Clinical trial NCT03019640
Conditions: Mantle Cell Lymphoma Recurrent Diffuse Large B-Cell Lymphoma Recurrent Follicular Lymphoma Recurrent Indolent Adult Non-Hodgkin Lymphoma Refractory Diffuse Large B-Cell Lymphoma Refractory Follicular Lymphoma Refractory Indolent Adult Non-Hodgkin Lymphoma
Sponsor: M.D. Anderson Cancer Center
Start date: 2017-10-10; Completion date: 2021-08-16
Enrollment: 22 participants; Allocation: NA; Intervention model: SINGLE_GROUP

Brief summary:
This phase II trial studies the side effects of cord blood-derived expanded allogeneic natural killer cells (umbilical cord blood natural killer \[NK\] cells), rituximab, high-dose chemotherapy, and stem cell transplant in treating patients with B-cell non-Hodgkin's lymphoma that has come back (recurrent) or that does not respond to treatment (refractory). Immune system cells, such as cord blood-derived expanded allogeneic natural killer cells, are made by the body to attack foreign or cancerous cells. Immunotherapy with rituximab, may induce changes in body's immune system and may interfere with the ability of tumor cells to grow and spread. Drugs used in chemotherapy, such as carmustine, cytarabine, etoposide, lenalidomide, melphalan, and rituximab, work in different ways to stop the growth of cancer cells, either by killing the cells, by stopping them from dividing, or by stopping them from spreading. A stem cell transplant using stem cells from the patient or a donor may be able to replace blood-forming cells that were destroyed by chemotherapy used to kill cancer cells. The donated stem cells may also replace the patient's immune cells and help destroy any remaining cancer cells. Giving cord blood-derived expanded allogeneic natural killer cells, rituximab, high-dose chemotherapy, and stem cell transplant may work better in treating patients with recurrent or refractory B-cell non-Hodgkin's lymphoma.

Detailed description:
PRIMARY OBJECTIVE:

I. To establish the safety of this treatment by determining its treatment-related mortality (TRM) within 30 days.

SECONDARY OBJECTIVES:

I. To estimate the relapse-free survival (RFS). II. To estimate the overall survival (OS). III. To quantify duration of infused allogeneic umbilical cord blood (UCB)-derived natural killer (NK) cells in the recipient.

OUTLINE:

PREPARATIVE REGIMEN: Patients receive carmustine intravenously (IV) over 2 hours on day -12, etoposide IV twice daily (BID) over 3 hours on days -11 to -8, cytarabine IV BID over 1 hour on days -11 to -8, melphalan IV over 30 minutes on day -7, and lenalidomide orally (PO) once daily (QD) on days -7 to -2 in the absence of disease progression or unacceptable toxicity. Patients who are CD20+ also receive rituximab IV over 3 hours on days -13 and -7.

NK-CELL INFUSION: Patients receive cord blood-derived expanded allogeneic NK cells IV over 1 hour on day -5 in the absence of disease progression or unacceptable toxicity.

STEM CELL TRANSPLANT: Patients undergo stem cell transplant IV over 30-60 minutes on day 0 in the absence of disease progression or unacceptable toxicity.

POST-TRANSPLANT: Patients receive filgrastim subcutaneously (SC) QD beginning on day +5. Treatment continues until white blood cell count recovers in the absence of disease progression or unacceptable toxicity.

After completion of study treatment, patients are followed up at 30, 100, and 180 days.

Arms: arm 1: See Detailed Description.
Interventions: intervention 1: Autologous Hematopoietic Stem Cell Transplantation intervention 2: Carmustine intervention 3: Cord Blood-derived Expanded Allogeneic Natural Killer Cells intervention 4: Cytarabine intervention 5: Etoposide intervention 6: Filgrastim intervention 7: Lenalidomide intervention 8: Melphalan intervention 9: Rituximab
Intervention descriptions: intervention 1: Undergo stem cell transplant intervention 2: Given IV intervention 3: Given IV intervention 4: Given IV intervention 5: Given IV intervention 6: Given SC intervention 7: Given PO intervention 8: Given IV intervention 9: Given IV

Protocol documents:
Prot_SAP_000.pdf: 
 
MD Anderson IND Sponsor Cover Sheet 
 
Protocol ID 
2015-0751 
Protocol Title 
Immunotherapy with Ex Vivo-expanded Cord Blood-derived NK 
Cells Combined with Rituximab High-dose Chemotherapy and 
Autologous Stem Cell Transplant for B-cell Non-Hodgkin’s 
Lymphoma 
Protocol Version 12 
Version Date 
05 May 2020 
 
Protocol PI 
Yago Nieto, M.D., Ph.D. 
Department 
Stem Cell Transplantation and Cellular Therapy 
 
IND Sponsor 
MD Anderson Cancer Center 
IND # 
17314 
 
 
 
 
 
 


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Immunotherapy with Ex Vivo-expanded Cord Blood-derived NK Cells 
Combined with Rituximab High-dose Chemotherapy and Autologous Stem 
Cell Transplant for B-cell Non-Hodgkin’s Lymphoma 
 
 
 
 
 
 
1 The University of Texas MD Anderson Cancer Center, Stem Cell Transplantation and Cellular Therapy Department 
2 The University of Texas MD Anderson Cancer Center, Biostatistics Department 
3 The University of Texas MD Anderson Cancer Center, Nuclear Medicine 
 
Institution Study Number:  2015-0751 
IND Sponsor:  The University of Texas MD Anderson Cancer Center  
 
IND Number:  17314 
Principal Investigator:  Yago Nieto, M.D., Ph.D. 
The University of Texas MD Anderson Cancer Center  
Stem Cell Transplantation and Cellular Therapy 
Department 
1515 Holcombe Blvd, Unit 0432 
Houston, TX 77030 
Telephone: (713) 792-2466 
Fax: (713) 794-4902 
ynieto@mdanderson.org 
 
Co-Chair:  Richard E. Champlin, M.D.1 
 
Collaborators:  Hubert H. Chuang, M.D., Ph.D.3 
Chitra M. Hosing, M.D.1 
Uday R. Popat, M.D.1 
Katy Rezvani, M.D., Ph.D. 1 
Elizabeth Shpall, M.D.1 
Peter F. Thall, Ph.D.2 
 


 
 
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Table of Contents 
 
1.0 OBJECTIVES .................................................................................................................................................................. 3 
2.0 BACKGROUND ............................................................................................................................................................. 3 
3.0 PATIENT ELIGIBILITY .................................................................................................................................................... 5 
4.0 PRETREATMENT EVALUATION ..................................................................................................................................... 5 
5.0 STUDY REGISTRATION ................................................................................................................................................. 6 
6.0 TREATMENT PLAN ....................................................................................................................................................... 6 
7.0 EVALUATION DURING STUDY ...................................................................................................................................... 9 
8.0 REPORTING REQUIREMENTS ...................................................................................................................................... 11 
9.0 CRITERIA FOR REMOVAL FROM THE STUDY ................................................................................................................ 15 
10.0 STATISTICAL CONSIDERATIONS ................................................................................................................................. 16 
11.0  BACKGROUND DRUG INFORMATION ........................................................................................................................ 17 
12.0 REFERENCES .............................................................................................................................................................. 25 
 
 
 


 
 
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Protocol Body 
1.0 Objectives 
Primary endpoint: 
To establish the safety of this treatment by determining its treatment-related mortality 
(TRM) within 30 days. 
 
