Autologous hematopoietic cell transplantation: An update for clinicians

Figures & data

Table I. Recommended evaluation in a HCT candidate.

Routine work-up

1. History and physical examination

2. Confirmation of histological diagnosis and remission status (review of biopsies by an experienced hematopathologist and radiological assessments by experienced radiologist)

3. Karnofsky performance score

4. ABO typing

5. Complete blood count

6. Serum tests of liver and kidney function

7. Left ventricular ejection fraction (two-dimensional echocardiography or MUGA scan)

8. EKG

9. Chest X-ray

10. Pulmonary function testing including FEV1, DLCO, arterial blood gas

11. Pregnancy test (female patients)

12. Lumbar puncture (high-risk patients^a and those with history of central nervous system involvement)

13. Dental evaluation

14. Cytomegalovirus serologies

15. Herpes simplex viral serologies

16. Varicella zoster virus serologies

17. HIV testing

18. Hepatitis B and C serologies

^aLymphoma presenting in sinuses, breast, testes; large cell lymphoma in bone marrow. Blastoid MCL patients. HIV+ patients. Patients with signs and symptoms suspicious of CNS disease.

Table II. Ideal physiological criteria for selecting patients for HCT.

Suggested selection criteria
Upper age limit (years)	70–75
Karnofsky performance status	≥ 60–70
Left ventricular ejection fraction (%)	≥ 45
Cardiac rhythm	No uncontrolled tachy- or brady-arrhythmia
Pulmonary function:
FEV1	≥ 50%
DLCO (adjusted)	≥ 50%
Hepatic function:
Serum bilirubin	≤ 2 mg/dL or ≤ 32 μmol/L^a
ALT/AST	≤ 2 × normal
Second active malignancy	Must be absent
Pregnancy test (females)	Negative
Serum creatinine	≤ 1.5 mg/dL or ≤ 132 μmol/L
Active uncontrolled infections	Must be absent

ALT/AST = alanine aminotransferase/aspartate aminotransferase; DLCO = diffusion capacity; FEV1 = force expiratory volume in 1 second.

^aUnless due to Gilbert's syndrome.

Figure 1. Methods of HPC mobilization for autologous transplantation.

Figure 2. Causes of death after autologous HCT (US data) reported to CIBMTR during 2010–2012.

Table III. Complications following autologous transplantation.

Complications^a	Prophylaxis/management
Conditioning regimen-related toxicities
Nausea/vomiting	Antiemetics
Diarrhea	Antidiarrheals and fluids to prevent dehydration
Alopecia
Loss of appetite	Dexamethasone to stimulate appetite
Altered taste sensation	Zinc tablets or lemon candy
Mucositis	Pelifermin, anesthetic mouth wash, supersaturated calcium phosphate oral rinse, opioid analgesic, parenteral nutrition in severe case
Myelosuppression	G-CSF, blood component transfusions
Fevers	Evaluate for infections, antipyretics
Fatigue	Exercise
Infections (bacterial, viral, fungal, etc.)	Antibiotic prophylaxis/treatment as appropriate
Clostridium difficile diarrhea	Hand washing/metronidazole, oral vancomycin
Pulmonary toxicity (carmustine, busulfan, radiation)	Careful patient selection, smoking cessation/steroids for therapy
Cardiac toxicity	Careful patient selection
Renal toxicity	Patient selection, avoiding nephrotoxic agents
Hemorrhagic cystitis (cyclophosphamide)	Mesna for prophylaxis
Dermatitis (etoposide)
Cataracts	Topical corticosteroids or emollients
Parotitis (radiation)	Chewing gums, lemon drops
Infertility	Sperm or oocyte cryopreservation
Hypothyroidism	Avoid TBI
Osteoporosis	Avoid TBI
Stem cell infusion
Flushing	Interrupting and slowing infusion rate
Hypotension
Breath odor due to DMSO
Allergic reactions	Acetaminophen, histamine blockers, corticosteroids
Chest tightness/dyspnea
Miscellaneous
Transfusion-associated graft-versus-host disease	Irradiated blood products; only curative therapy for tMDS/AML is allogeneic HCT
Second malignancies (especially tMDS/AML)	Short-course corticosteroids; high-dose corticosteroids and platelet transfusions
Engraftment syndrome
Diffuse alveolar hemorrhage

^aLong-term complications are indicated as bold text.

