sequential flamsa chemotherapy and t cell depleted …€¦ · reduced intensity conditioning...

LUMC 2012-02 TCD FLAMSA RIC alloSCT

LUMC 2012-02

Sequential FLAMSA chemotherapy and T cell depleted

reduced intensity conditioning allogeneic stem cell transplantation with postponed donor lymphocyte infusion

in elderly acute myeloid leukemia and high risk myelodysplasia patients

Version 2.1 February 2014


PROTOCOL TITLE

Sequential FLAMSA chemotherapy and T cell depleted reduced intensity conditioning allogeneic stem cell transplantation (TCD FLAMSA-RIC alloSCT) in elderly acute myeloid leukemia and high risk myelodysplasia patients Protocol ID LUMC 2012-02

Short title FLAMSA-RIC alloSCT in elderly AML and high risk MDS patients

Version 2.1

Date February 2014

TOL number NL42222.058.13

Principal investigator

Dr. P.A. von dem Borne

Leiden University Medical Center

Dept. of Hematology, C2-R

Albinusdreef 2

2333 ZA Leiden

Phone: +31 71 5262267

Fax: +31 71 5266755

E-mail: [email protected]

Sponsor LUMC

Independent physician(s) Dr. F.J.M. van der Meer

Leiden University Medical Center

Phone: +31 71 5264797

E-mail: [email protected]

Statistician Dr. L. C. de Wreede Leiden University Medical Center Department of Medical Statistics

mailto:[email protected]

mailto:[email protected]


PROTOCOL SIGNATURE SHEET Name Signature Date For non-commercial research, Head of Department: Prof. dr. J.H. Veelken

Principal Investigator: Dr. P.A. von dem Borne


TABLE OF CONTENTS 1. INTRODUCTION AND RATIONALE .............................................................................11 2. OBJECTIVES ................................................................................................................16 3. STUDY DESIGN ...........................................................................................................17 4. STUDY POPULATION ..................................................................................................18

4.1 Population (base) ...................................................................................................18 4.2 Inclusion criteria .....................................................................................................18 4.3 Exclusion criteria ....................................................................................................18 4.4 Sample size calculation ..........................................................................................18

5. TREATMENT OF SUBJECTS .......................................................................................19 5.1 Treatment regimen .................................................................................................19

5.1.1 Special management in conjunction with allogeneic transplantation ................19 5.1.2 Infection prophylaxis after transplantation .......................................................20 5.1.3 Therapy of CMV reactivation ...........................................................................20 5.1.4 Therapy of EBV reactivation or post transplant lymfoproliferative disease (PTLD) 20 5.1.5 Staging and handling of Graft versus Host Disease ........................................20 5.1.6 Eligibility criteria for donor lymphocyte infusion at 3 or 6 months .....................20 5.1.7 Inclusion criteria for donor lymphocyte infusion at 3 or 6 months .....................21 5.1.8 Exclusion criteria for donor lymphocyte infusion at 3 or 6 months....................21 5.1.9 Donor lymphocyte infusion ..............................................................................21 5.1.10 Salvage therapy ..............................................................................................21

6. NON INVESTIGATIONAL MEDICINAL PRODUCT .......................................................23 6.1 Summary of known and potential risks ...................................................................23

6.1.1 Fludarabine .....................................................................................................23 6.1.2 Amsacrine .......................................................................................................23 6.1.3 Cytarabine .......................................................................................................23 6.1.4 Busilvex (intravenous busulphan preparation) .................................................23 6.1.5 Alemtuzumab ..................................................................................................23 6.1.6 Thymoglobulin .................................................................................................24

6.2 Preparation and labelling ........................................................................................24 7. METHODS ....................................................................................................................25

7.1 Study endpoints .....................................................................................................25 7.1.1 Primary endpoints ...........................................................................................25 7.1.2 Secondary endpoints .......................................................................................25

7.2 Study procedures ...................................................................................................25 7.3 Evaluation criteria ...................................................................................................27

7.3.1 Safety evaluation during and after treatment ...................................................27 7.4 Withdrawal of individual subjects ............................................................................27 7.5 Premature termination of the study .........................................................................27 7.6 End of study ...........................................................................................................28

8. SAFETY REPORTING ..................................................................................................29


8.1 Section 10 WMO event ..........................................................................................29 8.2 Adverse and serious adverse events ......................................................................29

8.2.1 Suspected unexpected serious adverse reactions (SUSAR) ...........................29 8.2.2 Annual safety report ........................................................................................30

8.3 Follow-up of adverse events ...................................................................................30 9. STATISTICAL EVALUATION ........................................................................................31

9.1 Statistical design ....................................................................................................31 9.2 Sample size............................................................................................................31 9.3 Power calculation ...................................................................................................31 9.4 Statistical analysis ..................................................................................................31 9.5 Interim analysis ......................................................................................................31

10. ETHICAL CONSIDERATION .....................................................................................32 10.1 Regulation statement .............................................................................................32 10.2 Recruitment and consent........................................................................................32 10.3 Benefits and risks assessment ...............................................................................32 10.4 Compensation for injury .........................................................................................32

11. ADMINISTRATIVE ASPECTS AND PUBLICATION ..................................................34 11.1 Handling and storage of data and documents ........................................................34 11.2 Annual progress report ...........................................................................................34 11.3 End of study report .................................................................................................34 11.4 Public disclosure and publication policy ..................................................................34

12. REFERENCES ..........................................................................................................35 APPENDICES A WHO performance score B Common toxicity criteria C NYHA scoring list D Grading of GvHD


Version: 2.1; February 2014 6 of 40

LIST OF ABBREVIATIONS AND RELEVANT DEFINITIONS AlloSCT Allogeneic stem cell transplantation AML Acute myeloid leukemia ATG Anti-thymocyte globulin BM Bone marrow CMV Cytomegalovirus CR Complete remission CRF Case report form CTCAE Common terminology criteria for adverse events DLI Donor lymphocyte infusion EBV Epstein-Barr virus EudraCT European drug regulatory affairs Clinical Trials FLAMSA Fludarabine-cytarabine-amsacrine chemotherapy GCP Good Clinical Practice GvHD Graft versus host disease HLA Human leukocyte antigen HOVON Haemato Oncology Foundation for Adults in the Netherlands; in Dutch:

Stichting Hemato-Oncologie voor Volwassenen Nederland IPSS International prognostic scoring system IV Intravenous LUMC Leiden University Medical Center MDS Myelodysplastic syndrome METC Medical research ethics committee (MREC); in Dutch: medisch ethische

toetsing commissie (METC) NYHA New York heart association PBMC Peripheral blood mononuclear cells PO Per os PTLD Post transplantation lymphoproliferative disease RIC Reduced intensity conditioning SAE Serious Adverse Event SCT Stem cell transplantation SUSAR Suspected Unexpected Serious Adverse Reaction TCD T cell depletion UPN Unique patient number WHO World Health Organization

WMO Medical Research Involving Human Subjects Act (in Dutch: Wet Medisch-wetenschappelijk Onderzoek met Mensen



SUMMARY

Sequential FLAMSA chemotherapy and T cell depleted reduced intensity conditioning allogeneic stem cell transplantation with donor lymphocyte infusion in elderly acute myeloid leukemia and high risk myelodysplasia patients Objectives

Primary objectives: • To assess feasibility and safety of a sequential treatment regime in which standard

intensive chemotherapy (fludarabin-amsacrin-cytarabin) is directly followed by standard allogeneic stem cell transplantation (T cell depleted RIC alloSCT with donor lymphocyte infusion at 3 and 6 months), in elderly patients with AML or high risk myelodysplastic syndrome (IPSS ≥1.5).