Secondary endpoints: 
To estimate the relapse-free survival (RFS). 
To estimate the overall survival (OS). 
To quantify duration of infused allogeneic UCB-derived NK cells in the recipient. 
2.0 Background 
High-dose chemotherapy (HDC) with autologous stem-cell transplant (ASCT) is an 
established treatment for relapsed B lymphomas. The antitumor effect of ASCT results 
from the cytotoxic effect of HDC. Although ASCT is clearly safe (TRM <5%), tumor 
relapse constitutes a major cause of treatment failure. For example, the recent Coral 
trial in modern diffuse large B-cell lymphoma (DLBCL) patients who relapse after 1st 
line therapy with R-CHOP shows that up to 80% of patients who subsequently respond 
to salvage therapy and are thus become candidates to ASCT will still relapse after 
transplant.[1] Ways to improve ASCT results include the improvement of the efficacy of 
the HDC regimen, as well as the combination of HDC with immune therapies to 
increase tumor cell kill. 
 
Natural killer (NK) cells are part of the innate immune system and have been implicated 
in tumor immunity and defense.[2] Importantly, NK cells do not require prior exposure 
or sensitization to kill a specific target. While the exact mechanism of NK cells 
anti-tumor immunity remains unclear, a complex interplay between activating and 
inhibitory receptors determines cytotoxicity against a specific target.[3] This includes 
possible disinhibition of the killer immunoglobulin like receptor due to absence of HLA 
class I molecules on target cells ("missing self hypothesis"), as well as death 
receptor-induced apoptosis via Fas ligand and TNF-related apoptosis-inducing ligand 
(TRAIL).[4] 
 
Robust NK reconstitution has been associated with improved outcomes for non-Hodgkin 
lymphoma after AHSCT.[5, 6, 7]. Unfortunately, autologous NK cells from patients with 
lymphoma appear to be dysfunctional, due to, among other causes, an unfavorable 
balance between activating and inhibitory receptors.[8, 9] While immunomodulatory 
drugs, such as lenalidomide, or cytokines, such as IL-12, may augment NK cell function 
after ASCT,[10] clinical experience has shown that this is not sufficient to prevent 
disease progression. Therefore, successful NK immunotherapy activity against 
lymphoma probably requires an allogeneic source. Because of these limitations of 
autologous NK cell function, we have been interested in the application of allogeneic NK 
cells as an adoptive cellular therapy to treat patients receiving an ASCT. 
 
The clinical safety of peripheral blood-derived allogeneic NK cell infusions has been 


 
 
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demonstrated.[11, 12] This requires collection of peripheral blood from a normal donor 
to generate NK cells, which can be logistically cumbersome. To minimize obstacles to 
collection we have been interested in NK cells derived from cryopreserved umbilical 
cord blood (CB), a known source of hematopoietic progenitor cells and an “off-the-shelf” 
product. Our group has previously published a good manufacturing production 
(GMP)-grade method of NK cell expansion from thawed CB mononuclear cells based 
on artificial antigen-presenting cells (Fig. 1). This method yields a >1000-fold expansion 
of NK cells with in vitro and in vivo antitumor activity.[13] 
 
 
Fig. 1. GMP-compliant method of expansion of CB NK cells. 
 
Using this technology, our colleague Nina Shah conducted the first study of CB-NK cells 
for patients with myeloma receiving high-dose melphalan and autologous HSCT 
(MDACC 2011-0379).[14] In that trial CB-NK cells in doses up to 1e8 cells/kg could be 
reliably produced for clinical use and were well tolerated in the setting of high 
dose-melphalan and ASCT for myeloma. In that trial lenalidomide at 10 mg PO daily 
was used as immunomodulatory agent, with good tolerance. The early results suggest 
high activity from this treatment in the population of patients with myeloma enrolled in 
that trial. 
 
Preclinical data indicate that ex vivo activated and expanded CB-NK cells can mediate 
dose-dependent cytotoxicity against different B lymphoma cell lines, which is enhanced 


 
 
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in the presence of lenalidomide.[15] Those preclinical results and our clinical experience 
in myeloma have prompted us to further study of this novel cellular therapy in patients 
with B-cell lymphoma receiving an ASCT. 
3.0 Patient Eligibility 
Inclusion criteria: 
1. Age 15-70 
2. Patients with B-cell lymphoma who are candidates to autologous stem-cell 
transplantation: 
2.1. Primary refractory or relapsed diffuse large B-cell lymphoma in response to 
salvage treatment. 
2.2. Primary refractory or relapsed follicular lymphoma or other indolent B-cell 
histology in response to salvage treatment. 
2.3. Chemosensitive mantle-cell lymphoma in first or later line of treatment. 
3. Adequate renal function, as defined by estimated serum creatinine clearance       
>/= 60 ml/min and a normal serum creatinine for age. 
4. Adequate hepatic function (SGOT and/or SGPT </= 3 x ULN; total bilirubin  
</= 2 x ULN or </= 3 x ULN for Gilbert's disease. 
5. Adequate pulmonary function with FEV1, FVC and DLCO (corrected for Hgb)  
>/= 50% of the predicted value. 
6. Adequate cardiac function with left ventricular ejection fraction >/= 40%. No 
uncontrolled arrhythmias or symptomatic cardiac disease. 
7. Performance status <2 (ECOG). 
8. Negative Beta HCG in woman with child-bearing potential. 
 
Exclusion criteria: 
1. Primary CNS lymphoma. 
2. Grade >/= 3 non-hematologic toxicity from prior therapy that has not resolved to </= 
G1. 
3. Prior whole brain irradiation. 
4. Active hepatitis B, either active carrier (HBsAg +) or viremic (HBV DNA >/= 10,000 
copies/mL, or >/= 2,000 IU/mL). 
5. Evidence of either cirrhosis or stage 3-4 liver fibrosis in patients with chronic 
hepatitis C or positive hepatitis C serology. 
6. Active infection requiring parenteral antibiotics. 
7. HIV infection. 
8. Radiation therapy in the month prior to enroll. 
9. Breastfeeding females. 
4.0 Pretreatment Evaluation 
4.1. Anytime before enrollment (as early as possible): 
HLA typing (A, B, C, and DRB1). 
 
4.2. The studies listed below will be done within 30 days prior to starting treatment, 
only if not already done within this time period: 


 
 
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Lab work: 
CBC with differential, SGPT, SGOT, calcium, glucose, uric acid, magnesium, 
serum bilirubin, BUN and creatinine, serum protein, albumin, alkaline 
phosphatase, electrolytes, PT and PTT, complete urinalysis, blood typing and 
infectious disease panel (CMV Ab, HBsAg, HBcAb, HCVAb, HIV 1/2 Ab, HTLV I/II 
Ab, and Syphilis RPR). 
Chest X ray. 
Pulmonary function tests with 
DLCO. EKG. 
Echocardiogram or MUGA.  
 
4.3. The following will be performed before admission if clinically 
indicated: Brain MRI. 
 
Bone marrow biopsy and aspirate with cytogenetic studies. 
 
PET/CT 
4.4. Prior to start Preparative Regimen: 
 
Women of childbearing age must have a pregnancy test within 10-14 days 
and again 24 hours before prescribing lenalidomide, then 28 days (+/-2 days) 
after therapy discontinued. 
5.0 Study Registration 
Each patient will be evaluated and approved for enrollment by the primary attending 
physician and the Study Chairman (or his designee). The study research coordinator 
will register each patient on protocol. All protocol participants will be registered in the 
institutional CORe system. 
6.0 Treatment Plan 
The investigational component of the proposed treatment plan is the infusion of ex-vivo 
expanded CB NK cells in the setting of autologous stem cell transplantation. 
 
Apheresis of autologous peripheral blood progenitor cells (target 6 million CD34+/Kg, 
minimum 2 million CD34+/Kg) will be completed prior to beginning NK cell production. 
 