Figure 3. Common indications for autologous HCT in the United States, as reported to CIBMTR during 2010–2012. AL amyloidosis=Light chain amyloidosis, ALL=acute lymphoblastic leukemia, AML=acute myeloid leukemia, CLL=chronic lymphocytic leukemia, HL=Hodgkin lymphoma, MM=myeloma, NHL=non-Hodgkin lymphoma.

Table IV. Selected randomized trials of conventional chemotherapy compared to single autologous HCT as upfront therapy in multiple myeloma.

Study (year) (ref.)	Transplant arm^a	No.; age (y)	CR% CC vs. auto HCT	Comments
Attal (1996) (51)	MEL 140 + TBI 8 Gy	200; < 65	5 vs. 22^b	OS and EFS superior for HCT
Child (2003) (52)	MEL 200	401; < 64	8 vs. 44^b	OS and EFS superior for HCT
Blade, PETHEMA (2005) (53)	MEL 200 or MEL 140 + 12 Gy TBI	164; < 65	11 vs. 30^b	Only responders randomized. No OS and EFS benefit of HCT
Palumbo (2004) (139)	MEL 100 × 2 auto-HCT	194; 50–70	6 vs. 25^b	EFS and OS superior for autologous HCT
Barlogie (2006) (56)	MEL 140 + TBI 12 Gy	899; < 70	15 vs. 17	No OS and EFS benefit for HCT vs. conventional chemotherapy; 55% of patients relapsing after conventional chemotherapy received delayed HCT
Fermand (1998) (54)	BCNU + etoposide + cyclophosphamide + MEL and TBI	185; < 56	20 vs. 57	EFS superior for autologous HCT. No OS difference as patients in conventional chemotherapy randomized to HCT at relapse; QOL superior for HCT
Fermand (2005) (55)	MEL 200 or MEL 140 + busulfan	55–65	20 vs. 36	EFS and OS similar to conventional chemotherapy; QOL superior for early autologous HCT

CC = chemotherapy; EFS = event-free survival; MEL = melphalan; OS = overall survival; QOL = quality of life.

^aChemotherapy doses in mg/m². Definitions of response were based on non-uniform criteria.

^bStatistically significant difference (P < 0.05).

Table V. Select studies addressing the role of autologous transplantation in lymphoid malignancies.

Study (year) (ref.)	n	Study design	TRM	EFS/PFS (y)	OS (y)	Comments
Follicular lymphoma in first remission
GLSG (2004) (93)	307	Phase III Auto vs. Chemo	< 2.5% in both arms	Auto = 64%^a Chemo = 33% (5 y)	Not reported	Significantly more sMDS/AML with Auto (3.5%^a vs. 0%; P = 0.02)
GELA (2006) (94)	402	Phase III Auto vs. Chemo	Not reported	Auto = 38% Chemo = 28% (7 y)	Auto = 76% Chemo = 71% (7 y)	Second malignancies similar in both groups
GOELAMS (2009) (95)	166	Phase III Auto vs. Chemo	Not reported	Auto = 64%^a Chemo = 39% (9 y)	Auto = 76% Chemo = 80% (9 y)	Auto associated with significantly more second malignancies
GITMO (2008) (96)	136	Phase III Auto vs. Chemo	Auto = 3 Chemo = 2 at day 100	61%^a vs. 28% (4 y)	81% vs. 80% (4 y)	4-year sMDS/AML was higher with Auto (6.6% vs. 1.7%)
Relapsed follicular lymphoma
CUP (2003) (27)	89	Phase III Chemo vs. Purged Auto vs. Unpurged Auto	Not reported	Chemo = 26% Unpurged = 58%^a Purged = 55%^a (2 y)	Chemo = 46% Unpurged = 71%^a Purged = 77%^a (4 y)	No benefit of purging seen; done in pre-rituximab era
CIBMTR (2004) (99)	728	Retrospective	Purged = 14% Unpurged = 8%	Purged = 39% Unpurged = 31% (5 y)	Purged = 62%^a Unpurged = 55% (5 y)	OS favored purged autografts
Mantle cell lymphoma in first remission
Dreyling (2005) (85)	122	Phase III Auto vs. Chemo	Not reported	Auto = 54%^a Chemo = 25% (3 y)	Auto = 83% Chemo = 77% (3 y)	Performed in pre-rituximab era; no survival benefit
Hermine (2012) (90)	455	R-CHOP vs. R-CHOP/R-DHAP induction	4% vs. 4%	49 months vs. 84 months^a (median)	82 months vs. not reached^a (median)	Addition of cytarabine in induction improved OS
Relapsed diffuse large B-cell lymphoma
Philip (1995) (79)	215	Phase III Auto vs. Chemo	Not reported	Auto = 46%^a Chemo = 12% (5 y)	Auto = 53%^a Chemo = 32% (5 y)	Performed in pre-rituximab era
CORAL (2010) (84)	206	Prospective RICE vs. R-DHAP salvage	Not reported	53% (3 y)	Not reported	Established continued feasibility of auto-HCT for relapsed DLBCL
Relapsed Hodgkin lymphoma
CIBMTR (2001) (138)	414	Retrospective	7% at day 100	46%–64% (3 y)	58%–75% (3 y)	Patients in second CR had better outcomes
CIBMTR (1999) (116)	122	Retrospective	12% at day 100	38% (3 y)	50% (3 y)	Study established that primary refractory patients can be salvaged by auto-HCT
T-cell NHL in first remission
Corradini (2006) (106)	62	Phase II	4.8%	30% (12 y)	34% (12 y)	ALK+ anaplastic T-cell patients and ones in CR had favorable outcomes
Reimer (2009) (109)	83	Phase II	3.6%	36% (3 y)	48% (3 y)	66% of enrolled patients received auto-HCT
NLG-T-01 (2012) (110)	166	Phase II	4%	44% (5 y)	51% (5 y)	ALK-negative anaplastic T-cell had the best outcomes

