Ultra-Low Dose IL-2 Therapy as GVHD Prophylaxis in Haploidentical Allogeneic Stem Cell Transplantation

Although allogeneic stem cell transplantation (allo-SCT) is a curative option for many
hematologic malignancies, not all have a suitable donor. Haploidentical peripheral blood stem
cell transplantation (haplo-SCT) has the advantage of immediate availability, higher stem
cell dose, and feasibility of repeated cell collections for generating lymphocyte infusions
to treat or prevent relapse or infection. However, haplo-SCT incurs a risk of bidirectional
rejection with either severe graft versus host disease (GVHD) or graft rejection by the
recipient. Therefore it is important to develop novel strategies to optimize the outcome of
haplo-SCT. Designing a haplo-SCT that incorporates the concepts of modulating the immune
system and allowing the opportunity for graft manipulation and/or adoptive immunotherapy may
improve the treatment outcome. To achieve this, we are first interested in studying the
immune modulatory effect of ultra-low dose Interleukin 2 (ULD IL-2) as GVHD prophylaxis.

This is an investigator initiated pilot study to determine the safety and feasibility of ULD
IL-2 as GVHD prophylaxis in haploidentical allogeneic stem cell transplantation for patients
with hematologic malignancies. Because GVHD has previously been associated with low numbers
of circulating CD4+ CD25+FOXP3+ regulatory T cells (T(regs)), research efforts in increasing
T(regs) either ex-vivo with adoptive transfer of T(regs) or in vivo using immunomodulatory
agents such as IL-2, have shown promise in reducing incidences of GVHD.

The primary objective of this study is to evaluate safety and feasibility. Secondary
objectives are to determine the incidences of acute and chronic GVHD, engraftment, overall
survival, transplant related mortality, and relapse.

We will adopt the 2 step haplo-SCT method developed by Grosso et. al1 to study our method of
GVHD prophylaxis. This 2 step approach, in which the lymphoid and myeloid portions of the
graft are given in two separate steps in order to control and optimize T-cell, has already
been published as a feasible and safe platform for haplo SCT for patients with hematologic
malignancies and has been adopted by the Jefferson University Hospital (PA, USA), where they
continue to treat patients under this protocol. As an additional GVHD prophylaxis, we will
use sirolimus, an previously established GVHD prophylaxis which may work with ULD IL-2
synergistically to increase T(regs) .

The haploidentical donor will be mobilized by G-CSF and undergo one apheresis to collect
lymphocytes and CD34+ stem cell product after Miltenyi CD34+ selection. The products will be
cryopreserved until the time of transplantation. Recipients will receive a myeloablative
conditioning regimen of fludarabine and total body irradiation (TBI) on days -10 to -6. After
the last fraction of TBI, a donor lymphocyte infusion (DLI) product (2 times 10(8) CD3+/kg)
will be given. Cyclophosphamide will be given on days -3 and -2, followed by CD 34+ selected
donor stem cell product infused on day 0. Sirolimus will be initiated on day -1 until day+60.
ULD-IL2 (100,000 IU/m2) will give subcutaneously daily for 12 weeks starting day +1.

This study will evaluate 14 recipients (ages greater than or equal to 18 - less than or equal
to 75; planned accrual up to 20 recipient in event of replacement) with hematologic
malignancies meeting indication for transplant but who do not have matched related or
unrelated donor available. Safety will be monitored continuously with a stopping rule for
toxicity based on the treatment-related serious adverse event rate (TRSAE). Safety monitoring
will continue until at least 114 days after transplantation, and recipients experiencing
adverse events will be monitored until toxicity resolution or stabilization. Stopping rule is
defined as nonrelapse mortality and steroid refractory GVHD during the period of safety
monitoring for ULD IL-2. Recipients will be followed for up to 1 year to evaluate the
incidences of acute and chronic GVHD, engraftment, overall survival, transplant related
mortality, and relapse.

- INCLUSION CRITERIA RECIPIENT:

- Ages 18-70 years inclusive

- Haploidentical donor available

- Any one of the following hematologic conditions meeting a standard indication for
allogeneic stem cell transplant:

- Chronic myelogenous leukemia (CML): Subjects under the age of 21 in chronic phase
OR subjects ages 18-65 in chronic phase who have failed treatment with imatinib
or have intolerance to imatinib OR Subjects ages 18-65 in accelerated phase or
blast transformation. OR

- Acute lymphoblastic leukemia (ALL): any of these categories: Adult ALL including
standard risk. All second or subsequent remissions, primary induction failure,
partially responding or untreated relapse. OR

- Acute myelogenous leukemia (AML): AML in first remission - except AML with good
risk karyotypes: AML M3 (t15; 17), AML M4Eo (inv 16), c-kit unmutated AML t (8;
21). All AML in second or subsequent remission, primary induction failure and
resistant relapse. OR