The transplant day is referred as day zero (D0), treatment plan activities prior or after 
D0 are denominated as day minus (D-) or day plus (D+). 
 
The production of the NK cells will be carried out by the Good Manufacturing Process 
(GMP) Laboratory at M.D. Anderson Cancer Center. This process will start no less than 
14 days (D-19) prior to their infusion on D-5. 


 
 
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Chemotherapy agents doses and administration 
 
Day 
No later than -19 
Begin NK cell production 
-13 
Outpatient rituximab 375 mg/m2 IV* 
Admission 
-12 
Carmustine 300 mg/m2 IV 
-11 
Etoposide 200 mg/m2 IV BID 
Cytarabine 200 mg/m2 IV BID 
-10 
Etoposide 200 mg/m2 IV BID 
Cytarabine 200 mg/m2 IV BID 
-9 
Etoposide 200 mg/m2 IV BID 
Cytarabine 200 mg/m2 IV BID 
-8 
Etoposide 200 mg/m2 IV BID 
Cytarabine 200 mg/m2 IV BID 
-7 
Melphalan 140 mg/m2 
Lenalidomide, 10 mg PO 
Rituximab 375 mg/m2 IV* 
-6 
Lenalidomide, 10 mg PO 
-5 
CB NK Infusion (up to 1 x 10
8/kg) 
Lenalidomide, 10 mg PO 
-4 
Lenalidomide, 10 mg PO 
-3 
Lenalidomide, 10 mg PO 
-2 
Lenalidomide, 10 mg PO 
-1 
Rest 
0 
Autologous PBPC infusion 
* Rituximab: CD20+ patients only 
 
All drugs are commercially available, and patients will receive the commercial supply. 
 
On D-13, patient will receive rituximab at 375 mg/m2 as an outpatient. This will be 
followed by admission to start hydration. 
 
On D-12, carmustine will be administered at a dose of 300 mg/m
2 IV over 2 hours. 
 
On D-11 to D-8, etoposide will be administered at a dose of 200 mg/m
2 IV BID over 3 
hours, and cytarabine will be administered at a dose of 200 mg/m
2 IV BID over 1 hour. 
 
On D-7, melphalan will be administered at a dose of 140 mg/m
2 IV over 30 minutes, 
lenalidomide at a dose of 10 mg PO, and rituximab at a dose of 375 mg/m
2 IV. 
On D-6 to D-2, lenalidomide will be administered at a dose of 10 mg PO. 
 
On D-5, the NK cell infusion will be administered intravenously. Premedication will 


 
 
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include Benadryl 25 mg IV and Tylenol 650 mg po. The use of steroids is 
contraindicated from d-8 until d+3. 
 
Obtention of NK cells: 
Frozen cord blood units will be thawed and mononuclear cells will be isolated by Ficoll 
density gradient centrifugation. NK cells will be generated over 14 days in liquid 
cultures using APC feeder cells as described in detail in the Chemistry, Manufacturing 
and Controls (CMC). 
 
NK Product Release Criteria 
The following minimum criteria will be required for release of the expanded NK cells for 
reinfusion: 
 
Test 
Specifications 
Gram Stain 
No Organisms Seen 
Visual Inspection 
No Evidence of Contamination 
Endotoxin 
< 5 EU/kg 
CD3+ Cells 
< 2 x 105/kg CD3+ cells 
Immunophenotyping 
+ 
+ 
> 80% CD16 CD56 
+ 
+ 
- 
Undetectable CD32 CD19 CD56 of viable cells 
Viability (7AAD) (Final Product)  70% 
NK Cell Dose (CD16+CD56+) 
 1 x 10
8 NK Cells/kg 
 
 
If more than 2e5 CD3+ cells/kg are present, a second cycle of CD3 depletion may be 
performed. The cell dose for infusion may be reduced so that the infused CD3+ cells 
are 2e5/ kg or less. 
 
On D0, autologous stem cell infusion minimum cell dose of 2e6 cells/kg. This infusion 
can be administrated as in-patient or out-patient following standard SCT/CT department 
procedures. Steroids will NOT be used. 
 
G-CSF (filgrastim-sndz, Zarxio) at a dose of 5 mcg/kg/day (round up to the nearest vial) 
subcutaneously beginning on D+5, and continuing until evidence of an absolute 
neutrophil count (ANC) of 0.5 x 10
9/L per 3 consecutive days. 
 
Optional Procedure: With the patient's consent, if NK cell doses higher than 1 x 10
8 are 


 
 
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T
T
T
generated, or if the patient cannot receive the NK cells, the cells may be cryopreserved 
in the Stem Cell Laboratory. The cells may be used for research or discarded. If the 
patient refuses, the cells will be destroyed. 
 
Administration of Lenalidomide: 
From D-7 to D-2, lenalidomide will be administered at a dose of 10 mg PO daily. 
 
Lenalidomide will be provided in accordance with the Revlimid REMS 
program. Per 
standard Revlimid REMS program requirements, all physicians who prescribe 
lenalidomide for research subjects enrolled into this trial, and all research subjects 
enrolled into this trial, must be registered in, and must comply with, all requirements of 
the Revlimid REMS program. 
 
Females of childbearing potential must have a negative serum pregnancy test with a 
sensitivity of at least 50 mIU/mL within 10-14 days prior to and again 24 hours of 
prescribing lenalidomide (prescriptions must be filled within 7 days). 
 
If a dose of lenalidomide is missed, it should be taken as soon as possible on the same 
day. If it is missed for the entire day, it should not be made up. 
 
Patients who take more than the prescribed dose of lenalidomide should be instructed 
to seek emergency medical care if needed and contact study staff immediately. 
 
Reduced Dose BEAM: In patients who are >65 or with substantial comorbidities, a 
reduced dose of BEAM (with each dose of cytarabine and etoposide decreased to 100 
mg/m2) can be used, at the discretion of the patient's transplant physician. (See 
Appendices E. and F.) 
In patients whose lymphomas are CD20-negative, the use of rituximab will be omitted. 
Supportive treatment 
All patients will receive supportive care as clinically indicated following standard 
practice, except that steroids will be contraindicated from d-8 until d+3. 
7.0 Evaluation During Study 
1. Peripheral blood for NK chimerism studies: 
The first 12 patients enrolled will have chimerism analysis up to twice a week (as 
permitted by laboratory availability) from D-4 to D+7, then only if positive for donor NK 
cells, weekly up to around D+30 (+/- 3 days). After D+30 and until D+100 is not 
mandatory, only if positive for donor NK cells and if the patient comes for routine follow 
up. 
 
2. GvHD assessment: 
After the NK infusion (D-5) at each visit or as clinically indicated. When symptoms of 
GvHD are suspected a biopsy must be done prior to initiating treatment. 


 
 
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3. Disease assessments around D+30, D+100, and D+180: 
These evaluations follow our standard practice. If clinically indicated these studies 
may be done at other time points which can replace the nearest planned timepoint. 
 
 
History and physical exam. 
 
Lab work: CBC, differential, platelets, SGPT, calcium, glucose, uric acid, 
magnesium, serum bilirubin, BUN and creatinine, serum protein, albumin, 
alkaline phosphatase, electrolytes, urinalysis. 
 
PET study if it was positive pretransplant. If it was negative, CT scans of the 
neck, chest abdomen and pelvis. 
 
Bone marrow aspirate and biopsy if positive pretransplant. 
 
4. The following lab tests are to be performed as frequently as clinically indicated: CBC, 
differential, platelets, SGPT, calcium, glucose, uric acid, magnesium, serum bilirubin, 
BUN and creatinine, serum protein, albumin, alkaline phosphatase, electrolytes, 
urinalysis. 
 