• To evaluate the incidence of non-relapse mortality. Secondary objectives: • To evaluate progression free survival and overall survival • To evaluate the effect of FLAMSA chemotherapy in combination with T cell depleted RIC

alloSCT and donor lymphocyte infusion on quality of life Study design

Phase 1-2 feasibility study. Study population

Patients with AML or high risk myelodysplastic syndrome (IPSS ≥1.5) aged 60-75 years, not in remission after induction chemotherapy. Inclusion criteria

• Patients with AML or high risk MDS (IPSS ≥ 1.5) • Not in remission after first intensive induction chemotherapy (morphologically > 5% blasts

in bone marrow aspirate) • 60-75 years, inclusive • HLA-identical sibling or unrelated donor completely matched (10/10 for HLA A, B, C, DR,

DQ) • WHO-performance status 0-2 (see appendix A) • Written informed consent Exclusion criteria

• Previous autologous or allogeneic SCT • Acute promyelocytic leukemia • Severe pulmonary dysfunction (CTCAE grade III-IV, see appendix B); • Severe cardiac dysfunction (NYHA classification 3-4, see appendix C). • Significant hepatic dysfunction (serum bilirubin or transaminases ≥ 3 times upper limit of

normal);



• Significant renal dysfunction (creatinine clearance < 30 ml/min after rehydration); • Concurrent severe and/or uncontrolled medical condition (e.g. uncontrolled diabetes,

infection, hypertension, cancer, etc.); • Severe neurological or psychiatric disease; • Any psychological, familial, sociological and geographical condition potentially hampering

compliance with the study protocol and follow-up schedule • Patient known to be HIV-positive Study scheme

Intervention Patients will receive FLAMSA chemotherapy over the course of 5 days. After a 3 day rest, the conditioning of the allogeneic stem cell transplantation is started. T cell depletion of the patient consists of alemtuzumab in patients transplanted with a related donor and alemtuzumab in combination with rabbit ATG (Thymoglobulin) in patients with an unrelated donor. No further immunosuppressive drugs are given after transplantation. All patients are to be treated with donor lymphocyte infusions at 3 and 6 months after transplantation. A total of 15 patients will be included in the study. Study endpoints

FLAMSA chemotherapy+

T cell depleted RIC allogeneic stem cell transplantation

Salvage therapyResponse

+ day 90: first DLI0.3 x 106 CD3+ cells/kg (related donor)

0.15 x 106 CD3+ cells/kg (unrelated donor)

+ day 180: second DLI3 x 106 CD3+ cells/kg (related donor)


CR

NR

AML or high risk MDS (IPSS >= 1.5), age 60-75 yearsPatients treated with induction chemotherapy, not in complete remission

after first intensive induction chemotherapy



Primary endpoints • The number of patients eligible for DLI at 6 months after transplantation • Incidence of non-hematological grade 3-4 toxicity from the start of chemotherapy until 9

months after transplantation • Incidence of serious adverse events from the start of chemotherapy until 9 months after

transplantation • Incidence of severe overall grade 3 or 4 acute GvHD and incidence of extensive chronic

GvHD in the first 9 months after transplantation • Non-relapse mortality at 3 and 12 months after transplantation Secondary endpoints • 1-year progression free survival after transplantation • 1-year overall survival after transplantation Quality of life at 3, 6 and 12 months after transplantation in comparison with quality of life at

the start of therapy, as determined with the EORTC QLQ-C30 questionnaire

Sample size

We aim to include 15 patients. We expect to include 3-5 patients in the first year, increasing up to 10 patients per year in the following years, resulting in a study period of 2-3 years. Nature and extent of the burden and risks associated with participation, benefit and group relatedness Elderly patients with AML or high risk MDS have a poor prognosis; the only way to achieve long term survival is transplantation with an allogeneic donor after reaching a complete remission of the disease with intensive chemotherapy. Most patients starting with intensive chemotherapy are not transplanted, due to not achieving a complete remission with intensive chemotherapy, due to declining condition during the courses of intensive chemotherapy with long periods of neutropenia or due to early relapse after achieving a complete remission. Especially patients that are not in remission after the first induction chemotherapy have a dismal prognosis with current therapies. In a retrospective analysis of 20 patients not in remission after first induction chemotherapy, 16 patients received a second induction chemotherapy; 10 of these patients achieved a CR, 7 patients received a third chemotherapy course for consolidation, and 4 underwent RIC alloSCT. However, there were no long-term survivors in this group of 20 patients. At the moment our standard therapy for high risk acute myeloid leukemia is induction chemotherapy followed by consolidation chemotherapy in case of the achievement of a complete remission, followed by T cell depleted reduced intensity allogeneic stem cell transplantation and donor lymphocyte infusion at 3 and 6 months after transplantation. Because of the dismal prognosis that patients have when they are not in complete remission after the first induction, even despite further intensive chemotherapy and allogeneic stem cell



transplantation, further treatment with standard chemotherapy and transplantation protocols is questionable in these patients. In this study we explore the feasibility of the sequential use of FLAMSA chemotherapy and T cell depleted reduced intensity conditioning allogeneic stem cell transplantation followed by donor lymphocyte infusion at 3 and 6 months after transplantation in patients that are not in complete remission after the first induction chemotherapy. This treatment regimen combines an effective chemotherapy regimen (amsacrine-cytarabine) with a relatively non-toxic allogeneic transplantation conditioning regimen and a short time between chemotherapy and the time point of DLI administration (3 months). With this TCD FLAMSA-RIC alloSCT regimen we hope to be able to treat and cure more elderly patients with AML and high risk MDS with allogeneic transplantation. The benefit this treatment offers is a chance of curation, the risk is non-relapse mortality which will be between 10 and 20%. Interim analysis After the first 5 and 10 patients an interim analysis will be performed by the principal investigator. Premature termination of the study

A total number of 15 patients will be included in this study. If within the group of the first 5 patients that reach a complete remission after FLAMSA-RIC more than 2 patients die from non-relapse causes within the first 3 months, inclusion within the study will be stopped. If within the group of the first 10 patients that reach a complete remission after FLAMSA-RIC more than 4 patients die from non-relapse causes within the first 3 months, inclusion within the study will be stopped. After stopping the study, a careful evaluation of the causes of death will be performed to determine whether changes in the study are likely to diminish non-relapse death and whether further continuation of the study with amendments is possible.

End of study

End of the study is defined as 6 months after the infusion the second DLI, one year after transplantation.



1. INTRODUCTION AND RATIONALE Although considerable progress has been made during the last decades in the treatment of acute myeloid leukemia (AML), the treatment of elderly patients (≥ 60 years) still remains a challenge. With standard induction chemotherapy no more than 40-50% of patients achieve a complete remission, needed to continue with further post-remission therapy (1). In most studies, patients in remission receive post-remission chemotherapy, although no prospective randomized study has ever established its benefit (1, 2, 3). When using only chemotherapy treatment, long-term survival is poor due to high relapse rates, even in patients with favorable cytogenetics. However, cure is possible in elderly patients with AML using the immunotherapeutic potential of allogeneic stem cell transplantation (alloSCT) after reaching complete remission with intensive chemotherapy. Non-myeloablative (NMA) or reduced intensity conditioning (RIC) regimens have been developed which can be used in patients up to 75 years of age with long term overall survival of 40-50% (4, 5). However, only highly selected populations of fit patients reach the potentially curative alloSCT. Many patients do not reach this goal either due to early death during chemotherapy (10-20%), due to the inability to achieve a remission after chemotherapy, due to declining performance status during the courses of intensive chemotherapy with long periods of neutropenia, or due to early relapse after achieving a chemotherapy-induced remission (4). In a large study performed in the Netherlands by the HOVON, out of 813 AML and high risk MDS patients aged 60 to 79, only 47 patients (5.7%) reached allogeneic stem cell transplantation (6). Fit older adult patients tolerate chemotherapy as well as younger patients, but tolerate the period of prolonged bone marrow aplasia following the chemotherapy much less than younger patients (7). Towards a more tolerable curative treatment for elderly AML patients