- Myelodysplasticsyndromes(MDS): any of these categories - refractory anemia with
transfusion dependence, refractory anemia with ANC<500/ (Micro)L, refractory
anemia with excess of blasts, transformation to acute leukemia, chronic
myelomonocytic leukemia, atypical MDS/myeloproliferative syndromes. OR

- Myeloproliferative disorders including atypical (Ph-negative) chronic myeloid and
neutrophilic leukemias, progressing myelofibrosis, and polycythemia vera,
essential thrombocythemia either in transformation to acute leukemia or with
progressive transfusion requirements or pancytopenia. OR

- Non-Hodgkin s lymphoma including Mantle cell lymphoma relapsing or refractory to
standard of care treatments. OR

- Multiple myeloma, Waldenstroms macroglobulinemia, unresponsive or relapsed
following standard of care treatments. OR

- Hodgkin's Lymphoma relapsing following an autologous transplant. OR

- Other rare hematologic malignancies for which hematopoietic stem cell
transplantation has been performed and offers a durable remission or as the only
option with a potential for cure.

- Chemotherapy-resistant multisystem Langerhans cell histiocytosis (MSLCH)
especially involving organs like the bone marrow, liver, spleen, and lungs

- Aggressive systemic mastocytosis, and mast cell leukemia (MCL) in first CR
(CR1)

- Hypereosinophilic syndrome who have failed imatinib therapy or
FIP1L1-PDGFRa-negative patients who develop end-organ dysfunction

- Adult T-cell leukemia/lymphoma at first diagnosis

- Refractory or disseminated nasal-type extranodal NK/T-lymphoma or aggressive
Natural killer cell leukemia/lymphoma

- Mycosis fungoides and S(SqrRoot)(Copyright)zary syndrome after failure of
two or three initial therapies

- Primary or relapsed refractory Angioimmunoblastic T-cell lymphoma at first
diagnosis

- Hepatosplenic T-cell lymphoma (gamma/delta T-cell lymphoma) at first
diagnosis

- T-cell prolymphocytic leukemia at first diagnosis

- Subcutaneous panniculitic T-cell lymphoma at first diagnosis

- Hematodermic neoplasm (blastic natural killer cell lymphoma or Blastic
plasmacytoid dendritic cell neoplasm) at first diagnosis

- Ability to comprehend the investigational nature of the study and provide
informed consent.

EXCLUSION CRITERIA RECIPIENT (ANY OF THE FOLLOWING):

- HLA identical (6/6) related or (8/8 allele level matched) unrelated donor available
and readily accessible at time of transplantation evaluation

- Major anticipated illness or organ failure incompatible with survival from transplant

- Severe psychiatric illness or mental deficiency sufficiently severe as to make
compliance with the transplant treatment unlikely and making informed consent
impossible.

- Positive pregnancy test for women of childbearing age

- Contraindication to receive IL-2 including:

- Hypersensitivity to IL-2

- Sustained ventricular tachycardia (>5 beats)

- Cardiac arrhythmias not controlled or unresponsive to management

- Chest pain with ECG changes, consistent with angina or myocardial infarction

- Cardiac tamponade

- Intubation for >72 hours

- Renal failure requiring dialysis >72 hours

- Coma or toxic psychosis lasting > 48 hours

- Repetitive or difficult to control seizures

- Active bowel ischemia or perforation

- Active GI bleeding requiring surgery

- DLCO adjusted for Hb and ventilation< 50% predicted

- Left ventricular ejection fraction < 40% (evaluated by ECHO) or < 30% (evaluated by
MUGA)

- AST/SGOT > 5 times ULN

- Total bilirubin > 3 times ULN

- Estimated GFR <60ml/min (calculated by CKD-EPI, a formula routinely used in Clinical
Research Center at National Institutes of Health. In case of borderline estimated GFR,
CKD-EPI creatinine-cystatin C formula will be used for more accurate estimation)

- Prior allogeneic stem cell transplantation

INCLUSION CRITERIA DONOR:

- Related donor who shares 1 haplotype with the recipient

- Age greater than or equal to 18 or less than or equal to 80 years old

- Ability to comprehend the investigational nature of the study and provide informed
consent.

EXCLUSION CRITERIA DONOR (ANY OF THE FOLLOWING):

- Unfit to receive G-CSF and undergo apheresis such as abnormal blood counts, history of
stroke, uncontrolled hypertension

- Sickling hemaglobinopathy including HbSS, HbAS, HbSC

- Donors who are positive for HIV, active hepatitis B (HBV), hepatitis C (HCV) or human
T-cell lymphotropic virus (HTLV-I/II)

- Severe psychiatric illness. Mental deficiency sufficiently severe as to make
compliance with the BMT treatment unlikely and making informed consent impossible.