5. Antitumor responses will be evaluated according to the Lugano Revised Criteria for 
Response Assessment (see Appendix G.).[16] 
 
6. Pregnancy Testing: 
Pregnancy tests for females of childbearing potential. A female of childbearing potential 
(FCBP) is a sexually mature female who: 1) has not undergone a hysterectomy or 
bilateral oophorectomy; or 2) has not been naturally postmenopausal for at least 24 
consecutive months (i.e., has had menses at any time in the preceding 24 consecutive 
months). 
 
For FCBP, pregnancy tests must occur within 10 - 14 days and again within 24 hours 
prior to prescribing lenalidomide. (prescriptions must be filled within 7 days) and at Day 
+28 (+/- 2 days) post the last dose (D-2) of lenalidomide. 
 
7. Correlative Studies (Optional): 
To determine persistence of donor-derived CB-NK cells in the recipient we will collect 
serial PB samples at D-4, D0 (before infusion of PBPC), D+7 and weekly thereafter, 
until negative results are obtained. 
 
We will employ our institution’s standard DNA microsatellite chimerism assay to detect 
donor CB-NK cells.[17] Briefly, PCR-based microsatellite polymorphism analysis will be 
performed using capillary electrophoresis (CE-PCR) on DNA from the pre-transplant, 
CB donor and post-transplant PB samples. DNA from sorted T-lymphocytes (T-cells), 
myeloid cell (M-cells) and/or NK-cells will also be used in addition to the total DNA, as 
applicable. A total of 8 microsatellite regions (D6S264, D3S1282, D18S62, D3S1300, 
DM1, AR, D11S987 and D9S171) will be assessed in each specimen to identify the 
most distinct or discriminating (informative) marker/s between CB donor versus recipient 
DNA. The area under the curve for the informative marker will be used to calculate the 


 
 
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percent engraftment using the formula: % engraftment = 100 x 
[Donor/(Donor+Recipient)] DNA in post-transplant sample. The lower limit of detection 
for this assay has been established to be at 1%. 
 
In parallel, we will perform multiparameter flow cytometry to analyze the source (patient 
or CB) and the phenotype of circulating NK cells. PB MNCs will be subjected to 
ficoll-separation. Thereafter, cells will be stained for the following: CD56, CD3, CD16, 
PAN KIR, NKG2D, NKG2A, NKp30, NK p44, NKp46, NKG2C. When possible, 
chimerism will be determined by flow cytometry using fluorochrome-conjugated 
antibodies against HLA groups Bw4 or Bw6. 
8.0 Reporting Requirements 
The Principal Investigator or physician designee is responsible for verifying and 
providing source documentation for all adverse events and assigning the attribution for 
each event for all subjects enrolled on the trial. 
 
Adverse events and protocol specific data will be entered into REDCap/CORe. 
REDCap/CORe will be used as the electronic case report form for this protocol. 
Concomitant medications will captured in participants' medical records. 
 
Severity of the adverse events (AEs) 
The severity of the adverse events (AEs) will be graded according to the Common 
Terminology Criteria v4.03 (CTCAE) from Day -5 (the start of NK cell infusion) up to 
D+30 (+3 days if necessary). Events not included in the CTCAE chart will be scored as 
follows: 
 
General grading: 
Grade 1: Mild: discomfort present with no disruption of daily activity, no treatment 
required beyond prophylaxis. 
Grade 2: Moderate: discomfort present with some disruption of daily activity, require 
treatment. 
Grade 3: Severe: discomfort that interrupts normal daily activity, not responding to first 
line treatment. 
Grade 4: Life Threatening: discomfort that represents immediate risk of death 
 
Causality Assessment 
The investigational component of the treatment plan of this study is the infusion of ex-
vivo expanded CB NK cells when administrated with lenalidomide, high-dose 
chemotherapy with BEAM and autologous stem cell transplantation. 
 
Therefore, events known to be caused by the NK cell infusion and its direct 
consequences will be assessed as definitely related when assessing the causality. 
When the relationship of the adverse event cannot be rule out between the NK cell 
infusion and the treatment plan, the event will be scored as probably or possible related. 
 
Events known to be related to drugs used as part of the treatment plan as well as to 


 
 
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drugs used as supportive treatment will be scored as unrelated to the NK cells infusion. 
 
Causality will be determined as per the guidelines above and based on the expected 
toxicities listed below. 
 
The Principal Investigator or physician designee will be the final arbiter in determining 
the causality assessment. 
 
AEs related to the NK cells infusion: 
1. These expected events will be monitored during the first 24 hours post infusion: 
 
Fever, 
 
Chills, 
 
Decrease in blood pressure, 
 
Rash, 
 
Shortness of breath. 
 
2. Unexpected and related events: 
 
Grade 4 NK infusion related toxicity, 
 
Failure to engraft by D+28 or delayed engraftment, 
 
Grades 3-5 allergic reactions related to study cell infusion, 
 
Grade 3-5 organ toxicity (cardiac, dermatologic, gastrointestinal, 
hepatic, pulmonary, renal/genitourinary, or neurologic) not pre-existing 
or due to the underlying malignancy or due to preparative 
chemotherapy and occurring within 30 days (+3 days if necessary) 
post-transplant, 
 
Grades 3-4 acute GVHD occurring within 45 days post-transplant,
[10]
 
 
Treatment-related death within 8 weeks of the study cell infusion.
[32]
 
 
Expected AEs related to high dose chemotherapy followed by autologous stem 
cell infusion include the following: 
 
Related to myelosuppression: thrombocytopenia, bleeding, platelets and 
RBCs transfusions. 
 
Fever: Non Neutropenic or Neutropenic without infection. 
 
Infections in the presence or absence of neutropenia. 
 
Readmissions (lasting <10 days). 
 
Cytopenias post transplant including secondary graft failure. 
 
Low blood pressure due to dehydration requiring fluid replacement. 
 
Fluid overload leading to cardiac dysfunction. 
 
GI related: nausea, vomiting, diarrhea, mucositis. 
 
Organ dysfunction: cardiac, pulmonary, hepatic, CNS and/ or renal. 
 
Stem Cell Transplant Syndromes: Cytokine Storm, TTP, hemorrhagic 
cystitis, interstitial pneumonitis (including pulmonary hemorrhage). 
 
Adverse events data collection 
 
REDCap/CORe will be used as the electronic case report form (eCRF) for this protocol. 


 
 
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An adverse event is the appearance or worsening of any undesirable sign, symptom, or medical 
condition occurring after starting the study drug even if the event is not considered to be related 
to study drug. Medical conditions/diseases present before starting study drug are only 
considered adverse events if they worsen after starting study drug. 
 
Adverse events will be entered into the eCRF from day -5 to day +30.   The collection of 
adverse events will reflect the onset and resolution date and maximum grade. If a patient is 
taken off study while an event is still ongoing, this will be followed until resolution unless another 
therapy is initiated. Intermittent events should be labeled as such and followed until resolution. 
Subjects who are removed from study due to an adverse event will continue to be followed until 
resolution of the event, evidence emerges that the event is stable and will not progress, or until 
death. 
 
Abnormal laboratory values or test results constitute adverse events only if they induce clinical 
signs or symptoms, are considered clinically significant, or require therapy and otherwise meet 
the criteria for a reportable adverse event as defined above. They are to be captured under the 
signs, symptoms or diagnoses associated with them. 
 
Those adverse events that are suspected unexpected severe adverse reactions (SUSARs) 
should be reported to FDA in an expedited fashion as detailed in 21CFR312.32. Adverse events 
will be reported in aggregate as part of the IND’s annual report. 
 
The Principal Investigator or physician designee is responsible for verifying and 
providing source documentation for all adverse events and assigning the attribution for 
each event for all subjects enrolled on the trial. 
 