In order to increase the tolerability and applicability of combined chemotherapy and alloSCT in elderly patients, new treatment protocols are needed. In Leiden we have developed a T cell depleted RIC alloSCT protocol which is tolerated very well in patients up to 75 years. This protocol relies on the transplantation with a conditioning regimen using extensive T cell depletion resulting in a low incidence of acute and chronic GvHD. Anti-tumor effects are induced at a later point after transplantation by administration of T cells through a donor lymphocyte infusion (DLI). This DLI is known to induce potent curative anti-tumor effects with limited toxicity due to GvHD. The non-relapse mortality of this transplantation procedure is 10-15% (8,9). Retrospective analysis of 45 elderly patients treated in the LUMC between 2006 and 2011 for AML with intensive induction chemotherapy with the intention to proceed to alloSCT to achieve cure has shown that only certain subgroups of patients benefit from this approach. Median age of the patients was 67 years (range 60-79). Patients achieving complete remission (CR) after induction, went on to consolidation chemotherapy, followed by RIC alloSCT in case of continued CR. Patient not achieving CR after induction received a re-



induction course with high-dose cytarabine with or without amsacrine. Patients in CR after induction or re-induction were to receive one cycle of consolidation chemotherapy, followed by RIC alloSCT in case of continuous CR. Six patients (13%) died during first induction, 19 patients achieved a CR (43%) and 20 were not in CR after first induction (44%). Of the 19 patients in CR after first induction, 12 received a RIC alloSCT (63% of CR patients, or 27% of starting population) after consolidation chemotherapy. Causes why CR patients did not receive alloSCT were good-risk AML (n=1), early relapse after consolidation chemotherapy (n=2), high age (patient had become over 80 years) (n=1), infectious complication (n=1) and patient choice (n=2). Of the 20 patients not in complete remission after induction chemotherapy, 16 patients received a second induction chemotherapy; 10 of these patients achieved a CR, 7 patients received a third chemotherapy course for consolidation, and 4 underwent RIC alloSCT. There were no long-term survivors in this group. 19 patients without CR after 1st induction died from progressive AML. 15 AML deaths after 1st induction failure occurred in patients who were treated according to the institutional strategy (6 patients with progressive disease despite additional chemotherapy, 1 relapse prior to start of re-induction, 3 relapses early after consolidation, and 4 relapses after alloSCT). Relapses in patients not adhering to the pre-specified strategy occurred in patients opting to discontinue therapy while in CR (n=3), inability to find a donor (n=1), and complication preventing alloSCT (n=1). For the entire intent-to-treat population, the Kaplan-Meier estimate for overall survival at 1 and 2 years after start of treatment is 38% and 19%, respectively. For patients achieving CR after 1st induction and receiving alloSCT, Kaplan-Meier estimate overall survival at 2 years after start of treatment is 50%. The main reasons for dying when adhering to the protocol were early death (13%) and refractory / relapsing malignancy (47%). Only 2 patients (4%) died after 1st induction as a consequence of non-relapse mortality (NRM). Non-NRM reasons for not adhering to the protocol with subsequent death due to AML were patient preference (n=4; 9%) and inability to identify a matched donor (n=1; 2%). The median time to relapse in transplanted patients was 121 days, with a range of -18 to 183 days (one patient already showed progression before transplantation). In conclusion, alloSCT was only successful in patients transplanted in remission after the first induction, and the major cause of death after transplantation was relapse before or early after transplantation. In order to improve results, especially in patients not in remission after induction chemotherapy, new strategies need to be developed. The major problem, early relapse after transplantation may be resolved in several ways.



1) Donor lymphocyte infusion (DLI) can be administered in a save and effective way at 6 months after alloSCT. We recently studied the administration of a low dose of DLI at 3 months after transplantation and demonstrated this very early DLI to be feasible and most likely effective (10). In this study a group of 20 transplanted patients with high risk hematological disease received low dose DLI at 3 months. In the 18 patients evaluable three months later, four patients (1 transplanted with a related, 3 with an unrelated donor) developed acute GvHD grade 1-2 of the skin and one patient developed acute grade 4 GvHD of the liver. Acute GvHD necessitated systemic therapy in three patients and resolved in all patients. Among ten patients with mixed bone marrow chimerism before DLI, 5 patients converted to full donor chimerism as defined by <1% donor DNA in the mononuclear bone marrow cell fraction, indicating the induction of an immune response. Twelve patients received additional DLI dose escalation from 6 months after alloSCT. With a median follow up for survivors of 3.2 years (range 0.5-3.8), overall survival of these 20 high risk patients was 78% at 1 year and 65% at 3 years. Four patients died from relapse, 2 from infections. Recently, a larger group of 48 patients treated with DLI at 3 months was evaluated for the occurrence of acute GvHD. Of these patients 9% were non-evaluable due to death within 3 months after DLI due to relapse, 64% developed no GvHD, 19% developed overall grade 1-2 GvHD and 8% overall grade 3-4 GvHD. GvHD resolved in most patients, 4 patients developed limited chronic GvHD and 2 patients continuous acute GvHD ultimately leading to death. On the basis of these results, low dose DLI at 3 months has become standard treatment for patients transplanted in our institution for high risk hematological disease. 2) A sequential treatment regimen has been developed in which fludarabine-amsacrin-cytarabine chemotherapy is directly followed by a non-T cell depleted alloSCT using a cyclophosphamide and total body irradiation conditioning (FLAMSA-RIC) (11, 12). This regimen was shown to be not only effective in patients with AML (11) but even in patients transplanted with refractory AML not in remission (12). The effectiveness of the FLAMSA-RIC protocol was particularly shown by the results in young patients transplanted with refractory AML in whom 91% achieved a complete remission at day +30 after transplantation (12). This regimen was also successfully used in AML patients with bad prognosis complex cytogenetic karyotypes (13). The use of amsacrin and cytarabine in this regimen is of importance since this combination of chemotherapeutics has been shown to be effective in inducing remissions in 50% of AML patients refractory to standard daunorubicin-cytarabine chemotherapy (14). We have used amsacrin-cytarabine chemotherapy in a group of 9 elderly AML and MDS patients not in remission after induction chemotherapy (median age 64 years, range 62 to 70 years). Six out of 9 of these patients (67%) reached a complete remission with amsacrin-cytarabine, and no mortality was observed in this group. The use of allogeneic stem cell transplantation directly after induction chemotherapy can reduce the time period of aplasia after chemotherapy due to rapid repopulation with healthy transplanted stem cells, which is especially important in elderly patients that are known to badly tolerate long periods



of aplasia (7). The combination of FLAMSA chemotherapy and our T cell depleted RIC alloSCT regimen, together with DLI administration starting at 3 months after transplantation may prevent relapse in transplanted AML patients. In our transplanted group, the median time to relapse was only 121 days with a range of -18 to 183 days (one patient already showed progression before transplantation). In this group of relapsing patients the time between start of the last chemotherapy course and moment of relapse was 227 days with a range of 105 to 281 days, showing that an approach combining chemotherapy with transplantation followed by DLI at 3 months is worthwhile exploring. Current treatment of elderly patients with AML and high risk MDS in the LUMC Currently elderly AML and high risk MDS patients aged 60-75 years are treated with induction chemotherapy. If the patient is in complete remission (morphologically less than 5% blasts in a bone marrow aspirate) after the first induction course, a second induction course is administered. If the patient is in continuous remission after the second induction course, a reduced-intensity conditioning allogeneic stem cell transplantation is performed, in case a suitable donor has been found. If the patient is not in remission after the first induction course, also a second induction course is administered. If the patient is in complete remission after the second induction course, a third induction course is administered. If the patient is still in continuous remission after the third induction course, a reduced-intensity conditioning allogeneic stem cell transplantation is performed, in case a suitable donor has been found. Rationale of the study