AML = acute myeloid leukemia; Auto = autologous transplant arm; Chemo = chemotherapy; CHOP = cyclophosphamide, doxorubicin, vincristine, and prednisone; CIBMTR = Center for International Blood and Marrow Transplant Research; DHAP = dexamethasone, cytarabine, cisplatin; EFS/PFS = event-free survival/progression-free survival; GELA = Groupe d’Etude des Lymphomes de l’Adulte; GITMO = Gruppo Italiano Trapianto di Midollo Osseo; GLSG = German Low Grade Lymphoma Study Group; GOELAMS = Groupe Ouest-Est des Leucémies et Autres Maladies du Sang; OS = overall survival; RICE = rituximab, ifosphamide, etoposide, carboplatin; sMDS = secondary myelodysplastic syndrome; TRM = treatment-related mortality.

^aStatistically significant value.

Table VI. Post-autologous HCT vaccination schedule.

Vaccine	Time post transplantation to initiate vaccination	Recommended number of doses
Inactivated influenza	4–6 months	1 (followed by yearly vaccination)
Pneumococcal conjugate (PCV)	3–6 months	3 (after the 3 PCV doses, a dose of 23-valent polysaccharide pneumococcal vaccine to broaden the immune response might be given)
Haemophilus influenzae conjugate	6–12 months	3
Tetanus, diphtheria, acellular pertussis (DTaP)	6–12 months	3
Meningococcal conjugate	6–12 months	1
Inactivated polio	6–12 months	3
Recombinant hepatitis B	6–12 months	3
Measles, mumps, rubella	24 months	1–2

Modified from: Tomblyn M, Chiller T, Einsele H, et al. Guidelines for Preventing Infectious Complications among Hematopoietic Cell Transplantation Recipients: A Global Perspective. Biol Blood Marrow Transplant. 2009;15: 1143–238.

Table VII. Novel investigational agents and strategies in development.

Experimental agents and novel strategies in development
Novel conditioning regimens	Helical tomography
	Novel agents (e.g. bortezomib, carfilzomib) in conditioning regimens
	Propylene glycol-free melphalan
Novel mobilization strategies	FLT3 ligand-augmented mobilization
Myeloma	Novel maintenance and consolidation strategies with daratumumab (CD38 antibody), pomalidomide, MLN9708, carfilzomib, elotuzumab
	MRD-directed therapies
B-cell lymphomas	Novel maintenance (with MEDI-551, ABT-199, GA101) therapies post auto-HCT
	Post auto-HCT lenalidomide
	Post-transplant idiotype vaccines
	Post auto-HCT cellular therapy (e.g. CART)
	Tandem auto-allogeneic HCT for FL
	Ibrutinib maintenance/consolidation in DLBCL or MCL
	Disabling immune tolerance by PD1 blockade
Hodgkin lymphoma	Brentuximab vedotin maintenance
	HDAC inhibitors, lenalidomide, everolimus as maintenance therapies
T-cell lymphomas	Lenalidomide or alisertib maintenance
	Brentuximab vedotin maintenance or conditioning in CD30 +variants

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