Adverse events will be documented based on all available evidence, including the 
flowsheet in the electronic patient medical record. 
 
Concurrent medication 
As stated in the treatment plan, patients treated on this protocol will require supportive 
care treatment (concurrent medication). These medications are considered standard of 
care and have no scientific contributions to the protocol, therefore no data will be 
captured on the various medications needed or their sides effects. 
 
Serious Adverse Event (SAE) Reporting 
 
An adverse event or suspected adverse reaction is considered “serious” if, in the view of 
either the investigator or the sponsor, it results in any of the following outcomes: 
 
 Death 
 A life-threatening adverse drug experience – any adverse experience that places the 
patient, in the view of the initial reporter, at immediate risk of death from the adverse 
experience as it occurred. It does not include an adverse experience that, had it 
occurred in a more severe form, might have caused death. 
 Inpatient hospitalization or prolongation of existing hospitalization 
 A persistent or significant incapacity or substantial disruption of the ability to conduct 
normal life functions. 


 
 
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 A congenital anomaly/birth defect. 
 
Important medical events that may not result in death, be life-threatening, or require 
hospitalization may be considered a serious adverse drug experience when, based 
upon appropriate medical judgment, they may jeopardize the patient or subject and may 
require medical or surgical intervention to prevent one of the outcomes listed in this 
definition. Examples of such medical events include allergic bronchospasm requiring 
intensive treatment in an emergency room or at home, blood dyscrasias or convulsions 
that do not result in inpatient hospitalization, or the development of drug dependency or 
drug abuse (21 CFR 312.32). 
 
 Important medical events as defined above, may also be considered serious 
adverse events. Any important medical event can and should be reported as an SAE 
if deemed appropriate by the Principal Investigator or the IND Sponsor, IND Office. 
 All events occurring during the conduct of a protocol and meeting the definition of a 
SAE must be reported to the IRB in accordance with the timeframes and procedures 
outlined in “The University of Texas M. D. Anderson Cancer Center Institutional 
Review Board Policy for Investigators on Reporting Serious Unanticipated Adverse 
Events for Drugs and Devices”. Unless stated otherwise in the protocol, all SAEs, 
expected or unexpected, must be reported to the IND Office, regardless of attribution 
(within 5 working days of knowledge of the event). 
 All life-threatening or fatal events, that are unexpected, and related to the study 
drug, must have a written report submitted within 24 hours (next working day) of 
knowledge of the event to the Safety Project Manager in the IND Office. 
 Unless otherwise noted, the electronic SAE application (eSAE) will be utilized for 
safety reporting to the IND Office and MDACC IRB. 
 Serious adverse events will be captured from the time of the first protocol-specific 
intervention, until 30 days after the last dose of drug, unless the participant 
withdraws consent. Serious adverse events must be followed until clinical recovery is 
complete and laboratory tests have returned to baseline, progression of the event 
has stabilized, or there has been acceptable resolution of the event. 
 Additionally, any serious adverse events that occur after the 30 day time period that 
are related to the study treatment must be reported to the IND Office. This may 
include the development of a secondary malignancy. 
 
 Patients who withdraw consent due to toxicities will be evaluable and considered 
treatment failures. 
 
Reporting to FDA: 
 
 Serious adverse events will be forwarded to FDA by the IND Sponsor (Safety Project 
Manager IND Office) according to 21 CFR 312.32. 
 
It is the responsibility of the PI and the research team to ensure serious adverse 
events are reported according to the Code of Federal Regulations, Good Clinical 
Practices, the protocol guidelines, the sponsor’s guidelines, and Institutional 


 
 
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Review Board policy. 
 
A sterility and mycoplasma sample is removed from final fresh CB-NK product, as 
additional testing. Because of the nature of the final product to be infused, these results 
won’t be available at time of release; therefore this testing is not considered part of the 
release criteria. As a rapid microbial test, we perform a gram stain and endotoxin test  as 
release criteria of the final fresh CB-NK product. 
 
The expected acceptable results for the Mycoplasma and Sterility are the following: 
Additional Monitoring Tests: 
Test 
Specifications 
Sterility 
No Growth at 14 days 
Mycoplasma (PCR) 
Negative 
 
In the event the 14-day sterility or mycoplasma PCR results on the final cultured product 
return positive after the product has been infused, the Laboratory Director, Laboratory 
Medical Director, Laboratory Quality Assurance Unit, Principle Investigator, and the 
Investigational New Drug (IND) Office Sponsor will be notified. The Quality Assurance 
Unit will conduct an investigation to determine if any corrective and/or preventative 
actions are required. The investigation and proposed corrections for a failure of lot 
release sterility testing will include: identification of the microorganism(s) and 
anti-microbial agent sensitivity testing; evaluation of the current procedure for collecting 
and processing the product to determine the step at which contamination could be 
introduced; development of changes in procedures that will assist in preventing sterility 
lapses in the future; and implementation of appropriate testing to ensure that such 
changes to procedures produce a sterile product. 
The Principal Investigator will be responsible for notifying the appropriate regulatory 
agencies (FDA, IRB) of deviations and adverse events. Additionally, we will report the 
sterility failure, results of investigation of the cause and any corrective actions, in an 
information amendment submitted to the IND in a timely manner, within 30 calendar 
days after initial receipt of the positive culture test result. 
9.0 Criteria for Removal from the Study 
The study duration will be the time from study registration until death, patient request, 
disease progression, or day +180 after transplantation, whichever occurs first. 


 
 
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10.0 Statistical Considerations 
This is a phase II trial of high dose chemotherapy (Rituximab +BEAM + Lenalidomide) 
as a preparative regimen + umbilical cord blood derived NK cells + autologous stem cell 
transplant (autosct) for treatment of lymphoma that requires a stem cell transplant. A 
maximum of 40 patients will be treated, with an expected accrual rate of 2 patients per 
month. The primary outcome for safety monitoring is transplant related mortality within 
30 days, TRM30. A TRM30 probability of .10 will be considered unacceptably high. The 
method of Thall and Sung will be used for safety monitoring [18]. Assuming that pE = 
Pr(TRM30 with the experimental regimen) follows a non-informative beta (.10, .90) prior, 
and assuming standard probability pS ~ beta(100,900), the trial will be stopped early if 
Pr(pS < pE | data) > .50. Applying this rule continuously, the trial will be stopped early if 
[# TRM30] / [# patients evaluated] is greater than or equal to 1/7, 2/17, 3/27, 4/37 or 
5/39. 
 
Pr(TRM30) will be estimated using a 95% credible interval assuming a beta(.50, .50 ) 
prior. 
 
This rule has the following operating characteristics. 
 
True Pr(TRM30) 
Pr(Stop Early) 
Sample Size Quartiles 
.20 
.98 
2 
4 
7 
.15 
.92 
2 
5 
14 
.10 
.74 
3 
7 
40 
.09 
.69 
4 
10 
40 
.08 
.62 
4 
15 
40 
.07 
.55 
4 
23 
40 
.06 
.48 
5 
40 
40 
.05 
.39 
6 
40 
40 
.04 
.32 
7 
40 
40 
.03 
.24 
40 
40 
40 
.02 
.16 
40 
40 
40 
.01 
.07 
40 
40 
40 
 
The stopping rule and operating characteristics were calculated using multc99. 
 
Secondary Outcomes. Relapse-free survival (RFS) time, overall survival (OS) time, NK 
cell persistence, with NK cells measured weekly for 14 weeks will be recorded. RFS will 
be defined as the time from transplant to either progression/relapse or death, whichever 
occurs first, or last contact. OS will be defined as the time from transplant to death or 
last contact. 
 