Elderly patients aged over 60 years with AML or high risk MDS have a poor prognosis, the only way to achieve long term survival is transplantation with an allogeneic donor after achieving complete remission with intensive chemotherapy. Most patients starting with intensive chemotherapy are not transplanted, due to not achieving a complete remission with intensive chemotherapy, due to declining condition during the multiple courses of intensive chemotherapy with long periods of neutropenia or due to early relapse after chemotherapy. Patients that are in remission after the first induction chemotherapy and stay in remission after the second induction chemotherapy are good candidates for standard reduced intensity conditioning allogeneic stem cell transplantation. Patients that are not in remission after the first induction chemotherapy (50% of patients starting with induction chemotherapy) have a poor prognosis even if they are treated with the intention to reach allogeneic stem cell transplantation. They either stop with the chemotherapy treatments due to declining condition; they relapse before transplantation, or relapse early after transplantation. In this study we want to explore the feasibility of the sequential use of FLAMSA chemotherapy and our standard T cell depleted reduced intensity conditioning allogeneic stem cell transplantation, followed by our standard donor lymphocyte infusion regimen for high risk disease starting at 3 months after transplantation. This treatment regimen combines



a well known effective induction regimen (amsacrine-cytarabine) with a relatively non-toxic allogeneic transplantation conditioning regimen in combination with donor lymphocyte infusion at 3 and 6 months after transplantation. With this TCD FLAMSA-RIC alloSCT regimen we hope to cure patients that are not in remission after the first induction therapy, a patient group known to have a poor prognosis when treated with further chemotherapy courses followed by allogeneic stem cell transplantation. Patients in remission after induction chemotherapy and in continuous remission after consolidation therapy have a good curative chance with standard RIC alloSCT and will therefore not be included in the study.



2. OBJECTIVES Primary objective • To assess feasibility and safety of a sequential treatment regime in which standard

intensive chemotherapy (fludarabin-amsacrin-cytarabin) is directly followed by standard allogeneic stem cell transplantation (T cell depleted RIC alloSCT with donor lymphocyte infusion at 3 and 6 months), in elderly patients with AML or high risk myelodysplastic syndrome (IPSS ≥1.5).

• To evaluate the incidence of non-relapse mortality Secondary objectives • To evaluate progression free survival and overall survival • To evaluate the effect of FLAMSA chemotherapy in combination with T cell depleted RIC

alloSCT and donor lymphocyte infusion on quality of life



3. STUDY DESIGN The study is designed as a phase I-II study. Patients will receive FLAMSA chemotherapy over the course of 5 days. After a 3 day rest, the transplantation conditioning is started. T cell depletion of the patient consists of alemtuzumab in patients transplanted with a related donor and alemtuzumab in combination with rabbit ATG (Thymoglobulin) in unrelated patients. No further immunosuppressive drugs are given after transplantation. All patients are scheduled to be treated with donor lymphocyte infusions at 3 and 6 months after transplantation. A total of 15 patients will be included in the study.

FLAMSA chemotherapy+

T cell depleted RIC allogeneic stem cell transplantation

Salvage therapyResponse

+ day 90: first DLI0.3 x 106 CD3+ cells/kg (related donor)


+ day 180: second DLI3 x 106 CD3+ cells/kg (related donor)


CR

NR

AML or high risk MDS (IPSS >= 1.5), age 60-75 yearsPatients treated with induction chemotherapy, not in complete remission

after first intensive induction chemotherapy



4. STUDY POPULATION

4.1 Population (base)

Patients with AML or high risk myelodysplastic syndrome (IPSS ≥1.5) aged 60-75 years, not in remission after first induction chemotherapy

4.2 Inclusion criteria

• Patients with AML or high risk MDS (IPSS ≥ 1.5) • Not in remission after first intensive induction chemotherapy (morphologically > 5% blasts

in bone marrow aspirate) • 60-75 years, inclusive • HLA-identical sibling or unrelated donor completely matched (10/10 for HLA A, B, C, DR,

DQ) • WHO-performance status 0-2 (see appendix A) • Written informed consent

4.3 Exclusion criteria

• Previous autologous or allogeneic SCT • Acute promyelocytic leukemia • Severe pulmonary dysfunction (CTCAE grade III-IV, see appendix B); • Severe cardiac dysfunction (NYHA classification 3-4, see appendix C). • Significant hepatic dysfunction (serum bilirubin or transaminases ≥ 3 times upper limit of

normal); • Significant renal dysfunction (creatinine clearance < 30 ml/min after rehydration); • Concurrent severe and/or uncontrolled medical condition (e.g. uncontrolled diabetes,

infection, hypertension, cancer, etc.); • Severe neurological or psychiatric disease; • Any psychological, familial, sociological and geographical condition potentially hampering

compliance with the study protocol and follow-up schedule • Patient known to be HIV-positive

4.4 Sample size calculation

We aim to include 15 patients. We expect to include 3-5 patients in the first year, increasing up to 10 patients per year in the following years, resulting in a study period of 2-3 years.



5. TREATMENT OF SUBJECTS

5.1 Treatment regimen

Agent Dose/day Route of administration

Days

Fludarabine 1 dd 30 mg/m2 Intravenously -14, -13, -12, -11, -10 Amsacrine 1 dd 100 mg/m2 Intravenously -13, -12, -11, -10 Cytarabine 1 dd 2000 mg/m2 Intravenously -13, -12, -11, -10 Prednisolone 1 dd 30 mg Intravenously -13, -12, -11, -10, -9 Busilvex 4 dd 0.8 mg/kg Intravenously -6, -5 Alemtuzumab 1 dd 15 mg Intravenously -4, -3 Thymoglobulin* 1 dd 1 mg/kg Intravenously -2 Prednisolone 1 dd 2 mg/kg Intravenously -4, -3, -2, -1, 0 Alemtuzumab 20 mg “In the bag” 0 Stem cell infusion 0 * Only when transplanting with a matched unrelated donor, not when transplanting with a related donor.

5.1.1 Special management in conjunction with allogeneic transplantation

• Prednisolon is administered in a dose of 2 mg/kg IV from day -4 to 0, after which it is directly stopped. In case of Thymoglobulin administration prednisolon is also administered in a dose of 1 mg/kg between day 1 to 10, after which it is tapered (50% reduction every 3 days), to prevent serum sickness.

• To prevent the occurrence of seizures, phenytoin is started the day before Busilvex administration and continued until one day after the last administration of Busilvex (days -7, -6, -5, -4).

• Patients are advised to receive heparin (100 U/kg/day IV) or fraxiparin (2850 U per day SC) for veno-occlusive disease prophylaxis from day -7 to the moment of discharge.

• Premedication of alemtuzumab and Thymoglobulin administration and stem cell graft infusion consists of paracetamol 1000 mg PO and clemastine 2 mg IV

• HLA matching between patient and donor: HLA identical sibling donors or 10/10 matched unrelated donors (for HLA-A, B, C, DR and DQ) are allowed

• Stem cell source: only peripheral blood mobilized stem cells are allowed • T cell depletion of the stem cell graft: T cell depletion of the stem cell graft will be

performed by in vitro incubation of the cells with 20 mg of alemtuzumab. After the addition of alemtuzumab to the graft, it is incubated for 30 minutes at 20º C on a softly shaking plateau. Following in vitro incubation for 30 minutes, the stem cell graft is to be infused into the patient without further delay or manipulation.



