics was availabel on up to 60% of cases and gene expression on a subset of these. CTD is a well tolerated regimen with a good safety profile giving excellent survivals in both groups of patients despite a small increase in risk of VTE. Using modified EBMT criteria, the addition of thalidomide to induction treatment increases both response rates and depth of response for all age groups. Preliminary results as follows: overall response: CTD vs CVAD: 91% v 82%; CR 21% v 14% and 100 days post-HDM, better responses were seen in CTD with CR rates 65% v 48%. Remission depth was also greater in CTD with more patients achieving minimal residual disease negativity by flow cytometry. The addition of thalidomide increases response rates overall, and particularly complete response (CR) rates (a 17% increase in CR rates post HDM, p=.006). In older/less fit patients CTDa vs MP: overall response 83% v 46%; CR 21% v 4%. Definitive results of these analyses will be presented as well as how they translate into PFS and OS and by cytogenetic subgroup. There is a substantial increase in response with the inclusion of thalidomide but at a median follow-up of three years we are not as yet seeing a substantial increase in survival in either of the two broad patient groups. We have collected data on treatment at relapse to explore how this confounds OS data. Importantly modelling analyses indicate when and to what extent, with further follow-up, the survival differences that should accrue from this increase in CR rate are likely to translate into a survival benefit. These results have a number of important implications. We show the benefit of the addition of thalidomide to myeloma treatment but also highlight the importance of later analysis of such trials because of the emergence of significant changes at these later time points. We will present full updated results from the study including the impact of thalidomide on cytogenetic subgroups and in the maintenance setting. Disclosures: No relevant conflicts of interest to declare.

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