Data Analyses. Unadjusted RFS and OS will be estimated by the method of Kaplan 
and Meier [19]. A Bayesian hierarchical regression model [20] will be fit to the 
longitudinal NK cell data to assess its patterns over time and association with patient 


 
 
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covariates, including type of lymphoma, age, and disease severity. 
 
It is extremely unlikely that any patient in this trial would withdraw. In the case of this 
unlikely event, all withdrawals because of toxicity will be considered treatment failures in 
all analyses. In the case that a subject withdraws from the study for a reason other than 
toxicity, analyses both including a non-toxicity related withdrawal scored as a treatment 
failure and excluding a non-toxicity related withdrawal will be performed to assess 
sensitivity of final inferences. 
 
A Safety Summary will be submitted to the IND Office Medical Monitor after the first 7 
patients complete their 30 days of study treatment and every 10 evaluable patients 
thereafter, in cumulative method. Evaluability implies having completed 30 days on 
study and being assessed for the primary endpoint, i.e., TRM within 30 days. 
11.0 Background Drug Information 
11.1 Rituximab 
Rituximab is associated with hypersensitivity reactions that may respond to adjustments 
in the infusion rate. Hypotension, bronchospasm, and angioedema have occurred in 
association with Rituximab infusion as part of an infusion-related symptom complex. In 
most cases, patients who have experienced non-life-threatening reactions have been 
able to complete the full course of therapy. Medications for the treatment of 
hypersensitivity reactions, such as epinephrine, antihistamines, and corticosteroids, 
should be available for immediate use in the event of a reaction during administration. 
 
Patients who develop clinically significant arrhythmias as a result of Rituximab therapy 
should undergo cardiac monitoring during and after subsequent infusions of Rituximab. 
Patients with pre-existing cardiac conditions, including arrhythmias and angina, have 
experienced recurrences during Rituximab therapy and should be monitored during and 
immediately after the infusion. 
 
Rituximab rapidly decreases levels of benign and malignant CD20+ cells. Tumor lysis 
syndrome has been reported to occur within 12 to 24 hr after the first Rituximab infusion 
in patients with high numbers of circulating malignant lymphocytes. Patients with high 
tumor burden (ie, bulky lesions) may also be at risk.  Patients at risk of developing 
tumor lysis syndrome should be followed up closely and appropriate laboratory 
monitoring performed. 
 
After treatment for and resolution of tumor lysis syndrome, subsequent Rituximab 
therapy has been administered in conjunction with prophylactic therapy for this 
syndrome in a limited number of cases. 
 
Warnings and precautions: 
 
Bowel obstruction/perforation: Abdominal pain, bowel obstruction, and perforation have 
been reported (rarely fatal), with an average onset of symptoms of ~6 days (range: 1-77 
days); complaints of abdominal pain or repeated vomiting should be evaluated, 


 
 
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especially if early in the treatment course. 
 
• Hepatitis B virus reactivation: [U.S. Boxed Warning]: Hepatitis B virus (HBV) 
reactivation may occur with use and may result in fulminant hepatitis, hepatic failure, 
and death. Screen all patients for HBV infection by measuring hepatitis B surface 
antigen (HBsAg) and hepatitis B core antibody (anti-HBc) prior to therapy initiation; 
monitor patients for clinical and laboratory signs of hepatitis or HBV during and for 
several months after treatment. Discontinue rituximab (and concomitant medications) if 
viral hepatitis develops and initiate appropriate antiviral therapy. Reactivation has 
occurred in patients who are HBsAg positive as well as in those who are HBsAg 
negative but are anti-HBc positive; HBV reactivation has also been observed in patients 
who had previously resolved HBV infection. HBV reactivation has been reported up to 
24 months after therapy discontinuation. Use cautiously in patients who show evidence 
of prior HBV infection (eg, HBsAg positive [regardless of antibody status] or HBsAG 
negative but anti-HBc positive); consult with appropriate clinicians regarding monitoring 
and consideration of antiviral therapy before and/or during rituximab treatment. The 
safety of resuming rituximab treatment following HBV reactivation is not known; discuss 
reinitiation of therapy in patients with resolved HBV reactivation with physicians 
experienced in HBV management. 
 
• Infections: Use is not recommended if severe active infection is present; serious and 
potentially fatal bacterial, fungal, and either new or reactivated viral infections may occur 
during treatment and after completing rituximab. Infections have been observed in 
patients with prolonged hypogammaglobulinemia, defined as hypogammaglobulinemia 
>11 months after rituximab exposure; monitor immunoglobulin levels as necessary. 
Associated new or reactivated viral infections have included cytomegalovirus, herpes 
simplex virus, parvovirus B19, varicella zoster virus, West Nile virus, and hepatitis B and 
C. Discontinue rituximab (and concomitant chemotherapy) in patients who develop viral 
hepatitis and initiate antiviral therapy. Discontinue rituximab in patients who develop 
other serious infections and initiate appropriate anti-infective treatment. 
 
• Infusion reactions: [U.S. Boxed Warning]: Severe (occasionally fatal) infusion-related 
reactions have been reported, usually with the first infusion; fatalities have been 
reported within 24 hours of infusion; monitor closely during infusion; discontinue for 
severe reactions and provide medical intervention for grades 3 or 4 infusion reactions. 
Reactions usually occur within 30-120 minutes and may include hypotension, 
angioedema, bronchospasm, hypoxia, urticaria, and in more severe cases pulmonary 
infiltrates, acute respiratory distress syndrome, myocardial infarction, ventricular 
fibrillation, cardiogenic shock, and/or anaphylaxis. Risk factors associated with fatal 
outcomes include chronic lymphocytic leukemia, female gender, mantle cell lymphoma, 
or pulmonary infiltrates. Closely monitor patients with a history of prior cardiopulmonary 
reactions or with pre-existing cardiac or pulmonary conditions and patients with high 
numbers of circulating malignant cells (>25,000/mm3). Prior to infusion, premedicate 
patients with acetaminophen and an antihistamine (and methylprednisolone for patients 
with RA). Discontinue infusion for severe reactions and serious or life-threatening 
cardiac arrhythmias. Perform cardiac monitoring during and after the infusion in patients 


 
 
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who develop clinically significant arrhythmias or who have a history of arrhythmia or 
angina. Medications for the treatment of hypersensitivity reactions (eg, bronchodilators, 
epinephrine, antihistamines, corticosteroids) should be available for immediate use; 
treatment is symptomatic. Mild-to-moderate infusion-related reactions (eg, chills, fever, 
rigors) occur frequently and are typically managed through slowing or interrupting the 
infusion. Infusion may be resumed at a 50% infusion rate reduction upon resolution of 
symptoms. Due to the potential for hypotension, consider withholding antihypertensives 
12 hours prior to treatment. 
 
• Mucocutaneous reactions: [U.S. Boxed Warning]: Severe and sometimes fatal 
mucocutaneous reactions (lichenoid dermatitis, paraneoplastic pemphigus, 
Stevens-Johnson syndrome, toxic epidermal necrolysis and vesiculobullous dermatitis) 
have been reported; onset has been variable but has occurred as early as the first day 
of exposure. Discontinue in patients experiencing severe mucocutaneous skin 
reactions; the safety of re-exposure following mucocutaneous reactions has not been 
evaluated. 
 