5.1.2 Infection prophylaxis after transplantation

Standard SDD during the neutropenic phase: • Co-trimoxazol 1 dd 480 mg PO from day 0 • Valaciclovir 2 dd 500 mg PO or IV from day 0 • Itraconazol Oral Solution 2 dd 200 mg PO from day 0, dose adjustment according to

serum levels. Monitoring of CMV and EBV will be performed following standard procedures and pre-emptive therapeutic intervention will be initiated when appropriate. It is advised to perform weekly CMV and EBV monitoring during the first 90 days after transplantation.

5.1.3 Therapy of CMV reactivation

Valganciclovir 900 mg PO twice daily for 14 days. In case of insufficient response further treatment with intravenous foscarnet is to be used. In case of prolonged CMV reactivation not responding to therapy, treatment with CMV specific T cells or administration of DLI at a dose of 1 x 105 T cells/kg should be considered.

5.1.4 Therapy of EBV reactivation or post transplant lymfoproliferative disease (PTLD)

Rituximab 375 mg/m2 will be administered for EBV copy numbers in peripheral blood of >1000 geqs/ml (3 log EBV count). Repeat if EBV copies are higher than 50% of starting level after 72 hrs. For treatment of rituximab refractory PTLD, treatment with EBV specific T cells or administration of DLI at a dose of 1 x 105 T cells/kg should be considered.

5.1.5 Staging and handling of Graft versus Host Disease

Acute and chronic GvHD will be staged according to the criteria described in appendix D. Acute GvHD grade 2 should be treated with prednisolone 1 mg/kg PO or IV. Acute GvHD grade 3 or 4 should be treated with prednisone 2 mg/kg IV for 2 weeks and then tapered over 6 weeks. In case of insufficient response ciclosporin A in a dose of 3 mg/kg PO twice daily may be added. If there is concern of GI absorption, use IV route (1.5 mg/kg twice daily). Dosage of ciclosporin A should be adjusted according to serum levels.

5.1.6 Eligibility criteria for donor lymphocyte infusion at 3 or 6 months

Eligible for DLI • Disease status: bone marrow morphologically complete remission, partial remission,

stable disease or slowly progressive disease Ineligible for DLI • Disease status: bone marrow morphologically rapidly progressive disease



5.1.7 Inclusion criteria for donor lymphocyte infusion at 3 or 6 months

• Eligibility for donor lymphocyte infusion

5.1.8 Exclusion criteria for donor lymphocyte infusion at 3 or 6 months

• Bone marrow morphologically complete remission with evidence of an immune response

that occurred between the time point of transplantation and the time point of DLI (defined as the conversion from partial donor chimerism into complete donor chimerism in the presence of acute GvHD)

• The use of systemic immunosuppressive therapy for acute GvHD or chronic GvHD at the

time point of DLI administration

5.1.9 Donor lymphocyte infusion

Two donor lymphocyte infusions are projected to be administered to all patients at 3 and 6 months after transplantation, respectively. The first DLI at day +90 will consist of 0.3 x 106 T cells/kg from sibling and 0.15 x 106 T cells/kg from unrelated donors. The second DLI at day +180 will consist of 3 x 106 T cells/kg from sibling and 1.5 x 106 T cells/kg from unrelated donors. Administration of the first DLI may be delayed until day +150, if administration was not possible at an earlier moment. If the first DLI has been administered between day +90 and +150, the second DLI will be scheduled for administration at day +180 (according to eligibility criteria). If the first DLI has not been administered by day +150, administration of the first DLI will be cancelled and the patient will be scheduled for administration of DLI at day +180 at a dose of 3 x 106 T cells/kg from sibling and 1.5 x 106 T cells/kg from unrelated donors. For DLI using fresh PBMC, infusion will take place in the afternoon of the day of the PBMC collection. Infusions of cryopreserved PBMC will be performed taking into account a loss of T cells of 50% by the freezing and thawing of the product.

5.1.10 Salvage therapy

Our experience with AML and MDS patients not in remission after induction chemotherapy has shown that approximately two-thirds of these patients will reach a complete remission with amsacrin-cytarabine chemotherapy. In refractory AML patients treated with FLAMSA-RIC a complete remission rate of 91% was observed (12). Therefore we expect that a high percentage of patients will be in remission after transplantation. Patients that are not in complete remission after transplantation will be eligible for salvage therapy with azacitidine. Azacitidine is a hypomethylating agent which is registered for the treatment of MDS and AML



with limited amounts of blasts (<30%). It has been shown to be effective in AML (15) and chemotherapy refractory AML (16) and has been used to successfully treat impending AML relapse after allogeneic stem cell transplantation using the standard dose of 75 mg/m2 for 7 days every 4 weeks (17). Recently the use of even higher dosages of azacitidine for relapse AML after allogeneic SCT was reported to be feasible (100 mg/m2 for 5 days every 4 weeks) (18). Decitabine is a hypomethylating agent which is registered for the treatment of AML (20% bone marrow blasts or more) (19) Patients not in remission (more than 5% bone marrow blasts) at the time of the first bone marrow examination after transplantation will be treated with azacitidine in standard doses (75 mg/m2 for 7 days, every 4 weeks) or decitabine in standard doses (20 mg/m2 for 5 days, every 4 weeks) Patients responding to the azacitidine or dectabine treatment will be eligible for DLI administration at 3 and 6 months after transplantation. In patients with rapidly progressive disease despite azacitidine or decitabine administration, salvage therapy with azacitidine / decitabine will be stopped.



6. NON INVESTIGATIONAL MEDICINAL PRODUCT

6.1 Summary of known and potential risks

6.1.1 Fludarabine

Most common side effects (>10%) are low counts of blood cells (white blood cells, platelets and red blood cells), hair loss, nausea, vomiting, diarrhoea, fever, weakness, infections. Common side effects (1-10%) include myelodysplastic syndrome, anorexia, peripheral neuropathy, visual disturbances, stomatitis, rash, shivering.

6.1.2 Amsacrine

Most common side effects (>10%) are low counts of blood cells (white blood cells, platelets and red blood cells), hair loss, nausea, vomiting, diarrhoea, fever, weakness, infections, reversible hepatic dysfunction. Common side effects (1-10%) include cardiotoxicity, hypotension, headaches, dizziness and visual disturbances.

6.1.3 Cytarabine

Most common side effects (>10%) are low counts of blood cells (white blood cells, platelets and red blood cells), hair loss, nausea, vomiting, diarrhoea, fever, myalgia, rash, conjunctivitis, weakness, infections. Common side effects (1-10%) include reversible hepatic dysfunction, cerebellar dysfunction.

6.1.4 Busilvex (intravenous busulphan preparation)

Most common side effects (>10%) are low counts of blood cells (white blood cells, platelets and red blood cells), rhinitis, pharyngitis, hyperglycemia, hypocalcaemia, hypopotassemia, hypophosphatemia, depression, headache, dizziness, tachycardia, hair loss, nausea, vomiting, diarrhoea, fever, myalgia, pruritus, rash, shivering, edema, dysuria, olguria, arthralgia, anorexia, weakness, infections, reversible hepatic dysfunction, reversible kidney dysfunction. Common side effects (1-10%) include arythmia, hyponatriemia, pericarditis, hematuria.

6.1.5 Alemtuzumab

The most frequent side effects (>10%) are infusion reactions (fever, chills, low blood pressure, itching, feeling sick, hives, increased heart rate, breathlessness), low counts of blood cells (white blood cells, platelets and red blood cells), infections (signs of cytomegalovirus in the blood, cytomegalovirus infection or other infections), vomiting, abdominal pain, insomnia, anxiety.



6.1.6 Thymoglobulin

The most frequent side effects (>10%) are infusion reactions (fever, chills, low blood pressure, itching, feeling sick, hives, increased heart rate, breathlessness), low counts of blood cells (white blood cells, platelets and red blood cells), diarrhoea, dysphagia, nausea, vomiting, infections, myaligia

6.2 Preparation and labelling

All medication should be stored and handled in accordance with the instructions in the summary of product characteristics or package insert..



7. METHODS

7.1 Study endpoints

7.1.1 Primary endpoints

• The number of patients eligible for DLI at 6 months after transplantation • Incidence of non-hematological grade 3-4 toxicity from the start of chemotherapy until 9

months after transplantation • Incidence of serious adverse events from the start of chemotherapy until 9 months after

transplantation • Incidence of severe grade 3 or 4 acute GvHD and incidence of extensive chronic GvHD in

the first 9 months after transplantation • Non-relapse mortality at 3 and 12 months after transplantation

7.1.2 Secondary endpoints

• 1-year progression free survival after transplantation • 1-year overall survival after transplantation • Quality of life at 3, 6 and 12 months after transplantation in comparison with quality of life

at the start of therapy, as determined with the EORTC QLQ-C30 questionnaire

7.2 Study procedures

Bone marrow aspiration and biopsy are performed at entry and at the time of repopulation after stem cell transplantation (approximately 28 days after the start of chemotherapy or 14 days after transplantation), defined as the time point at which the peripheral granulocyte number is higher than 1 x 109/l. When this criterium of repopulation is not reached at day 35 after the start of chemotherapy (or at day 21 after transplantation), a bone marrow aspiration and biopsy are performed at this time point. These procedures performed before and after intensive chemotherapy and allogeneic transplantation are considered to be standard care in the treatment of patients with AML to determine the effect of the treatment. During these procedures 20-25 ml of bone marrow is aspirated for standard morphology, immunophenotyping, molecular diagnostics and cytogenetics. For scientific purposes an additional 20 ml of bone marrow is aspirated and frozen. After transplantation, bone marrow aspiration is performed every three months after transplantation, as is normally performed, to guide DLI administration. During these procedures 25 ml of bone marrow is aspirated for standard morphology, immunophenotyping, molecular diagnostics and cytogenetics. For scientific purposes an additional 20 ml of bone marrow is aspirated and frozen.



For scientific purposes a single bone marrow aspiration and biopsy is additionally performed at day -6 before transplantation. During this procedure 20 ml of bone marrow is aspirated for standard morphology, immunophenotyping, molecular diagnostics and cytogenetics and 20 ml of bone marrow is aspirated and frozen. Quality of life will be assessed by means of the EORTC QLQ-C30 questionnaire. The QLQ-C30 is a multidimensional, cancer-specific quality of life questionnaire developed by the European Organization for Research and Treatment of Cancer (EORTC) Study Group on Quality of Life for use in international clinical trial settings. The questionnaire is designed for use with a wide range of cancer patient populations, irrespective of specific diagnosis. The QLQ-C30 includes 5 functional scales (physical, role, emotional, social and cognitive functioning), 3 symptom scales (fatigue, pain, and nausea and vomiting), a global health status/quality of life scale and a number of single items assessing additional symptoms (dyspnoea, sleep disturbance, constipation and diarrhea) and perceived financial impact. For the majority of the QLQ-C30 items a 4-point Likert-type response scale is used. Exceptions are the items for the global quality of life scale (where a 7-point scale is used). All subscale and individual item responses are linearly converted to 0 to 100 scales. For the functional and global quality of life scales, a higher score represents a better level of functioning. For the symptom scales and items, a higher score reflects a greater degree of symptomatology. During informed consent the patient will be asked to participate in the quality of life part of this study. Quality of life will be measured: - at entry of the study, prior to the start of therapy - at 3, 6 and 12 months after transplantation Entry Day

-6 Re-

population 3 months 6 months

9 months 1 year

History X X X X X X Physical exam X X X X X X Hematology X X X X X X Chemistry X X X X X X BM morphology 5 ml X X X X X X X BM immune phenotyping 5 ml

X X X X X X X

BM molecular diagnostics 5 ml

X X X X X X X

BM chimerism 5 ml X X X X X BM cytogenetics 5 ml X X X X X X X BM scientific 20 ml X X X X X X X BM biopsy X X X QLQ-C30 X X X X



questionnaire

7.3 Evaluation criteria

7.3.1 Safety evaluation during and after treatment

General non-hematological toxicity will be scored according to the NCI Common Terminology Criteria for Adverse Events (CTCAE) Version 4.0 (see appendix B). Acute and chronic GvHD will be graded using the criteria outlined in appendix C. Serious adverse events will be scored according to the criteria defined in chapter 8. Non-relapse mortality is defined as mortality occurring by any cause in the absence of relapse or progression. Only patients that have achieved a morphological complete remission (< 5% blasts) at repopulation are eligible for non-relapse mortality evaluation. Progression free survival is defined as the time from registration until objective disease progression or death from any cause. Overall survival is defined as the time from registration until death from any cause.

7.4 Withdrawal of individual subjects

Subjects can leave the study at any time for any reason if they wish to do so without any consequences. The investigator can decide to withdraw a subject from the study for medical reasons.

7.5 Premature termination of the study

A total number of 15 patients will be included in this study. Taking into account a non-relapse mortality of 15%, the chance that more than 2 of 5 patients die from non-relapse mortality is 2.7%, and the chance that more than 4 of 10 patients die from non-relapse mortality is 1%. Therefore, if within the group of the first 5 patients that reach a complete remission after FLAMSA-RIC more than 2 patients die from non-relapse causes within the first 3 months, inclusion within the study will be stopped. If within the group of the first 10 patients that reach a complete remission after FLAMSA-RIC more than 4 patients die from non-relapse causes within the first 3 months, inclusion within the study will be stopped. After stopping the study, a careful evaluation of the causes of death will be performed to determine whether changes in the study are likely to diminish non-relapse death and whether further continuation of the study with amendments is possible.



7.6 End of study

End of the study is defined as 6 months after the infusion of the second DLI, one year after transplantation of the last patient treated in the study.



8. SAFETY REPORTING

8.1 Section 10 WMO event

In accordance to section 10, subsection 1, of the WMO, the investigator will inform the subjects and the METC if anything occurs, on the basis of which it appears that the disadvantages of participation may be significantly greater than was foreseen in the research proposal. The study will be suspended pending further review by the METC, except insofar as suspension would jeopardize the subjects’ health. The investigation will take care that all subjects are kept informed.

8.2 Adverse and serious adverse events

Adverse events are defined as any undesirable experience occurring to a subject during a clinical trial, whether or not considered related to the investigational drug. All adverse events reported spontaneously by the subject or observed by the investigator will be recorded. A serious adverse event (SAE) is any untoward medical occurrence or effect that at any dose results:

- in death; - is life threatening (at the time of the event); - requires hospitalization or prolongation of existing inpatients’ hospitalization; - in persistent or significant disability or incapacity.

All SAEs will be reported to the METC, within 15 days after the responsible investigator has first knowledge of the serious adverse reactions. SAEs that result in death or are life threatening should be reported expedited. The expedited reporting will occur not later than 7 days after the responsible investigator has first knowledge of the adverse reaction. This is for a preliminary report with another 8 days for completion of the report.