• Progressive multifocal leukoencephalopathy: [U.S. Boxed Warning]: Progressive 
multifocal leukoencephalopathy (PML) due to JC virus infection has been reported with 
rituximab use; may be fatal. Cases were reported in patients with hematologic 
malignancies receiving rituximab either with combination chemotherapy, or with 
hematopoietic stem cell transplant. Cases were also reported in patients receiving 
rituximab for autoimmune diseases who had received concurrent or prior 
immunosuppressant therapy. Onset may be delayed, although most cases were 
diagnosed within 12 months of the last rituximab dose. A retrospective analysis of 
patients (n=57) diagnosed with PML following rituximab therapy, found a median of 16 
months (following rituximab initiation), 5.5 months (following last rituximab dose), and 6 
rituximab doses preceded PML diagnosis. Clinical findings included 
confusion/disorientation, motor weakness/hemiparesis, altered vision/speech, and poor 
motor coordination with symptoms progressing over weeks to months (Carson, 2009). 
Promptly evaluate any patient presenting with neurological changes; consider neurology 
consultation, brain MRI and lumbar puncture for suspected PML. Discontinue rituximab 
in patients who develop PML; consider reduction/discontinuation of concurrent 
chemotherapy or immunosuppressants. 
 
11.2 
Etoposide 
Etoposide (VP-16) is a semisynthetic podophyllotoxin derivative with antineoplastic 
activity. 
 
Pharmaceutical data: VP-16 is supplied as 100 mg/5cc ampules. 
 
Solution preparation: The contents of the vial are diluted with 0.9% sodium chloride 
for injection, USP. The final concentration of the admixture must be 0.2 mg/mL - 0.4 
mg/mL. Solutions prepared above 0.4 mg/mL may contain precipitate. 
 
Route of administration: Slow IV infusion. 


 
 
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Known side-effects: Myelosuppression, primarily granulocytopenia is the dose-limiting 
toxicity. Other side effects include gastrointestinal toxicity comprising of nausea, emesis 
and mucositis. At high doses reversible hepatotoxicy is seen. Acute side effects include 
occasional bronchospasm and hypotension. These can be avoided by slow intravenous 
administration. 
 
Hypersensitivity reaction: May cause anaphylactic-like reactions manifested by chills, 
fever, tachycardia, bronchospasm, dyspnea, and hypotension. In addition, facial/tongue 
swelling, coughing, chest tightness, cyanosis, laryngospasm, diaphoresis, hypertension, 
back pain, loss of consciousness, and flushing have also been reported less commonly. 
Incidence is primarily associated with intravenous administration (up to 2%) compared 
to oral administration (<1%). Infusion should be interrupted and medications for the 
treatment of anaphylaxis should be available for immediate use. High drug 
concentration and rate of infusion, as well as presence of polysorbate 80 and benzyl 
alcohol in the etoposide intravenous formulation, have been suggested as contributing 
factors to the development of hypersensitivity reactions. Etoposide intravenous 
formulations may contain polysorbate 80 and/or benzyl alcohol, while etoposide 
phosphate (the water soluble prodrug of etoposide) intravenous formulation does not 
contain either vehicle. Case reports have suggested that etoposide phosphate has been 
used successfully in patients with previous hypersensitivity reactions to etoposide. 
 
• Secondary malignancies: Secondary acute leukemias have been reported with 
etoposide, either as monotherapy or in combination with other chemotherapy agents. 
 
Pharmacokinetics: The main site of metabolism is in the liver. Major metabolites of 
etoposide are hydroxy acids and cistactone which appear in the plasma and urine. The 
half-life of the drug is 4 to 11 hours. 
 
Mechanism of action: Two different dose dependent responses are seen. At high 
concentrations (10 ug/ml) lysis of cells entering mitosis is seen. At low concentrations 
(0.3 to 10 ug/ml) cells are inhibited from entering prophase. The predominant 
macromolecular affect of etoposide appears to be the induction of DNA strand breaks 
by an interaction with DNA topoisomerase II or by the formation of free radicals. 
 
11.3. 
Cytarabine 
Cytarabine is a synthetic antimetabolite antineoplastic agent. 
 
Dosing information: Usual induction dose for ANLL (acute non-lymphocytic leukemia) 
has been 100 to 200 mg/m2 daily for 5 to 7 days (in combination with other cytoxic 
agents). 
Pharmacokinetics: Following IV administration, cytarabine is widely distributed to 
areas including the CNS and tears; the drug is orally active. Cytarabine is metabolized 
in the liver to an inactive metaolite; both cytarabine and its metabolite are excreted in 
the urine. The elimination half-life is between 1 and 3hours. 


 
 
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Side Effects: The major toxic effect of cytarabine is myelosuppression resulting in 
megaloblastic changes in erythropoiesis and reticulocytopenia. Other adverse effects 
include neuropathies, GI distress, hepatic toxicity, and hypersensitivity. 
 
Clinical Applications: Cytarabine is useful in various neoplastic disorders including 
myelocyticleukemia, lymphoblastic leukemia, and non lymphocytic. 
 
11.4. 
Melphalan 
Melphalan is an alkylating agent with cell cycle nonspecific cytotoxic effects on tumor 
cells. 
 
Dosing Information: The usual dose for conditioning in stem cell transplantation is 
100-200 mg/m
2intravenously. 
 
Pharmacokinetics: Orally administered melphalan demonstrates considerable variation 
in bio availability, does not undergo active metabolism, and is primarily eliminated in the 
feces. However, compromised renal function may significantly impact melphalan 
excretion. 
 
Side Effects: 
 
(>10%) Gastrointestinal: Nausea and vomiting, diarrhea, oral mucosa ulcer 
Hematologic & oncologic: Anemia, bone marrow depression, leukopenia (nadir: 14 to 21 
days; recovery: 28 to 35 days), metastases (ꞏ20%; cumulative dose and duration 
dependent; includes acute myeloid leukemia, myeloproliferative syndrome, carcinoma), 
thrombocytopenia (nadir: 14 to 21 days; recovery: 28 to 35 days) 
(1% to 10%) Hypersensitivity: Hypersensitivity reaction (IV: 2%; includes 
bronchospasm, dyspnea, edema, hypotension, pruritus, skin rash, tachycardia, 
urticaria) 
Frequency not defined: 
Cardiovascular: Cardiotoxicity (angina pectoris, cardiac arrhythmia, hypertension, 
myocardial infarction; with high-dose therapy), hepatic veno-occlusive disease (hepatic 
sinusoidal obstruction syndrome; SOS; high-dose IV melphalan), vasculitis 
Central nervous system: Brain disease, flushing sensation, seizure (with high-dose 
therapy), tingling sensation 
Dermatologic: Allergic skin reaction, alopecia, maculopapular rash, pruritus 
Endocrine & metabolic: Amenorrhea, SIADH (syndrome of inappropriate antidiuretic 
hormone secretion) 
Gastrointestinal: Mucositis (with high-dose therapy), paralytic ileus (with high-dose 
therapy), stomatitis 
Genitourinary: Hemorrhagic cystitis, inhibition of testicular function, nephrotoxicity (with 
high-dose therapy), ovarian function suppression, sterility 
Hematologic & oncologic: Agranulocytosis, bone marrow failure (irreversible), hemolytic 
anemia, hemorrhage (with high-dose therapy) 
Hepatic: Hepatitis, increased serum transaminases, jaundice 
Hypersensitivity: Anaphylaxis (rare), hypersensitivity reaction 


 
 
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Infection: Infection, sepsis 
Local: Injection site reaction (injection site necrosis, ulceration) 
Neuromuscular & skeletal: Myelopathy (radiation) 
Renal: Increased blood urea nitrogen 
Respiratory: Interstitial pneumonitis, pulmonary fibrosis 
 
Clinical Applications: Melphalan has a broad spectrum of antitumor activity, but its 
main use in the palliative treatment of multiple myeloma and non-resectable. 
 
11.5. Carmustine 
Carmustine is a nitrosourea derivative alkylating agent. 
 
Dosing Information: As a single agent 150 to 200 mg/m2 IV. 
 
Pharmacokinetics: Carmustine is highly lipid soluble and readily crosses into the CSF. 
The drug is rapidly metabolized with no intact drug detectable in the plasma after 15 
minutes; some metabolites are known to be active. About 60 to 70% of a dose is 
eliminated in the urine. 
 
Side Effects: Delayed and cumulative myelosuppression is the most frequent and 
profound toxicity of Carmustine. Thrombocytopenia is usually more serious than 
leukopenia; however, both may be dose-limiting. Other adverse effects include 
pulmonary fibrosis, nausea and vomiting, hepatotoxicity, and nephrotoxicity. 
 
Clinical Applications: Carmustine is used alone or in combination with other 
appropriate therapeutic measures in the treatment of various neoplastic conditions such 
as Hodgkin's disease, brain tumors, multiple myeloma, and non-Hodgkin's lymphoma. 
 
11.6. Lenalidomide 
Common trade named: Revlimid® 
 
Class 
Angiogenesis inhibitor 
immunomodulating agents (IMiDs). 
Antineoplastic agent 
Tumor Necrosis factor (TNF) blocking agent 
 
Administration 
Lenalidomide capsule are administrated orally with water. Patients should not 
break, chew or open the capsules 
 
Monitoring 
Platelet count, hemoglobin, WBC, and differential at start of therapy and prior to each 
subsequent course of therapy; serum creatinine, liver function tests, thyroid function tests; 
monitor for signs and symptoms of thromboembolism. 
 
Women of childbearing age must have a pregnancy test within 10-14 days and 24 hours before 
lenalidomide, then 28 days (+/- 2 days) after therapy discontinued. 


 
 
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Pregnancy Testing 
Females must follow pregnancy testing requirements as outlined in the Revlimid REMS 
program. 
 
Pregnancy tests for females of childbearing potential. A female of childbearing potential (FCBP) 
is a sexually mature female who: 1) has not undergone a hysterectomy or bilateral 
oophorectomy; or 2) has not been naturally postmenopausal for at least 24 consecutive months 
(i.e., has had menses at any time in the preceding 24 consecutive months). 
 
For FCBP, pregnancy tests must occur within 10 - 14 days and again within 24 hours prior to 
prescribing lenalidomide. (prescriptions must be filled within 7 days) and at Day +28 (+/- 2 days) 
post the last dose (D-2) of lenalidomide. 
 
Contraindications 
- Hypersensitivity of lenalidomide products 
- Previous resistance to the drug 
- Pregnancy 
 
Precautions 
- No formal studies have been conducted in patients with renal impairment. this drug is known to 
be excreted by the kidney, and the risk of adverse reactions to this drug may be greater in 
patients with impaired renal function. 
- Patients with Hepatic Disease: The pharmacokinetics of lenalidomide in patients 
with hepatic impairment have not been studied. 
- Age: lenalidomide has been used in multiple myeloma (MM) clinical trials in 
patients up to 86 years of age. 
- Check pregnancy test before administering lenalidomide 
- Check CBC before administering lenalidomide 
- Hypersensitivity reaction; do not re challenge 
- Impairment of fertility 
- Mutagenic, potentially 
- Severe bone marrow depression 
- Women of childbearing age should avoid becoming pregnant 
- monitor for signs and symptoms of thromboembolism: prophylaxis 
 
Adverse effects 
>10%: 
- Cardiovascular: Peripheral edema (8% to 21%) - Central nervous system: Fatigue (31% to 
38%), pyrexia (21% to 23%), dizziness (20% to 21%), headache (20%) 
- Dermatologic: Pruritus (42%), rash (16% to 36%), dry skin (14%) 
- Endocrine & metabolic: Hyperglycemia (15%), hypokalemia (11%) 
- Gastrointestinal: Diarrhea 
(29% to 49%), constipation (24% to 39%), nausea (22% to 24%), weight loss 
(18%), dyspepsia (14%), anorexia (10% to 14%), taste perversion (6% to 13%), 
abdominal pain (8% to 12%) 
- Genitourinary: Urinary tract infection (11%) 
- Hematologic: Thrombocytopenia (17% to 62%; grades 3/4:10% to 50%), 
neutropenia (28% to 59%; grades 3/4: 21% to 53%), anemia (12% to 24%: grades 3/4: 6% to 
9%); myelosuppression is dose-dependent and reversible with treatment interruption and/or 
dose reduction 


 
 
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- Neuromuscular & skeletal: Muscle cramp (18% to 30%), arthralgia (10% to 22%), 
back 
pain (15% to 21%), tremor (20%), weakness (15%), paresthesia (12%), limb pain (11%) 
- Ocular: Blurred vision (15%) 
- Respiratory: Nasopharyngitis (23%), cough (20%), dyspnea (7% to 20%), pharyngitis (16%), 
epistaxis (15%), upper respiratory infection (14% to 15%), pneumonia (11% to 12%) 
 
Pregnancy category - X 
- Breast feeding: Infant risk cannot be ruled out 
 
- How supplied: 5 mg, 10 mg, 15 mg and 25 mg capsules. 
 
 


 
 
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12.0 References 
[1] 
Gisselbrecht C, Glass B, Mounier N, et al. Salvage regimens with autologous 
transplantation for relapsed large B-cell lymphoma in the rituximab era. J Clin 
Oncol 2010;28:4184-90. 
[2] 
Guillerey C, Smyth MJ: NK Cells and Cancer Immunoediting. Curr Top Microbiol 
Immunol 2016;395:115-45. 
[3] 
Long EO, Kim HS, Liu D, et al: Controlling natural killer cell responses: integration 
of signals for activation and inhibition. Annu Rev Immunol 31:227-58, 2013. 
[4] 
Zamai L, Ahmad M, Bennett IM, et al: Natural killer (NK) cell-mediated 
cytotoxicity: differential use of TRAIL and Fas ligand by immature and mature 
primary human NK cells. J Exp Med 188:2375-80, 1998. 
[5] 
Leung W, Handgretinger R, Lyengar R, et al. Inhibitory KIR-HLA receptor-ligand 
mismatch in autologous haematopoietic stem cell transplantation for solid tumour 
and lymphoma. Br J Cancer, 97 (2007), pp. 539- 542. 
[6] 
Porrata LF, Inwards DJ, et al. Interleukin-15 Affects Patient Survival through 
Natural Killer Cell Recovery after Autologous Hematopoietic Stem Cell 
Transplantation for Non-Hodgkin Lymphomas. Clinical and Developmental 
Immunology, vol. 2010, Article ID 914945, 13 pages, 2010. 
doi:10.1155/2010/914945 
[7] 
Porrata LF, Inwards DJ, Ansell SM, et al. Early lymphocyte recovery predicts 
superior survival after autologous stem cell transplantation in non-Hodgkin 
lymphoma: a prospective study. Biol Blood Marrow Transplant 2008; 14:807-816. 
[8] 
Fauriat C, Mallet F, Olive D, et al: Impaired activating receptor expression pattern 
in natural killer cells from patients with multiple myeloma. Leukemia 20:732-3, 
2006 
[9] 
Costello RT, Boehrer A, Sanchez C, et al: Differential expression of natural killer 
cell activating receptors in blood versus bone marrow in patients with monoclonal 
gammopathy. Immunology 139:338-41, 2013. 
[10] Robertson MJ1, Pelloso D, Abonour R, et al. Interleukin 12 immunotherapy after 
autologous stem cell transplantation for hematological malignancies. Clin Cancer 
Res 2002;8:3383-93. 
[11] Shi J, Tricot G, Szmania S, et al: Infusion of haplo-identical killer 
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