8.2.1 Suspected unexpected serious adverse reactions (SUSAR)

Adverse reactions are all untoward and unintended responses to an investigational product related to any dose administered. Unexpected adverse reactions are adverse reactions, of which the nature, or severity, is not consistent with the applicable product information. All SUSARs during this study will be reported to the METC within 15 days. For fatal or life-threatening cases, a preliminary report will be send within 7 days, followed by a definite repost within 8 days.



8.2.2 Annual safety report

In addition to the expedited reporting of SUSARs, the investigator will submit, once a year throughout the clinical trial, a safety report to the accredited CCMO. This safety report consists of: - a report of progress of the study - a list of all serious adverse events and serious adverse reactions, along with an

aggregated summary table of all reported serious adverse events and serious adverse reactions, ordered by organ system;

- a report concerning the safety of the subjects, consisting of a complete safety analysis and an evaluation of the balance between the efficacy and the harmfulness of treatment

8.3 Follow-up of adverse events

All adverse events will be followed until they have abated, or until a stable situation has been reached. Depending on the event, follow up may require additional tests or medical procedures, and/or referral to a medical specialist.



9. STATISTICAL EVALUATION

9.1 Statistical design

This is a non-randomized phase I/II feasibility study to treat patients with AML or high risk MDS not in remission after induction chemotherapy with FLAMSA chemotherapy directly followed by allogeneic stem cell transplantation.

9.2 Sample size

We aim to include 15 patients. We expect to include 3-5 patients in the first year, increasing up to 5-10 patients per year in the following years, resulting in a study period of 2-3 years.

9.3 Power calculation

We consider the FLAMSA-RIC approach feasible when at least 40% of patients are eligible for DLI administration at 6 months after transplantation. The expected 95% confidence interval for the proportion of successes ranges from 13.3% to 66.7%, indicating a significantly positive result in this group of patients with a very poor prognosis when treated with a standard approach.

9.4 Statistical analysis

The primary endpoint of feasibility analysis will be the estimated proportion of registered patients eligible for DLI at 6 months after transplantation is performed by calculation (≥40% of patients equals 6 or more out of 15 registered patients). The primary endpoints of analysis of treatment toxicity will be performed by tabulation of the incidence of serious adverse events, non-hematological side effects with CTCAE grade 3 or 4 and acute GvHD grade 3 or 4 or extensive chronic GvHD.

9.5 Interim analysis

After the first 5 and 10 patients an interim analysis will be performed by the principle investigator. Evaluation of this analysis will take place as described under 7.6.



10. ETHICAL CONSIDERATION

10.1 Regulation statement

The study will be conducted according to the principles of the Declaration of Helsinki (version 2008) and in accordance with the Medical Research Involving Human Subjects Act (WMO).

10.2 Recruitment and consent

The treating physician will inform the patient about this study and explain the patient about the informed consent procedure. All patients will be informed of the aims of the study, the possible adverse events, the procedures and possible hazards to which the patient will be exposed. They will be informed as to the strict confidentiality of their patient data, but that their medical records may be reviewed for trial purposes by authorized individuals other than their treating physician. It will be emphasized that the participation is voluntary and that the patient is allowed to refuse further participation in the protocol whenever he/she wants. This will not prejudice the patient’s subsequent care. The patient is given the information letter. During a second visit, information will be repeated if necessary and participation to the study will be considered. Only after written informed consent is obtained will the participants be entered into the study.

10.3 Benefits and risks assessment

Potential benefit of participation is cure from the AML or MDS in a patient group with a dismal prognosis. A potential risk of participation to this study is death due to non-relapse mortality.

10.4 Compensation for injury

The chance of injury as a result of this study is extremely small. However, the LUMC has insured this risk by taking a liability insurance, which is in accordance with article 7, subsection 6 of the WMO. The LUMC (also) has an insurance which is in accordance with the legal requirements in the Netherlands (Article 7 WMO and the Measure regarding Compulsory Insurance for Clinical Research in Humans of 23th June 2003). This insurance provides cover for damage to research subjects through injury or death caused by the study. 1. € 450.000,-- (i.e. four hundred and fifty thousand Euro) for death or injury for each subject who participates in the Research; 2. € 3.500.000,-- (i.e. three million five hundred thousand Euro) for death or injury for all subjects who participate in the Research; 3. € 5.000.000,-- (i.e. five million Euro) for the total damage incurred by the organization for all damage disclosed by scientific research for the Sponsor as ‘verrichter’ in the meaning of



said Act in each year of insurance coverage. The insurance applies to the damage that becomes apparent during the study or within 4 years after the end of the study.



11. ADMINISTRATIVE ASPECTS AND PUBLICATION

11.1 Handling and storage of data and documents

Patients will be included after verification of eligibility by checking inclusion and exclusion criteria and date of written informed consent. Patients will be assigned for the purpose of the study and publication, a unique patient number (UPN). Data will be recorded on Case Report Forms (CRF) and will be entered after validation into a computer system for subsequent tabulation and analyses. The data will be handled confidentially and, as far as possible, anonymously. The investigator will retain the originals of the source documents generated for a minimum of ten years after the study is completed. After this all documents will be archived according to Good Clinical Practice (GCP) regulations. The results of the study will be published in recognized medical journals if applicable. If so, the patient identity will not be revealed.

11.2 Annual progress report

The principal investigator will submit a summary of the progress of the trial to the METC once a year. Information will be provided on the date of inclusion of the first subject, numbers of subjects included and numbers of subjects that have completed the trial, serious adverse events, other problems, and amendments.

11.3 End of study report

The investigator will notify the METC of the end of the study within a period of 8 weeks. The end of the study is defined as the last patients’ last control visit. This will be 12 months after the transplantation of patient number 15. In case the study is ended prematurely, the investigator will notify the METC including the reason for the premature termination. Within one year after the end of the study, the investigator will submit a final study report with the results of the study, including any publications/abstracts of the study, to the METC.

11.4 Public disclosure and publication policy

The principal investigator will be responsible for the publication of the results of this study.



12. REFERENCES 1. Luger SM. Treating the elderly patient with acute myelogenous leukemia. Hematology Am Soc

Hematol Educ Program 2010: 62-9

2. Mayer RJ, Davis RB, Schiffer CA, Berg DT, Powell BL, Schulman P, Omura GA, Moore JO, McIntyre OR, Frei E 3rd. Intensive postremission chemotherapy in adults with acute myeloid leukemia. N Engl J Med 1994; 331: 941-2.

3. Jehn U, Suciu S, Thomas X, Lefrère F, Muus P, Berneman Z, Marie JP, Adamo F, Fillet G, Nobile F, Ricciuti F, Leone G, Rizzoli V, Montanaro M, Beeldens F, Fazi P, Mandelli F, Willemze R, de Witte T, Amadori S. Non-infusional vs intravenous consolidation chemotherapy in elderly patients with acute myeloid leukemia: final results of the EORTC-GIMEMA AML-13 randomized phase III trial. Leukemia 2006; 20: 1723-30

4. Estey E, de Lima M, Tibes R, Pierce S, Kantarjian H, Champlin R, Giralt S. Prospective feasibility analysis of reduced-intensity conditioning (RIC) regimens for hematopoietic stem cell transplantation (HSCT) in elderly patients with acute myeloid leukemia (AML) and high-risk myelodysplastic syndrome (MDS). Blood. 2007; 109: 1395-400

5. Kurosawa S, Yamaguchi T, Uchida N, Miyawaki S, Usuki K, Watanabe M, Yamashita T, Kanamori H, Tomiyama J, Nawa Y, Yano S, Takeuchi J, Yakushiji K, Sano F, Uoshima N, Yano T, Nannya Y, Moriuchi Y, Miura I, Takaue Y, Fukuda T. Comparison of allogeneic hematopoietic cell transplantation and chemotherapy in elderly patients with non-M3 acute myeloid leukemia in first complete remission. Biol Blood Marrow Transplant 2010; 17: 401-411

6. Rowe JM, Tallman MS. How I treat acute myeloid leukemia. Blood 2010; 116: 1839-1848

7. Löwenberg B, Ossenkoppele GJ, van Putten W, Schouten HC, Graux C, Ferrant A, Sonneveld P, Maertens J, Jongen-Lavrencic M, von Lilienfeld-Toal M, Biemond BJ, Vellenga E, van Marwijk Kooy M, Verdonck LF, Beck J, Döhner H, Gratwohl A, Pabst T, Verhoef G. High-dose daunorubicin in older patients with acute myeloid leukemia. N Engl J Med. 2009; 361: 1235-48.

8. Von dem Borne PA, Starrenburg CW, Halkes SJ, Marijt WA, Fibbe WE, Falkenburg JH, Willemze R. Reduced-intensity conditioning allogeneic stem cell transplantation with donor T cell depletion using alemtuzumab added to the graft ('Campath in the bag'). Curr Opin Oncol. 2009 Jun;21 Suppl 1:S27-9

9. Von dem Borne PA, Halkes CJ, Starrenburg CW, Marijt WA, Falkenburg JH. Post-transplant immune suppressive therapy is not necessary in related and unrelated reduced intensity conditioning stem cell transplantation using low dose alemtuzumab in vivo T cell depletion combined with alemtuzumab-mediated in vitro T cell depletion of the graft (abstract American Society of Hematology Meeting, Orlando, 2010)

10. Von dem Borne PA, Halkes CJ, Marijt WA, Veelken H, Falkenburg JH. Feasibility of very low dose of donor lymphocyte infusion (DLI) early after T cell depleted allogeneic stem cell transplantation (abstract European Bone Marrow Transplantation Meeting, Paris, 2011)

11. Schmid C, Schleuning M, Ledderose G, Tischer J, Kolb HJ. Sequential regimen of chemotherapy, reduced-intensity conditioning for allogeneic stem-cell transplantation, and



prophylactic donor lymphocyte transfusion in high-risk acute myeloid leukemia and myelodysplastic syndrome. J Clin Oncol 2005; 23: 5675-87.

12. Schmid C, Schleuning M, Schwerdtfeger R, Hertenstein B, Mischak-Weissinger E, Bunjes D, Harsdorf SV, Scheid C, Holtick U, Greinix H, Keil F, Schneider B, Sandherr M, Bug G, Tischer J, Ledderose G, Hallek M, Hiddemann W, Kolb HJ. Long-term survival in refractory acute myeloid leukemia after sequential treatment with hemotherapy and reduced-intensity conditioning for allogeneic stem cell transplantation. Blood 2006; 108: 1092-9

13. Schmid C, Schleuning M, Tischer J, Holler E, Haude KH, Braess J, Haferlach C, Baurmann H, Oruzio D, Hahn J, Spiekermann K, Schlimok G, Schwerdtfeger R, Buechner T, Hiddemann W, Kolb HJ. Early allo-SCT for AML with a complex aberrant karyotype-results from a prospective pilot study. Bone Marrow Transplant. 2012; 47: 46-53

14. Jehn U, Heinemann V. Phase-II study of treatment of refractory acute leukemia with intermediate-dose cytosine arabinoside and amsacrine. Ann Hematol 1993; 66:131-134

15. Maurillo L, Venditti A, Spagnoli A, Gaidano G, Ferrero D, Oliva E, Lunghi M, D'Arco AM, Levis A, Pastore D, Di Renzo N, Santagostino A, Pavone V, Buccisano F, Musto P. Azacitidine for the treatment of patients with acute myeloid leukemia : Report of 82 patients enrolled in an Italian compassionate program. Cancer 2012; 118: 1014-22

16. Al-Ali HK, Jaekel N, Junghanss C, Maschmeyer G, Krahl R, Cross M, Hoppe G, Niederwieser D. Azacitidine in patients with acute myeloid leukemia medically unfit for or resistant to chemotherapy: a multicenter phase I/II study. Leuk Lymphoma 2012; 53: 110-7

17. Platzbecker U, Wermke M, Radke J, Oelschlaegel U, Seltmann F, Kiani A, Klut IM, Knoth H, Röllig C, Schetelig J, Mohr B, Graehlert X, Ehninger G, Bornhäuser M, Thiede C. Azacitidine for treatment of imminent relapse in MDS or AML patients after allogeneic HSCT: results of the RELAZA trial. Leukemia 2012 [Epub ahead of print]

18. Schroeder T, Czibere A, Platzbecker U, Bug G, Uharek L, Luft T, Giagounidis A, Zohren F, Bruns I, Wolschke C, Rieger K, Fenk R, Germing U, Haas R, Kröger N, Kobbe G. Azacitidine and donor lymphocyte infusions as first salvage therapy for relapse of AML or MDS after allogeneic stem cell transplantation. Leukemia. 2013 [Epub ahead of print]

19. Kantarjian HM, Thomas XG, Dmoszynska A, Wierzbowska A, Mazur G, Mayer J, Gau JP, Chou WC, Buckstein R, Cermak J, Kuo CY, Oriol A, Ravandi F, Faderl S, Delaunay J, Lysák D, Minden M, Arthur C. Multicenter, randomized, open-label, phase III trial of decitabine versus patient choice, with physician advice, of either supportive care or low-dose cytarabine for the treatment of older patients with newly diagnosed acute myeloid leukemia.J Clin Oncol. 2012; 30: 2670-7



APPENDIX A: WHO performance score

0 Normal activity

1 Symptoms, but nearly ambulatory

2 Some bed time, but to be in bed less than 50% of normal daytime

3 Needs to be in bed more than 50% of normal daytime

4 Unable to get out of bed



APPENDIX B: Common Toxicity Criteria The grading of toxicity and adverse events will be done using the NCI Common Terminology

Criteria for adverse events, CTC version 4.0, published May 28, 2009. A complete document

(78 pages) may be downloaded from the following site: http://evs.nci.nih.gov/ftp1/CTCAE/CTCAE_4.03_2010-06-14_QuickReference_5x7.pdf

http://evs.nci.nih.gov/ftp1/CTCAE/CTCAE_4.03_2010-06-14_QuickReference_5x7.pdf



APPENDIX C: NYHA scoring list The New York Heart Association functional and therapeutic classification applied to dyspnoea. Grade 1 No breathlessness

Grade 2 Breathlessness on severe exertion

Grade 3 Breathlessness on mild exertion

Grade 4 Breathlessness at rest



APPENDIX D: Grading of GvHD Acute GvHD

Stage Skin Liver Bowel

0 No rash Bilirubin < 2 mg / dl (< 34 umol/L)

Diarrhea < 500 ml/day

1 Maculopapular rash on < 25% of body surface

Bilirubin 2-3 mg/dl (34-50 umol/L)

Diarrhea 500-1000 ml/day

2 Maculopapular rash on 25-50% of body surface

Bilirubin 3-6 mg/dl (51-102 umol/L)

Diarrhea 1000-1500 ml/day

3 Generalized erythroderma Bilirubin 6-15 mg/dl (103-225 umol/L)

Diarrhea > 1500 ml/day

4 Generalized erythroderma with formation of bullea and desquamation

Bilirubin > 15 mg/dl (> 225 umol/L)

Severe abdominal pain with or without ileus

Chronic GvHD Limited: localized skin involvement and/or liver function abnormalities Extensive: generalized skin involvement or localized skin involvement and/or liver

function abnormalities + other organ involvements

sequential flamsa chemotherapy and t cell depleted …€¦ · reduced intensity conditioning...

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